",isbn:"978-1-83881-119-8",printIsbn:"978-1-83881-118-1",pdfIsbn:"978-1-83881-120-4",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"8bd4f03c89e63ef15984ee1b7f1485c4",bookSignature:"Prof. Andrew James Manning",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10407.jpg",keywords:"Hydrodynamics, Suspension/Saltation/Bedload, Numerical Modeling / CFD, Deposition, Flocculation, Sediment Types, Regional/Temporal Variability, Turbidity Currents, Dust Storms, Socio-Economic Effects, Contaminants, Storm / Severe Weather Effects",numberOfDownloads:205,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 27th 2020",dateEndSecondStepPublish:"September 11th 2020",dateEndThirdStepPublish:"November 10th 2020",dateEndFourthStepPublish:"January 29th 2021",dateEndFifthStepPublish:"March 30th 2021",remainingDaysToSecondStep:"6 months",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:"Dr. Manning is a highly published and world-renowned scientist in the field of depositional sedimentary flocculation processes.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"23008",title:"Prof.",name:"Andrew James",middleName:null,surname:"Manning",slug:"andrew-james-manning",fullName:"Andrew James Manning",profilePictureURL:"https://mts.intechopen.com/storage/users/23008/images/system/23008.jpeg",biography:"Professor Andrew J. Manning is a Principal Scientist (Rank Grade 9) in the Coasts & Oceans Group at HR Wallingford (UK) and has over 23 years of scientific research experience (in both industry and academia) examining natural turbulent flow dynamics, fine-grained sediment transport processes, and assessing how these interact, (including both field studies and controlled laboratory flume simulations). Andrew also lectures in Coastal & Shelf Physical Oceanography at the University of Plymouth (UK). Internationally, Andrew has been appointed Visiting / Guest / Adjunct Professor at five Universities (Hull, UK; Delaware, USA; Florida, USA; Stanford, USA; TU Delft, Netherlands), and is a highly published and world-renowned scientist in the field of depositional sedimentary flocculation processes. 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1. Introduction
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Interstitial lung disease (ILD) comprises a group of lung diseases principally affecting the pulmonary interstitium, for example, pulmonary fibrosis [1]. An injured lung as a result of infection, inhalation of chemical, and other harmful substances either resolves over time or progresses into irreversible damage and fibrosis. Therefore, lung injury as in acute respiratory distress syndrome (ARDS), due to conditions like hypoxia can progress to interstitial lung damage or fibrosis similar to ILD-associated pulmonary fibrosis. Yet, another important pulmonary pathological condition associated with hypoxia is the pulmonary arterial hypertension (PAH) [2]. The ARDS is a devastating clinical syndrome of acute lung injury (ALI) that affects both medical and surgical patients [3]. The official definition of ARDS was first published in 1994 by American-European Consensus conference (AECC), according to which ARDS is characterized by arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FIO2] ≤200 mm Hg with bilateral infiltrates on frontal chest radiograph, with no evidence of left atrial hypertension. A new entity—ALI was also introduced as a condition of less severe hypoxemia [PaO2/FIO2] ≤300 mm Hg. Arterial hypoxemia that is refractory to treatment with supplemental oxygen is a characteristic feature of acute lung injury. ALI is characterized by alveolar-capillary injury, inflammation with neutrophil accumulation and release of pro-inflammatory cytokines leading to alveolar edema [3]. Patients with ALI develop hypoxia. The term ALI was eventually removed in 2011 in the updated Berlin definition of ARDS. According to Berlin definition, ARDS was classified into three mutually exclusive categories based on the degree of hypoxemia; mild (200 mm Hg < PaO2/FIO2 ≤ 300 mm Hg), moderate (100 mm Hg < PaO2/FIO2 ≤ 200 mm Hg) and severe (PaO2/FIO2 ≤ 100 mm Hg) [4]. Hypoxia may be a consequence of ALI leading to deviation in lung function and preventing repair. Hypoxia induces destructive exudative changes within the lung parenchyma, which include the following: (1) increased alveolar paracellular permeability due to hypoxia disrupted alveolar epithelial cell (AEC) cytoskeleton and tight junction (TJ) protein organization; (2) Prolonged hypoxia induces loss of stress fibers such as actin (including breakdown of spectrin), internalization of TJ protein occludin and a decrease in zona occludens-1 (ZO-1) protein levels that are associated with trans-epithelial permeability; (3) reduced efficacy of AEC to clear alveolar edema fluid as a result of decreased expression of two major proteins, the apical epithelial sodium channel (ENaC) and the basolateral Na/K-ATPase channel which are involved in transcellular sodium (Na) transport. Thus, hypoxia-mediated effects not only enhance alveolar edema but also impair alveolar edema clearance contributing to reduced alveolar gaseous exchange capacity in ALI [5].
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2. Hypoxia in alveolar edema and fluid clearance in the lungs
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The mechanism by which hypoxia promotes pulmonary edema is not completely understood and is still under scrutiny. Alveolar edema accumulation is a result of enhanced pulmonary vascular permeability. Vascular endothelial growth factor (VEGF) is a potent inducer of endothelial dysfunction and thus can play a crucial role in vascular permeability [6]. Since VEGF is induced in hypoxic conditions and recovery from hypoxia, its role in pulmonary vascular remodeling and enhanced alveolar edema is prominent [7]. The source of VEGF in the inflammatory milieu of lung injury includes monocytes, eosinophils and aggregated platelets. Research on hypoxia-induced VEGF expression as a cause for pathological conditions has been carried out for more than two decades now. Studies have shown that both acute and chronic hypoxia induce an upregulation in the gene expression of VEGF, and its receptors (KDR/Flk and Flt) in the animal models of prolonged hypoxia-induced pulmonary hypertension [8]. In fact, the increase in the VEGF gene expression was seen as early as 2 h upon hypoxic challenge in isolated and perfused rat lungs while chronic hypoxia resulted in greater upregulation of the VEGF receptor genes. These studies also scrutinized the mechanism by which hypoxia induces VEGF expression by examining the role of nitric oxide synthase (NOS) and hypoxia inducible factors (HIFs) as the downstream regulators [8, 9]. Studies on transcriptional regulation of VEGF by hypoxia have revealed a functional HIF-1 binding site on the rat VEGF 5′-flanking region as a possible transcriptional activator of VEGF gene by hypoxia [9]. Further studies have shown the involvement of specific regions in 3′-untranslated region (UTR) of VEGF gene in the stability of VEGF mRNA induced by hypoxia [10]. This has led to investigation of proteins that bind to this specific region to control the posttranscriptional regulation of VEGF expression. One such protein is HuR, a member of Elav-like protein family (Elav is a Drosophila RNA-binding protein required for neuronal differentiation). HuR was found to post-transcriptionally regulate VEGF expression by binding within four nucleotides of a canonical nonameric instability element in the VEGF AU-rich element [10]. Thus, hypoxia regulates VEGF at both transcriptional and posttranscriptional levels. Transcriptional regulation is by the hypoxia-induced transcription factor HIF-1 which activates VEGF transcription by binding to specific promoter sequences. A study exploring possible mechanisms involved in securing efficient translation of VEGF during hypoxic stress showed that internal ribosome entry site (IRES) present in the 5′-UTR of VEGF gene functions as an alternative to cap-dependent translation during such stressful conditions [11].
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Becker et al. studied hypoxia-induced VEGF’s role in enhancing pulmonary vascular permeability. They showed that ischemia/hypoxia-induced upregulation of VEGF mRNA and protein was associated with increased pulmonary vascular permeability [12]. Their study was also supported by several other studies which have reported an increase in vascular permeability due to exogenously administered VEGF in skin, muscle, GI tract and airways. In their study, hypoxic ischemia-enhanced VEGF expression, which was associated with increased HIF-1α protein expression and redistribution of VEGF protein to alveolar septae as demonstrated by immunohistochemical staining. This distribution of VEGF protein in the alveolar septae was further associated with increased pulmonary vascular permeability, suggesting its role in acute lung injury and alveolar edema [12]. The enhanced pulmonary vascular permeability effect of VEGF was also confirmed by another study in a sepsis-induced lung injury model, which showed that enhanced plasma VEGF level was accompanied by increased expression of vascular permeability-mediating VEGF receptor, Flt-1 and not the angiogenic-mediating receptor, Flk-1. As a result, enhanced lung edema was observed confirming the role of VEGF in causing alveolar edema [13].
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Na,K-ATPase channels present in the alveolar epithelial cells play a major role in edema clearance from the alveoli [14]. Hypoxia-induced pulmonary edema also disrupts their function and inhibits edema clearance. Studies have shown that hypoxia generated reactive oxygen species (ROS) activates PKCζ (Protein Kinase C Zeta is a key regulator of critical intracellular signaling pathways induced by various extracellular stimuli), which in turn, phosphorylates the α1-subunit of Na,K-ATPase at Ser-18 site leading to its endocytosis through a clathrin-dependent mechanism and eventually to lysosomal degradation. With the loss of Na,K-ATPase, edema reabsorption is impaired and thus hypoxia not only promotes pulmonary edema but also inhibits its clearance as observed in conditions like ALI [14].
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3. Hypoxia in pulmonary aquaporin’s expression and edema
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Aquaporins (AQPs) comprise a group of cell membrane water-transporting proteins that are involved in physiological as well as pathological fluid transport. They have been identified in the lung and are believed to play a major role in pulmonary edema [15]. AQPs can bidirectionally transport fluid across the alveolar epithelium and hence are involved in both edema formation and clearance of edema from alveoli (thus injury resolution). About 6 (AQP-1, -3, -4, -5, -8 and -9) of the 13 different AQPs are distributed in lung tissue, and it is very interesting to study how hypoxia regulates the expression of these AQPs and thus pulmonary edema formation or clearance of edema. AQPs expression could play a major role in the pathological condition of hypoxia-induced enhanced pulmonary edema and ALI [15]. Several studies have scrutinized the role of aquaporins in pulmonary edema, and the results are controversial, yet intriguing. For example, Wu et al. studied the role of AQP-1 [expressed on pulmonary endothelial cells (ECs) and alveolar type II cells] and AQP-4 (expressed throughout the airways epithelial cells) in relation to high-altitude hypoxia lung injury. They found that hypoxia-induced pulmonary edema was associated with a decreased expression of AQP-1 and no change in the expression of AQP-4 [16]. They went on to reason that hypoxia resulted in pulmonary edema as a consequence of decreased function of AQP-1, which plays a regulatory role in water clearance around the bronchi and vessels. However, the relation of AQP-1 expression and pulmonary edema, as a result of hypoxia was only correlative and the study did not use knockout models to confirm the relationship between these effects of hypoxia. On the contrary, Su et al. showed that depletion of AQP-1 does not affect isosmolar fluid clearance and had no effect on lung edema. Nevertheless, depletion of AQP-1 resulted in a 10-fold decrease in the alveolar-capillary osmotic water permeability. They concluded that depletion of AQP-1 did not have any effect on lung edema formation and resolution [17]. Several other reports have also ruled out the role of AQP-1, -4 and -5 in physiological clearance of water in the lung or the accumulation of edema in the injured lung. Another report using gene knockout mouse model of AQP5 in hypoxic conditions showed a significant increase in pulmonary edema with the loss of AQP-5 [18]. As aforementioned, a few other reports also demonstrated that upregulation and downregulation of AQPs expression is related to pulmonary edema in different kinds of lung injuries. AQP-1 has also been shown to facilitate stabilization of HIF and has been speculated that besides its role as water transporter, it could also be involved in oxygen transport [19]. Therefore, the effect of hypoxia on AQPs expression especially in the lung and its effect on pulmonary edema warrants further studies before arriving at a conclusion [16–20].
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4. Hypoxia in pulmonary arterial hypertension (PAH)
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Prolonged lung injury can lead to lung fibrosis as well as PAH. Hypoxia is a well-studied trigger for pulmonary vascular remodeling and PAH development [2]. In fact, hypoxia-induced PAH is an established animal model for studying the pathophysiology and therapeutic management of PAH. PAH is a refractory disease characterized by uncontrolled vascular remodeling involving enhanced proliferation and differentiation of pulmonary vascular ECs and pulmonary vascular smooth muscle cells [2]. This vascular remodeling ensues enhanced pulmonary arterial pressure (≥25 mm Hg on right heart catheterization) due to increased pulmonary vasoconstriction and increased pulmonary vascular resistance and eventually right ventricular failure [2]. Chronic hypoxia is a well-known trigger for the abovementioned events. The mechanism by which hypoxia induces PAH has been extensively studied and involves several molecular signaling pathways. Leptin, a non-glycosylated protein, synthesized and secreted by adipocytes is encoded by obese (ob) gene, which is hypoxia sensitive. HIF-1 induces the expression of ob gene in adipocytes, and clinical studies have suggested an association between plasma leptin levels and severity of PAH [21]. Results of studies scrutinizing the role of leptin signaling in hypoxia-induced PAH show that hypoxia-induced leptin expression results in pulmonary arterial smooth muscle cells (PASMCs) proliferation through ERK, STAT and AKT pathways [21]. These results were further confirmed in ob/ob mice. Obese gene knockout mice subjected to hypoxia showed an attenuated hypoxia-induced PAH that was gauged in terms of reduced right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) when compared to wild-type (WT) mice. Thus, leptin signaling could be a potential therapeutic target to treat hypoxia-induced PAH [21]. In hypoxia-induced pulmonary hypertension, iron supplementation has been found to be beneficial [22]. A study involving human subjects in an acute model of mountain sickness has shown that iron supplementation was associated with a decrease in pulmonary arterial systolic pressure (PASP) while progressive development of iron deficiency correlated with worsening of pulmonary arterial pressure determined by echocardiography, thus suggesting a causal relationship between iron deficiency and acute hypoxic PAH [23]. Recent studies speculate that iron deficiency may worsen hypoxic pulmonary hypertension through HIFs signaling [24].
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HIFs are transcription factors comprising of an O2-sensitive α-subunit, mainly HIF-1α and HIF-2α and a constitutively expressed β-subunit which are responsible for mediating adaptive responses to hypoxia and ischemia [25]. HIF-α and HIF-β form heterodimer and induce the transcription of over 100 genes that affect cellular functions ranging from metabolism, survival, proliferation, migration and angiogenesis among several others [25]. While HIF-1α is more ubiquitously expressed, HIF-2α expression is predominant in the lung tissue [25]. Several studies have shown the mechanistic role of HIF-2α in hypoxia-induced PAH. In hypoxia-induced PAH studies, even partial deficiency of either HIF1α (HIF1α+/−) or HIF2α (HIF2α+/−), achieved using murine models, significantly decreased pulmonary arterial pressure and right ventricular hypertrophy induced by chronic hypoxia in comparison with wild-type mice that did not have any alteration in HIF1α or HIF2α expression [26]. The role of HIFs in hypoxia-induced PAH was further scrutinized and deficiency in HIFs-related beneficial effects in PAH was at least partly due to the reduced pulmonary vascular remodeling observed in these animals. Further in vitro analysis on PASMCs showed that HIF-1-dependent smooth muscle hypertrophy contributed to pulmonary vascular remodeling during hypoxia [26]. HIF1α is involved in hypoxia-induced PASMC depolarization, reduction in K+ channel expression and activity and elevated intracellular calcium concentration and pH. This eventually results in altered PASMC ion homeostasis contributing to a more contractile, apoptosis resistant, proliferative and migratory phenotype [26]. Furthermore, in human PAH patients and mouse models of PAH, dysregulation of HIF pathway was reported and it has been associated with HIF-2α mutations, which was confirmed by studies where loss of one copy of HIF-2α gene was sufficient to attenuate hypoxia-induced PAH in these animal models [27]. On the other hand, HIF-2α gain of functions is associated with PAH. Studies scrutinizing the mechanism by which HIF-2α regulates hypoxic PAH have found several ways by which it mediates the hypoxic effects. In human PASMC, hypoxia increases expression of transcription factor forkhead box M1 (FoxM1), through HIF-2α, to promote PASMC proliferation [27]. Secreted matricellular protein thrombospondin-1 (TSP-1) is believed to play an important role in vascular health and disease via inhibition of vasodilation in part by limiting NO production and signaling [28]. Vascular remodeling in PAH involves the proliferation of both pulmonary artery smooth muscle cells (PASMCs) and fibroblasts apart from endothelial dysfunction. In a recent study published from our laboratory, we showed that hypoxia-induced pulmonary rarefaction and fibrosis in mice lung, and mechanistically, we found that hypoxia-induced Akt1 expression in fibroblasts was associated with enhanced TSP-1 expression resulting in fibroproliferation and fibrosis [29]. Another study has shown that hypoxia, in a HIF-2α-dependent manner, increases the expression of TSP-1 in pulmonary tissue and pulmonary artery cells which in turn contributes to enhanced endothelial permeability (mediated in part by changes in cell-cell adhesion) and accompanied by increased fibroblast and PASMC proliferation which is at least partially due to restricted adhesion of these cells in their mouse model of hypoxia-induced PAH. Also it was speculated that TSP-1 could promote hypoxic pulmonary artery contraction through enhanced TSP-1–induced endothelin-1 expression [28].
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Prolyl hydroxylase domain-containing enzymes (PHDs) use molecular O2 as a substrate to hydroxylate-specific proline residues of HIF-α which subsequently promotes HIF-α binding to von Hippel-Lindau (VHL protein) and ubiquitin E3 ligase, resulting in ubiquitination and proteasomal degradation [27]. In patients with idiopathic pulmonary fibrosis (IPF), PHD2 expression is diminished in ECs of obliterative pulmonary vessels [27]. A study using mouse model of endothelial and hematopoietic cells-specific knockdown of gene encoding PHD2 has shown that these mice spontaneously develop PAH with obliterative vascular remodeling as seen in human PAH [27]. They found that PHD2 deficiency in ECs promoted HIF-2α-mediated (and not HIF-1α) expression of CXCL12 (also known as stromal cell-derived factor 1α) that had a paracrine effect on PASMC proliferation contributing to the pathogenesis of severe PAH in this mouse model. PHD2 deficiency in ECs also promoted endothelin-1 expression that resulted in pulmonary artery-vasoconstriction. Thus, HIF-2α-mediated vascular remodeling and plexiform-like lesions formation (due to PASMC proliferation) resulted in PAH in this mouse model [27, 28]. As discussed above, prevention of PASMC apoptosis along with enhanced proliferation is an important pathological event in hypoxic PAH. Another study showed the mechanism by which hypoxia mediates this effect. In PASMCs, hypoxia induces opening of mitochondrial ATP-sensitive potassium channels (mitoKATP), which results in calcium-dependent increase in mitochondrial permeability or mitochondrial membrane transition (MPT). MPT eventually leads to loss of mitochondrial membrane potential (denoted by ΔΨm), thus preventing the cytochrome C release from mitochondria and inhibition of cytochrome C–caspase 9 pathway induced PASMC apoptosis [30]. The involvement of mitoKATP channels in hypoxia-induced PASMC apoptosis resistance was further confirmed by administering 5-hydroxydecanoate (5-HD), a compound that prevents opening of mitoKATP channels abolishes these effects of hypoxia to a certain extent and prevents mitoKATP channels opening and PASMC apoptosis. Hypoxia-induced opening of mitoKATP was not only associated with prevention of PASMC apoptosis but also increased the production of H2O2 in mitochondria. The effect of this ROS production was an increased transcriptional activity of AP-1, which is responsible for the proliferation of PASMCs. Thus, hypoxia through mitoKATP opening prevented apoptosis and enhanced proliferation of PASMCs. As discussed, apart from proliferation of PASMCs, hypoxia-induced prevention of PASMC apoptosis also plays a major role in PAH. Another mechanism involves inhibition of the mitochondrial pro-apoptotic Bax protein expression and induction of the anti-apoptotic Bcl-2 expression, thus preventing the release of mitochondrial cytochrome C into cytoplasm and eventually inhibiting cleavage of caspase 9 resulting in PASMC apoptosis [31]. Therefore, hypoxia-HIF signaling is a potential therapeutic target to treat PAH, and several in vivo studies have demonstrated this [30–32].
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5. Hypoxia and alveolar epithelial-to-mesenchymal transition (EMT)
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Several groups have studied the role of hypoxia in disease progression and pathogenesis of ILDs such as pulmonary fibrosis [33, 34]. Activated myofibroblasts play an important role in the production of collagen and ECM proteins during pulmonary fibrosis. The source of these myofibroblasts are numerous, which include resident stromal fibroblasts, bone marrow-derived fibroblasts, and mesenchymal transition of epithelial and ECs [33]. Epithelial-to-mesenchymal transition (EMT) is a cellular process during which epithelial cells lose many of their epithelial characteristics such as cell-cell interaction and apicobasal polarity and acquire properties typical to mesenchymal cells. EMT is driven by a cytokine, transforming growth factor-β1 (TGF-β1) and is characterized by changes in cell morphology and acquisition of mesenchymal markers including α-smooth muscle actin (α-SMA) and vimentin as well as loss of epithelial markers such as E-cadherin [33, 34]. Active TGF-β1 binds to its receptors (transmembrane serine-threonine kinase receptor I and II), which leads to a downstream activation of the transcription factor Smad, whose target genes include α-SMA and vimentin [33]. Increasing evidence over the years has highlighted the critical role of EMT in pathological conditions such as fibrosis apart from its well-known involvement in tissue development during embryogenesis. Exposure to hypoxia during ALI could promote phenotypic changes in AEC consistent with EMT. In vitro studies on rat AEC cultured on semipermeable filters showed that prolonged hypoxic exposure (1.5% O2 for up to 12 days) induced profound changes in AEC phenotype consistent with EMT including change in cell morphology, decrease in transepithelial resistance and in the expression of epithelial markers such as zona occludens (ZO-1), E-cadherin, AQP-5, TTF-1, together with an increase in mesenchymal markers such as vimentin and α-SMA. Supporting this phenotypical switch, expression of transcription factors driving EMT such as SNAIL1, ZEB1 and TWIST1 increased after 2, 24 and 48 h of hypoxia, respectively. Hypoxia also induced expression and secretion of two EMT inducers TGF-β1 and connective tissue growth factor (CTGF) [35].
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Similarly, Zhou et al. investigated the effect of hypoxia on the induction of EMT in AEC. Results from this study suggest that hypoxia induces EMT in transformed human, rat and mouse AEC lines, and freshly isolated rat type II AECs [36]. They also scrutinized the mechanism by which hypoxia induces EMT in AEC and showed the involvement of hypoxia-induced mitochondrial ROS production and HIF-1α stabilization in TGF-β1 production, resulting in EMT [37]. Treatment of cells with ROS scavenger Euk-134 or using mitochondria-deficient cells prevented hypoxia-induced EMT illustrating their importance in this cellular process. Moreover, although ROS is known to stabilize HIF-1α, their results showed that normoxic stabilization of HIF-1α failed to induce α-SMA expression, suggesting that HIF alone is not sufficient to induce EMT in AEC. Their data suggest that ROS and HIF-1α stabilization are upstream of TGF-β1 production in hypoxia-induced EMT in AEC. However, TGF-β1 can also increase ROS production and HIF-1α stabilization. TGF-β1 can either directly activate NADPH (Nicotinamide adenine dinucleotide phosphate) oxidase or upregulate gene expression of Nox4 NADPH oxidase to generate ROS [38, 39]. TGF-β1 decreases mitochondrial complex IV activity resulting in disruption of mitochondrial membrane potential and ROS production [40]. TGF-β1 was reported to stabilize HIF-1α through selective inhibition of PHD2 (a HIF-1α prolyl hydroxylase) expression thus reducing HIF-1α prolyl hydroxylation leading to its stabilization [41]. Therefore, TGF-β1 and ROS/HIF may form a feedback loop to maintain a prolonged signaling cascade initiated by either ROS/HIF or TGF-β1 leading to hypoxia-induced EMT in AECs [36].
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In one interesting study, investigators evaluated the possible role of tissue hypoxia in the development of fibrotic lesions in lung fibrosis [42]. In this study, they used animal models of ALI/ARDS, in which severe inflammation progresses into the early (exudative) phase of ALI and sequentially fibrosis develops as the late (fibrotic) phase of ALI. They found intriguing effects of acute versus persistent hypoxia as seen in exudative and fibrotic phases of ALI, respectively. Acute hypoxia induced de novo Surfactant Protein-D (SP-D) expression in AECs followed by stabilization of HIF-1α expression [42]. Contrastingly, persistent hypoxia-induced HIF-1α stabilization repressed SP-D expression and enhanced the mRNA levels of an EMT-driving transcription factor TWIST, but not SNAIL. This was accompanied by phenotypic switch in the AECs exposed to persistent hypoxia (72-h hypoxia for in vitro studies) as seen by decreased E-cadherin expression and enhanced vimentin expression. SP-D is mainly derived from alveolar epithelial cells and therefore loss of its expression during persistent hypoxia along with enhanced EMT transcription factor expression clearly indicates phenotypic switch of these alveolar epithelial cells to more proliferative phenotype contributing to lung fibrosis [42].
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Endothelial-to-mesenchymal transition (EndMT) is similar to EMT, which is characterized by a loss of endothelial cell-cell junctions, the acquisition of migratory properties, and phenotypic switch involving loss of endothelial-specific markers such as CD31 and vascular endothelial (VE)-cadherin expression, and the acquisition of mesenchymal markers α-SMA, and vimentin [43]. EndMT also contributes to fibrosis. The role of EndMT in pulmonary fibrosis involves phenotypic switch in the pulmonary EC lining the pulmonary capillaries. Radiation-induced pulmonary fibrosis (RIPF) may involve hypoxia-mediated EndMT as an initial pathological insult leading to fibrosis [13]. Fleckenstein and colleagues have shown that radiation during thoracic radiotherapy for lung cancer induces tissue hypoxia, in part, due to enhanced oxygen consumption by Macrophages. These macrophages are activated because of radiation-induced reduction in blood perfusion in the lungs contributing to lung injury [44]. This suggests that hypoxia plays a major role in the radiation-induced lung injury. Fleckenstein et al. also reported that hypoxia is important in triggering continuous production of fibrogenic cytokines and perpetuation of late lung tissue injury [44]. However, the precise mechanism by which hypoxia affects radiation-induced fibrosis remains elusive. EndMT of the pulmonary ECs was shown as a possible consequence of radiation-induced hypoxia resulting in lung fibrosis and injury by Choi et al. [43]. They investigated the reason behind fibrotic effects of radiation in a mouse model of RIPF and in in vitro studies on human pulmonary ECs. Since fibrosis is a long-term event, their investigation aimed at elucidating the mechanisms behind the early damage to ECs by radiation and its link to the later observed fibrosis. Their results indicate ECs specifically expressing hypoxic marker, CA9, just prior to the substantial fibrogenesis. They went on to show that radiation-induced vascular hypoxia-triggered EndMT in vascular ECs, and in fact, this was observed prior to the onset of alveolar EMT and thus could be a trigger to EMT as well. Thus, EndMT contributed to chronic tissue fibrosis and targeting EndMT was speculated to be a potential therapeutic target to treat RIPF [43, 44].
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In conclusion, current evidences suggest that the pathogenesis of human pulmonary fibrosis might involve the recruitment of fibroblasts derived from AECs through hypoxia-induced EMT as well as fibroblasts derived from pulmonary ECs through hypoxia-induced EndMT, apart from the bone marrow-derived precursors forming the fibrotic lesions. Thus, hypoxia could contribute to the formation of fibrotic lesions in the lung and hence the pathogenesis of pulmonary fibrosis (see Figure 1).
Figure 1.
Summary of the effect of hypoxia on pulmonary tissue and vasculature. Hypoxia induces pulmonary edema by enhancing vascular permeability and decreasing the ability of alveolar fluid clearance. Hypoxia induces pulmonary vascular EndMT and alveolar EMT that result in myofibroblast proliferation ensuing pulmonary fibrosis. Hypoxia-induced PAH is a result of enhanced proliferation and survival of PASMCs. ALI and PAH can eventually progress to pulmonary fibrosis.
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6. Hypoxia in lung injury resolution (fate of hypoxia as a consequence of pathological conditions)
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While in the early stages of ALI, hypoxia plays a major role in the progression of lung injury, intriguingly in chronic pulmonary pathological conditions that ensue hypoxic milieu, and hypoxia has also been found to be involved in enhancing injury resolution. Studies indicate a protective and anti-inflammatory role of HIFs such as HIF-1α in lung protection during the early exudative phase of ALI [45–47]. As mentioned above, hypoxia inactivates PHDs and stabilizes HIF-1α [45–47]. During the acute stage of ALI, inflammation, including enhanced neutrophil activity within the alveoli, leads to an increased alveolar edema and decreased alveolar gaseous exchange capacity. HIF stabilization has been shown to have anti-inflammatory role in conditions like intestinal inflammation. The protective role of HIF activators in the treatment of inflammatory bowel disease or ischemia and reperfusion injury of several organs has been shown in several studies [48–50]. Interestingly, Eckle et al. showed the beneficial role of normoxic HIF1A stabilization in lung protection during ALI, where HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation [51]. In vivo HIF-1α increased glycolysis, lactate production and glucose flux rates in alveolar epithelium. Overall, this normoxic stabilization of HIF-1α in alveolar epithelium increased glycolytic capacity and TCA flux thus optimizing mitochondrial respiration to enhance ATP production. This HIF-dependent protection of mitochondrial function in ALI not only enhanced ATP production but also concomitantly prevented ROS accumulation and lung inflammation [51]. Hence, the role of hypoxia and subsequent HIF stabilization in reducing inflammation is prominent in resolution of ALI.
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6.1. Hypoxia and adenosine signaling in lung injury resolution
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Emigration of polymorphonucleated neutrophils (PMNs) through the endothelial barrier in an injured lung creates a potential for vascular fluid leakage leading to edema and decreased oxygenation [52]. The vascular endothelial adaptations to hypoxia include enhanced extracellular adenosine production during limited oxygen availability. In the vascular ECs, hypoxia induces enhanced expression of surface ectonucleotidases, CD39 that converts ATP/ADP to AMP (ectoapyrase), as well as CD73 that is involved in phosphohydrolysis of AMP to adenosine thus forming the source for extracellular adenosine production [52]. This enhanced extracellular adenosine can then signal through four different G-protein-coupled adenosine receptors, all of which are present on vascular endothelia thus enhancing adenosine signaling that is implicated in tissue protection in different models of injury including ALI. Several studies, notably couple of them from Eltzschig, H.K., et al. [52, 53], have shown the role of extracellular adenosine and its signaling in attenuating hypoxia-induced vascular leakage. They also showed that the source of ATP in hypoxic milieu is the PMNs. Hypoxia induces the production of ATP by PMNs, however, the exact mechanism by which ATP is produced still needs to be explored. This ATP is then phosphohydrolyzed as mentioned above to produce extracellular adenosine [53]. Enhanced adenosine concentrations activate adenosine receptor, (AdoRA2A/A2B on ECs, which when activated increases intracellular cyclic AMP (cAMP) and activates protein kinase A (PKA) to induce resealing of the endothelial-barrier [54]. The resealing of endothelial-barrier during PMN transmigration was obviated by inhibition of cAMP formation. This resealing effect is mediated by PKA-induced phosphorylation of vasodilator-stimulated phosphoprotein, a protein responsible for changes in the geometry of actin filaments and distribution of junctional proteins as a result affecting the characteristics of junctional proteins and increasing barrier function [54]. Intriguingly, adenosine not only activates the endothelial A2B receptor, but also neutrophil A2 adenosine receptor which has been shown to play an important role in limitation and termination of PMN mediated systemic inflammatory responses. Few others have also demonstrated that PMN A2 adenosine receptor stimulation decreased leukocyte adherence and transmigration which might contribute to attenuated vascular leak associated with leukocyte accumulation [53–55]. Thus, hypoxia-induced adenosine signaling in vascular ECs and PMNs contributes to decreased vascular leak and inflammation, both of which are beneficial in inflammatory conditions such as ALI (see Figure 2).
Figure 2.
Hypoxia and adenosine signaling in the lungs. Hypoxia-induced extracellular adenosine production acts through adenosine receptors on ECs to enhance intracellular cAMP and PKA production. PKA catalyzes the phosphorylation of VASP, which integrates into stress fibers and helps seal the endothelial barrier by enhancing expression of AJs, TJs and also focal adhesion. PKA also enhances HIF-1A expression, which translocates into nucleus and enhances adenosine receptor transcription. Extracellular adenosine also acts on A2-receptors on PMNs and prevents their adhesion, rolling and infiltration into lung tissue. Thus, hypoxia-induced extracellular adenosine seals endothelial junctions, prevents PMN infiltration and protects lung tissue by preventing alveolar edema accumulation. PKA, protein kinase-A; PMN-polymorphonuclear neutrophils; ATP, adenosine triphosphate; AMP, adenosine monophosphate; A2bR, adenosine 2b receptor; cAMP, cyclic AMP; VASP, vasodilator-stimulated phosphoprotein; AJ, adherent junction; TJ, tight junction and ECM, extracellular matrix.
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When adenosine signaling was inhibited in transgenic mice with targeted disruption of CD73 that were subjected to hypoxia, fulminant vascular leakage, associated with severe edema and inflammation was seen [56]. Recently, studies have shown three other mechanisms by which hypoxia enhances extracellular adenosine levels, including hypoxia-mediated repression of the equilibrative nucleoside transporters (ENT-1 and ENT-2) that are responsible for adenosine transport across the membrane into the cytoplasm; HIF-1α mediated inhibition of intracellular adenosine kinase that converts intracellular adenosine to AMP and transcriptional induction of AdoRA2B receptor [57]. These studies indicate the protective role of adenosine signaling during hypoxia, especially in the pulmonary tissue [37]. On the other hand, chronically increased adenosine levels are detrimental as seen in pathological conditions, such as asthma and chronic obstructive pulmonary disease (COPD), and they also correlate with degree of inflammation in COPD. In order to regulate excessive adenosine signaling, chronic exposure to hypoxia eventually induces endothelial CD26 and extracellular adenosine deaminase (ADA). CD26 on EC surface acts as the ADA-complexing protein and localizes ADA accumulation on EC surface limiting extracellular adenosine accumulation during prolonged hypoxia [55].
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6.2. Hypoxia and lung inflammation
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Uncontrolled inflammation is one of the major players in ALI and suppression of inflammation is beneficial for injury resolution [58, 59]. Interestingly, as mentioned above, hypoxia-induced, HIF-1–mediated enhanced expression of Adenosine A2 receptor on different types of immune cells, along with enhanced extracellular adenosine levels, which activate these receptors, are responsible for anti-inflammatory and tissue-protecting effects of hypoxia [58, 59]. This anti-inflammatory effect is attributed to elevated intracellular cAMP levels through activation of adenylyl cyclase. Even pharmacological immunosuppressive molecules, such as catecholamines, neuropeptides, histamine and prostaglandins are known to have their effects through elevation of cAMP levels [59]. Therefore, this extracellular adenosine serves to report excessive collateral immune damage and prevents further damage by suppressing-activated immune cells. Adenosine triggers high-affinity A2A adenosine receptors on activated immune cells resulting in enhanced intracellular cAMP levels to suppress these immune cells. Few studies also show that hypoxia inhibits adenosine kinase, an enzyme responsible for re-phosphorylation of adenosine to AMP, to maximize the anti-inflammatory effect [60].
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6.3. Adenosine receptors in inflammation
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Adenosine receptors are a family of heptahelical transmembrane G-protein-coupled purinergic receptors that are classified into four types based on the potency of agonists with respect to the intracellular production of cAMP [37]. They are A1, A2A, A2B and A3 receptors. Extracellular agonists signal through these G protein receptors and can either stimulate (Gs) or inhibit (Gi) adenylyl cyclase, an enzyme that catalyzes the formation of cAMP. Cloning experiments show that high-affinity A2A and low-affinity A2B receptors activate adenylyl cyclase (Gs) enhancing the levels of intracellular cAMP, whereas high-affinity A1 and low-affinity A3 receptors inhibit (Gi) adenylyl cyclase [37].
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6.4. Hypoxia induced adenosine signaling in individual immune cells
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Polymorphonuclear Leukocytes (PML): Pathological stimulation of inflammation can result in deleterious nonspecific PML bactericidal effector functions directed towards hosts’ healthy tissue resulting in extensive collateral damage [54]. PMN toxic effects on microvascular endothelium are more prominent as they attach to ECs, easily because they use the same receptors (CR3, CD11b/CD18) that ensure PML attachment to pathogenic microorganisms [54]. Hypoxia-induced extracellular adenosine acts through adenosine receptor (high affinity A1 and A2 receptors) to mediate its anti-inflammatory effect. However, since both A1 and A2 are high affinity receptors, the overall effects of adenosine on PML might depend on the interplay between them and their expression on PML [61]. Studies show that the anti-inflammatory effects of A2A receptor are to a certain extent prevented by A1 receptor, on the other hand, deleterious effects such as chemotaxis, adhesion and oxygen radical production stimulated by A1 were inhibited by A2A [61, 62]. Overall, hypoxia-induced extracellular adenosine may protect the microvascular endothelium from PML by inhibiting the expression of β2-integrins and adhesion, ROS production, TNF-α production and degranulation, all of which without compromising the bactericidal function of PML such as production of bactericidal toxins and complement receptor type-3–mediated phagocytosis of bacteria [54, 63].
Mononuclear phagocytes and dendritic cells: In macrophages, activation of A1 receptor is stimulatory, while A2 receptor activation is inhibitory [54]. A2A receptor activation in lipopolysaccharide (LPS)-stimulated macrophages was associated with the inhibition of IL-12 production but enhanced IL-10 secretion. In LPS-stimulated dendritic cells, adenosine enhanced A2A receptor expression and intracellular cyclic AMP production along with inhibition of IL-12 production. In dendritic cells, except adenosine, other cAMP-elevating agents increase IL-10 and lower expression of MHC type II [64]. However, adenosine-mediated A2A activation decreases the capacity of maturing dendritic cells to induce T-helper (Th1) polarization of native CD4+ T-lymphocytes (possible anti-inflammatory effect). Upon LPS-induced differentiation of dendritic cells, A2A activation favors production of CCL17 over CXCL10 chemokines [65]. Overall, these studies suggest that extracellular adenosine stimulation of adenosine receptors on antigen-presenting cells (macrophages and dendritic cells) might play an important role in the downregulation and polarization of immune response, modulation of MHC class I and II expression, and/or decrease in IL-12 and increase in IL-10 or IL-4 production to favor the initiation of a Th2 response over a Th1 response. This effect of adenosine on innate and adoptive immune system plays a crucial role in the modulation of inflammatory response [54, 64–66].
Thymocytes: The microenvironment of thymocytes is hypoxic even under normal physiological condition when compared to other lymphoid and non-lymphoid tissues [54]. Thus, the thymic environment favors increased adenosine levels and its signaling. Patients with severe combined immunodeficiency were found to be ADA deficient (enzyme responsible for decreased adenosine levels), where ADA deficient patients had developmental defects in T- and B-cells [67, 68]. This enhanced extracellular adenosine signals through A2A receptor and induces apoptosis in a subset of immature thymocytes through its cAMP elevating effects. In peripheral T-cells, activation of extracellular adenosine-mediated A2A receptor inhibits TCR-triggered IL-2 receptor upregulation, thereby inhibiting T-cell proliferation [69]. Other effects of adenosine signaling in CD8+ cytotoxic T-lymphocytes include inhibition of inflammatory cytokine production, lethal hit delivery by granule exocyotosis, as well as FasL mRNA upregulation. It is interesting to note that in human blood peripheral leukocytes, more CD4+ than CD8+ T-cells express A2A receptor, but on activation of T-cells increased A2A receptor expression is predominantly observed in CD8+ T-cells. These studies suggest the variable expression of A2A receptors on T-cell subset and how they favor the production of anti-inflammatory cytokines over inflammatory cytokines. Compared to T-lymphocytes, not much is known about the effects of A2A receptor signaling in B-cell development, activation, antibody-production and class switching, and cytokine secretion [70].
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However, it is very important to note that all the above mentioned effects of extracellular adenosine on immune cells were mostly observed in pharmacological experiments and is yet to be explored whether there are sufficient levels of extracellular adenosine in vivo to signal through A2A receptor on immune cells. So far, there is no evidence of physiological downregulation of immune cells by extracellular adenosine in vivo. However, hypoxia-induced extracellular adenosine may have anti-inflammatory effects even in in vivo similar to in vitro studies [67, 71, 72].
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7. Conclusions and future directions
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Hypoxia, either as a consequence of the pathological condition during ILDs or as an etiology for ILDs has several roles in modulating the severity of the disease condition. Most of the effects of hypoxia are regulated through HIFs. Interestingly, stabilization of HIFs at various stages of lung injury can have different consequences either favoring injury resolution or worsening the condition. This complicates to provide a potential therapeutic target against HIFs to treat ILDs. Targeting hypoxia signaling was speculated to have therapeutic importance in inflammatory and ischemic conditions, such as inflammatory bowel disease, myocardial ischemic-reperfusion injury, ALI and so on. However, most of the clinical trials for drug discovery examined HIF inhibitors in the context of cancer treatment. Some of the examples include pharmacological HIF inhibitors such as dutasteride152 (ClinicalTrials.gov identifier: NCT00880672), topotecan153 (ClinicalTrials.gov identifier: NCT00117013), PX-478 (ClinicalTrials.gov identifier: NCT00522652) or digoxin13 (ClinicalTrials.gov identifier: NCT01763931) or the antisense oligonucleotide HIF inhibitor EZN-2968 (ClinicalTrials.gov identifier: NCT01120288). Apart from HIF inhibitors, HIF-stabilizing agents such as PHD inhibitors are also being studied as potential therapeutic targets in conditions where HIF stabilization is beneficial, such as, conditions which require enhanced angiogenesis (HIF activates VEGF and enhances angiogenesis) like bronchopulmonary dysplasia, a chronic disease effecting preterm neonates in which enhanced angiogenesis improves lung growth and function. Favoring the plethora of evidence from preclinical studies, in future, we can expect more clinical trials targeting PHD-HIF pathway as a potential therapy for ILDs and several other ischemic conditions.
\n',keywords:"acute lung injury, wound resolution, hypoxia, interstitial lung disease, PAH",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/53376.pdf",chapterXML:"https://mts.intechopen.com/source/xml/53376.xml",downloadPdfUrl:"/chapter/pdf-download/53376",previewPdfUrl:"/chapter/pdf-preview/53376",totalDownloads:1059,totalViews:533,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"April 19th 2016",dateReviewed:"November 9th 2016",datePrePublished:null,datePublished:"February 1st 2017",dateFinished:null,readingETA:"0",abstract:"Interstitial lung disease (ILD) comprises a group of lung diseases principally affecting the pulmonary interstitium, for example, pulmonary fibrosis. Following acute lung injury (ALI), the fate of an injured lung progressing towards either injury resolution or pulmonary fibrosis is dictated by hypoxia at various stages during the disease progression. Hypoxia that is tissue destructive at one stage of lung injury becomes beneficial at a different stage, with each hypoxic stage involving a different scheme of molecular pathways, cellular interplay and tissue remodeling. In this chapter, we provide a detailed account of hypoxia during the different stages of lung injury in ILDs, delineate the cellular and molecular mechanisms mediating tissue remodeling in the hypoxic lungs as well as the basic and clinical findings in this field with an emphasis on future therapeutics to modulate hypoxia to treat ILD.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/53376",risUrl:"/chapter/ris/53376",book:{slug:"hypoxia-and-human-diseases"},signatures:"Sandeep Artham and Payaningal R. Somanath",authors:[{id:"189411",title:"Dr.",name:"Payaningal R.",middleName:null,surname:"Somanath",fullName:"Payaningal R. Somanath",slug:"payaningal-r.-somanath",email:"sshenoy@augusta.edu",position:null,institution:{name:"University of Georgia",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Hypoxia in alveolar edema and fluid clearance in the lungs",level:"1"},{id:"sec_3",title:"3. Hypoxia in pulmonary aquaporin’s expression and edema",level:"1"},{id:"sec_4",title:"4. Hypoxia in pulmonary arterial hypertension (PAH)",level:"1"},{id:"sec_5",title:"5. Hypoxia and alveolar epithelial-to-mesenchymal transition (EMT)",level:"1"},{id:"sec_6",title:"6. Hypoxia in lung injury resolution (fate of hypoxia as a consequence of pathological conditions)",level:"1"},{id:"sec_6_2",title:"6.1. Hypoxia and adenosine signaling in lung injury resolution",level:"2"},{id:"sec_7_2",title:"6.2. Hypoxia and lung inflammation",level:"2"},{id:"sec_8_2",title:"6.3. Adenosine receptors in inflammation",level:"2"},{id:"sec_9_2",title:"6.4. Hypoxia induced adenosine signaling in individual immune cells",level:"2"},{id:"sec_11",title:"7. Conclusions and future directions",level:"1"}],chapterReferences:[{id:"B1",body:'Wallis, A. and K. Spinks, The diagnosis and management of interstitial lung diseases. BMJ, 2015. 350: p. h2072.'},{id:"B2",body:'Archer, S.L., E.K. Weir, and M.R. Wilkins, Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies. Circulation, 2010. 121(18): p. 2045–66.'},{id:"B3",body:'Ware, L.B. and M.A. Matthay, The acute respiratory distress syndrome. N Engl J Med, 2000. 342(18): p. 1334–49.'},{id:"B4",body:'Ranieri, V.M., et al., Acute respiratory distress syndrome: the Berlin Definition. JAMA, 2012. 307(23): p. 2526–33.'},{id:"B5",body:'Bouvry, D., et al., Hypoxia-induced cytoskeleton disruption in alveolar epithelial cells. 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Oncogene, 2005. 24(11): p. 1895–903.'},{id:"B41",body:'McMahon, S., et al., Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. J Biol Chem, 2006. 281(34): p. 24171–81.'},{id:"B42",body:'Sakamoto, K., et al., Differential modulation of surfactant protein D under acute and persistent hypoxia in acute lung injury. Am J Physiol Lung Cell Mol Physiol, 2012. 303(1): p. L43–53.'},{id:"B43",body:'Choi, S.H., et al., A Hypoxia-Induced Vascular Endothelial-to-Mesenchymal Transition in Development of Radiation-Induced Pulmonary Fibrosis. Clin Cancer Res, 2015. 21(16): p. 3716–26.'},{id:"B44",body:'Fleckenstein, K., et al., Temporal onset of hypoxia and oxidative stress after pulmonary irradiation. Int J Radiat Oncol Biol Phys, 2007. 68(1): p. 196–204.'},{id:"B45",body:'Kaelin, W.G., Jr. and P.J. Ratcliffe, Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell, 2008. 30(4): p. 393–402.'},{id:"B46",body:'Eltzschig, H.K., D.L. Bratton, and S.P. Colgan, Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov, 2014. 13(11): p. 852–69.'},{id:"B47",body:'Vohwinkel, C.U., S. Hoegl, and H.K. Eltzschig, Hypoxia signaling during acute lung injury. J Appl Physiol (1985), 2015. 119(10): p. 1157–63.'},{id:"B48",body:'Colgan, S.P. and H.K. Eltzschig, Adenosine and hypoxia-inducible factor signaling in intestinal injury and recovery. Annu Rev Physiol, 2012. 74: p. 153–75.'},{id:"B49",body:'Cummins, E.P., et al., The hydroxylase inhibitor dimethyloxalylglycine is protective in a murine model of colitis. Gastroenterology, 2008. 134(1): p. 156–65.'},{id:"B50",body:'Eltzschig, H.K. and T. Eckle, Ischemia and reperfusion--from mechanism to translation. Nat Med, 2011. 17(11): p. 1391–401.'},{id:"B51",body:'Eckle, T., et al., HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium. PLoS Biol, 2013. 11(9): p. e1001665.'},{id:"B52",body:'Eltzschig, H.K., et al., Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J Exp Med, 2003. 198(5): p. 783–96.'},{id:"B53",body:'Eltzschig, H.K., et al., Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood, 2004. 104(13): p. 3986–92.'},{id:"B54",body:'Sitkovsky, M.V., et al., Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol, 2004. 22: p. 657–82.'},{id:"B55",body:'Eltzschig, H.K., et al., Endothelial catabolism of extracellular adenosine during hypoxia: the role of surface adenosine deaminase and CD26. Blood, 2006. 108(5): p. 1602–10.'},{id:"B56",body:'Thompson, L.F., et al., Crucial role for ecto-5\'-nucleotidase (CD73) in vascular leakage during hypoxia. J Exp Med, 2004. 200(11): p. 1395–405.'},{id:"B57",body:'Morote-Garcia, J.C., et al., HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood, 2008. 111(12): p. 5571–80.'},{id:"B58",body:'Clambey, E.T., et al., Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A, 2012. 109(41): p. E2784–93.'},{id:"B59",body:'Bruzzese, L., et al., NF-kappaB enhances hypoxia-driven T-cell immunosuppression via upregulation of adenosine A(2A) receptors. Cell Signal, 2014. 26(5): p. 1060–7.'},{id:"B60",body:'Kohler, D., et al., Inhibition of Adenosine Kinase Attenuates Acute Lung Injury. Crit Care Med, 2016. 44(4): p. e181–9.'},{id:"B61",body:'Cronstein, B.N., et al., The adenosine/neutrophil paradox resolved: human neutrophils possess both A1 and A2 receptors that promote chemotaxis and inhibit O2 generation, respectively. J Clin Invest, 1990. 85(4): p. 1150–7.'},{id:"B62",body:'Cronstein, B.N., et al., Adenosine: an endogenous inhibitor of neutrophil-mediated injury to endothelial cells. J Clin Invest, 1986. 78(3): p. 760–70.'},{id:"B63",body:'Thiel, M., et al., Effects of adenosine on the functions of circulating polymorphonuclear leukocytes during hyperdynamic endotoxemia. Infect Immun, 1997. 65(6): p. 2136–44.'},{id:"B64",body:'Panther, E., et al., Expression and function of adenosine receptors in human dendritic cells. FASEB J, 2001. 15(11): p. 1963–70.'},{id:"B65",body:'Panther, E., et al., Adenosine affects expression of membrane molecules, cytokine and chemokine release, and the T-cell stimulatory capacity of human dendritic cells. Blood, 2003. 101(10): p. 3985–90.'},{id:"B66",body:'Xaus, J., et al., IFN-gamma up-regulates the A2B adenosine receptor expression in macrophages: a mechanism of macrophage deactivation. J Immunol, 1999. 162(6): p. 3607–14.'},{id:"B67",body:'Apasov, S.G. and M.V. Sitkovsky, The extracellular versus intracellular mechanisms of inhibition of TCR-triggered activation in thymocytes by adenosine under conditions of inhibited adenosine deaminase. Int Immunol, 1999. 11(2): p. 179–89.'},{id:"B68",body:'Aldrich, M.B., et al., Adenosine deaminase-deficient mice: models for the study of lymphocyte development and adenosine signaling. Adv Exp Med Biol, 2000. 486: p. 57–63.'},{id:"B69",body:'Huang, S., et al., Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood, 1997. 90(4): p. 1600–10.'},{id:"B70",body:'Kojima, H., et al., Abnormal B lymphocyte development and autoimmunity in hypoxia-inducible factor 1alpha-deficient chimeric mice. Proc Natl Acad Sci U S A, 2002. 99(4): p. 2170–4.'},{id:"B71",body:'Hale, L.P., et al., Hypoxia in the thymus: role of oxygen tension in thymocyte survival. Am J Physiol Heart Circ Physiol, 2002. 282(4): p. H1467–77.'},{id:"B72",body:'Caldwell, C.C., et al., Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol, 2001. 167(11): p. 6140–9.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Sandeep Artham",address:null,affiliation:'
Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and the Charlie Norwood VA Medical Center, Augusta, GA, USA
'},{corresp:"yes",contributorFullName:"Payaningal R. Somanath",address:"sshenoy@augusta.edu",affiliation:'
Program in Clinical and Experimental Therapeutics, College of Pharmacy, University of Georgia and the Charlie Norwood VA Medical Center, Augusta, GA, USA
Department of Medicine, Vascular Biology Center and Cancer Center, Augusta University, Augusta, GA, USA
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1. Introduction
Almost but a few would recognize the relation between fossil fuel burning and the global greenhouse issue. However many of them tend to be in favor of expensive and inefficient but immediately harmless renewable energy than existing nuclear. A major barrier to persuade con-nuclear elements is the nuclear waste issue which should have directly associated with Pu production for the traditional strategy to close fuel cycle to ensure national energy security by using the liquid metal fast breeder reactor (LMFBR). In coping with this circumstance, resolutions to address both issues, i.e., decreasing radiotoxicity of the high-level radioactive waste (HLW) and sustaining energy using the molten salt reactor (MSR) technology, have been expected.
The MSR technology was developed and culminated by successful operation of the molten salt reactor experiment (MSRE) and conceptual design of the molten salt breeder reactor (MSBR) in Oak Ridge National Laboratory (ORNL) by 1975 to make thorium as a naturally available fuel usable in addition to uranium.
Many attempts have been made to realize breeder reactors based on the U-Pu cycle using molten salt fuels; however such endeavors had been limited in the chloride salts, because of the feasibility to obtain high enough energy of neutron flux [1].
In addition to the predicted solubility data from thermodynamic calculations [2], recently actualized high solubility data of various fluorides of actinides and lanthanides specifically in the LiF-NaF-KF eutectic mixture (traditionally named as FLiNaK) [3, 4, 5, 6] reportedly could allow utilizing the high enough energy neutrons for the U-Pu breeding cycle aided by a high heavy element inventory (2.8 t/m3) and a small neutron moderating capability [7].
It was reported that a system nominated as a 3.2 GWt U-Pu fast-spectrum molten salt reactor (U-Pu FMSR) of 21.2 m3 core volume (31.8 m3 total primary system volume) starting from 68.5 tons of uranium with 15 tons of plutonium solving in FLiNaK to reach an equilibrium state after 10 years with an online chemical processing in which the conversion ratio (CR) became positive with inventory of 68.6 tons uranium, 20.9 tons plutonium, and 1.4 tons miner actinides did not need fissile material in feeding and consumed 238U only [7].
It does not intend to reduce doubling time but can breed fissile to guarantee stable operation without a blanket. It does not deliberately decrease TRU but confines them into the reactor core and isolates them from improper uses indefinitely. It does continuously renew fissionable actinides by the metabolic function with an online processing and produce nearly actinide-free fission product streams to be wasted. This implies that fluoride molten salt reactor technology is being available based upon U-Pu breeding cycle to afford reasonable approach to global task addressed to sustaining natural resources, decreasing stockpile of plutonium as well as depleted uranium, relieving radioactive waste burden from the use of nuclear energy, achieving complete nonproliferation, inheriting safety characteristics of the liquid fuel, and establishing complete stand-alone system associating with only the waste disposal facility.
The author and associates have successfully performed a follow-up calculation not only for FLiNaK but also NaF-KF-UF4 system as a matrix of the fuel salt [8, 9]. Their efforts have borne a fruit as a nuclear reactor plant using a mixture of NaF-KF-UF4 fertile and NaF-KF-TRUF3 fissile as the fuel salt incorporated with designated online chemical processes based upon the oxide selective precipitation process with extremely low heavy element released to the environment which was nominated as the fast-spectrum fluoride molten salt reactor (FFMSR) [10, 11, 12].
2. Preliminary survey and study
2.1 Is FLiNaK the best choice as the matrix for a liquid fuel?
Composing the fuel salt for a thermal reactor such as the Molten Salt Breeder Reactor (MSBR) had nothing to do with solubility. The fertile salt 0.72LiF-0.16BeF2-0.12ThF4 had a unique phase relationship in which liquidus was constant at 500°C during ThF4 content was varied between 10 and 20 mol%. The fissile salt 233UF4 was not dissolved in the fertile salt, but displaced 232ThF4, as they had the same monoclinic crystal structure. During the freezing process, almost 75% of the fuel salt was solidified at 500°C as the same composition as the liquid phase. Eventually 0.47LiF-0.515BeF2-0.015ThF4 containing very small amount of 233UF4 solidified as eutectic at 370°C [13]. This freezing process was evaluated as nuclear criticality safety in the fuel salt drain tank, and it became as a basis of the technological feasibility.
In serious attempt to use hexagonal PuF3 as a fissile instead of monoclinic 233UF4 in 0.72LiF-0.16BeF2-0.12ThF4, it had been treated as the solubility of PuF3. The term “solubility” has been used as a convenient synopsis of “liquefied fraction” on the phase diagram [14]. However they are not the same exactly because “solubility” is defined as the mole fraction of solute in solvent, while “liquefied fraction” is defined as the fraction in total mole value.
The elaborated solubility measurements in FLiNaK by Russian scientists [3, 4, 5, 6] should have been more appropriately respected if they had made the chemical composition of alkali fluoride matrix of liquefied samples analytically quantified instead of their customary practice in which the matrix had been always assumed as FLiNaK, even if they have found no UF4 or PuF3 but 2KF-UF4, 7KF-6UF4, KPu2F7, KPuF4, and NaPuF4 in the solidified residue by the X-ray diffractometric analysis.
The author tries to interpret the solubility of UF4 and PuF3 in the FLiNaK by producing liquefied components at respective temperatures as shown in Table 1 based upon the material balance referring from relevant phase diagrams in Figure 1 [15] and Figure 2 [16]. The red line in each ternary diagram which starts from the actinide fluoride corner, passes through the eutectic point, and ends in the alkali fluoride edge represents the actinide concentration in a fixed matrix composition.
Table 1.
Interpretation of solubility upon accumulated liquefied compounds.
Figure 1.
Phase diagrams for LiF, NaF, KF, and UF4 system [15].
Figure 2.
Phase diagrams for LiF, NaF, KF, and PuF3 system [16].
The increasing process of liquefied fraction consists of two types, firstly composing compounds at the eutectic temperature and secondly increasing content of liquefied fraction according to rising temperature. Alkali fluoride compounds of UF4 have a wider range of liquid zone than those of PuF3 in the relevant phase diagrams.
Coexistence of UF4 and PuF3 obviously competes each other in the first mechanism. The eutectic formation at lower temperature should have the priority.
These results would be summarized as:
The liquefied mixture of FLiNaK and heavy metal fluorides is not a solution.
KF (mp = 865°C) might have been temporally solidified prior to producing 0.445KF-0.555UF4 (735°C) during the ascending temperature process in the solubility measurement of UF4.
KF (mp = 865°C) and NaF (mp = 900°C) might have been temporally solidified prior to producing 0.651KF-0.349PuF3 (619°C) or 0.772NaF-0.228PuF3 (726°C) during the ascending temperature process in the solubility measurement of PuF3.
The saturated FLiNaK solution of UF4 and PuF3 is elucidated as the mixture of three types of alkali fluoride compound assumed as 0.321 (0.435LiF-0.243NaF-0.322UF4)-0.241 (0.730LiF-0.270UF4)-0.438 (0.651KF-0.349PuF3) with liquidus temperature of 619°C and solidus temperature of 445°C.
The liquidus temperature of the FLiNaK mixture might be substantially higher than that of solvent. Any physical favorable properties of FLiNaK should have not been directly attributed to the fuel salt.
2.2 Alternative choice to prepare the liquid fuel
Taking the lessons learned, the liquid fuel has to be a mixture of fertile salt and fissile salt both frozen into eutectic phases. Extensive numbers of phase diagram, which show the relationship between the variation of compositions and the liquidus temperature of mixtures, for alkali fluoride systems containing UF4 and for those containing PuF3 have been defined. The eutectic temperature means that nothing but liquid is stable over this temperature and that nothing but solid is stable under this temperature. The eutectic compositions and temperatures for the alkali fluoride systems containing UF4 and PuF3 are listed in Table 2.
Alkali fluoride eutectic mixture containing UF4 or PuF3.
Eutectic temperature.
There are various candidates for the combination of fertile salt and fissile salt as shown in Table 3. Technologically the liquidus temperature is preferably as low as possible. The lower heavy metal content of a component could imply higher liquidus temperature apart from the indicated eutectic temperature.
Case
Fertile salt (eutectic temp.)
Fissile salt (eutectic temp.)
Li
0.730LiF-0.270UF4 (490°C)
0.788LiF-0.212PuF3 (745°C)
Na
0.720NaF-0.280UF4 (623°C)
0.779NaF-0.221PuF3 (726°C)
K
0.850KF-0.150UF4 (618°C)
0.651KF-0.349PuF3 (619°C)
Li-Na
0.435LiF-0.243NaF-0.322UF4 (445°C)
0.611LiF-0.167NaF-0.222PuF3 (685°C)
Li-Na-K
0.435LiF-0.243NaF-0.322UF4 (445°C)
0.341LiF-0.461KF-0.188PuF3 (513°C)
Li-K
0.267LiF-0.476KF-0.257UF4 (500°C)
0.341LiF-0.461KF-0.188PuF3 (513°C)
Li-K-Na
0.267LiF-0.476KF-0.257UF4 (500°C)
0.611LiF-0.167NaF-0.222PuF3 (685°C)
Na-K
0.504NaF-0.216KF-0.280UF4 (490°C)
0.053NaF-0.608KF-0.340PuF3 (605°C)
Table 3.
Candidates for the combination of fertile salt and fissile salt.
The author is particularly interested in the fuel system consisting of NaF-KF-UF4 and NaF-KF-PuF3 which do not contain enriched 7LiF for economic as well as technological reasons associated with tritium control and irradiation defects after being solidified. If there might be a particular reason to contain LiF in the fuel, it is decreasing viscosity.
It is revealed that this combination can provide 0.35NaF-0.29KF-0.28UF4-0.08PuF3 composed of mixing 0.762 (0.504NaF-0.216KF-0.280UF4) and 0.238 (0.053NaF-0.608KF-0.340PuF3) at the liquidus of 605°C and the solidus of 490°C. This means that nothing but liquid is stable at 605°C or higher and nothing but solid is stable at 490°C or lower according to the phase diagrams Figures 1 and 2.
2.3 Density of alkali fluoride mixture with heavy metal fluoride
The density of a liquid mixture has been customarily obtained as a reciprocal of a weighted average of molecular volume of components; though this procedure worked satisfactorily during the MSRE and MSBR project in ORNL [17], concurrently it has been recognized that the results might be significantly erroneous without pertinent information about the respective components, e.g., liquid UF4 or PuF3. If the components would compose a complex compound, e.g., 2KF + UF4 → K2UF6 or 3KF + PuF3 → K3PuF6, it might cause a serious deviation from linearity.
Since most molten salt reactors considered during the early stages of MSR project in ORNL were thermal or epithermal, the fluorides of lithium, beryllium, sodium, and zirconium have been given the most serious attention for the carrier salt of liquid fuels. However some alkali fluoride mixtures including potassium with UF4 were also investigated in ORNL during the earlier stage of MSR project although details had been classified [18]; however the density data were perceived as not from additivity calculation as listed in Table 4.
Some physical properties of alkali fluorides containing UF4 [18].
Explicitly marked as experimental value.
However it seems that the density of listed mixtures is approximately expressed by a couple of second-order approximate least square functions according to UF4 molar concentration, one for binary systems and another for ternary (or pseudo-ternary) systems, regardless of alkali fluoride matrix as shown in Figure 3.
Figure 3.
Density of alkali fluorides containing UF4 [18].
Based upon the density data for solid UF4, UF3, PuF4, and PuF3, i.e., 6.72, 8.97, 7.0, and 9.32 g/cm3 at the room temperature [19], it is hypothetically assumed that PuF3 can be substituted by 1.389 molecules of UF4 and UF3 by 1.335 molecules of UF4 in the sense of density effect. The average temperature coefficients were reported as 0.0008/oC in the range of 0–4 mol% and as 0.0011/oC in the range higher than 22 mol% [18].
This procedure to estimate the density of fuel salts with substantially high concentration of actinides became a major breakthrough in the whole study; however it should be experimentally verified further (Table 5 [19]).
Comparison of properties of PuF3 with ThF4, UF4, PuF4, UF3, and CeF3 [19].
M, monoclinic; H, hexagonal.
2.4 Implication of density of the liquid fuel in the feasibility of reactor
2.4.1 Effect of density on conversion of inventories to concentrations
The physical feasibility of the U-Pu FMSR was independently verified by us in the sense of heavy element inventory with small deviations [8]; however there have been drastic differences in mol% concentrations of UF4 and PuF3 to provide the required inventory as shown in Table 6. We have learned that the reported work [7] have applied density of the fuel salt as 5.32 g/cc at 680°C derived from the weighted average process of molecular volume for 0.704 (FLiNaK)-0.21UF4-0.067PuF3-0.0045MaF3-0.014FP [20], while it was 3.86 g/cc according to our procedure.
The calculated molar concentration of the heavy elements in the fuel salt is inversely proportional to the density of the fuel salt for the identical inventories. The nuclear characteristics rely on the heavy metal inventory; however the phase relationship and chemical/hydrothermal characteristic solely rely on molecular concentration of heavy metal fluorides. Accordingly the fuel composition for which we have to examine the technological feasibilities should be 0.612 (FLiNaK)-0.290UF4-0.098TRUF3 instead of 0.704 (FLiNaK)-0.21UF4-0.067PuF3-0.0045MaF3-0.014FP.
Establishing the standard process to evaluate reliable density value of the fuel salt is an indispensable step of research and development work of the molten salt reactor technology particularly when it is across multiple research parties.
2.4.2 Deviation of density due to UF3 formation
The physical calculations up to now for the FFMSR are performed for the fuel salt having chemical composition as.
However if [UF3]/[UF4] ratio should have been kept at 5% for the redox buffer control as will be discussed in Section 2.5.2, the chemical composition might have been altered as.
This unique temperature unrelated factor (±0.06% of fuel density) on the reactivity should be evaluated accordingly.
2.5 Challenges for realization of FFMSR
2.5.1 Characteristic arrangement for the unmoderated MSR
The authors have never dared to realize molten salt fast reactors for burning TRU, unless we could have seen a tank-within-tank layout proposed by Forsberg [21] and reproduced in Figure 4, to ensure characteristic safety of the unmoderated MSR based on the technology for the fluoride high-temperature reactor (FHR).
Figure 4.
Comparison between unmoderated and moderated arrangement [21].
A unique criticality safety challenge associated with unmoderated MSR is that criticality can occur if the fissile materials leak from the system and come near the neutron moderators, such as concrete. This has to exclude the “catch pan” arrangement to transfer gravitationally the spilled fuel material into the drain tank, which has been traditionally adapted by graphite-moderated MSR.
The combination of the direct reactor cooling system (DRACS), the pool reactor auxiliary cooling system (PRACS), and the buffer-salt pool which includes drain tanks in the bottom and is located in the underground silo can accommodate the decay heat removal and criticality issues under the design basis as well as the beyond-design-basis accident, even including the outer vessel failure.
2.5.2 Redox control of FFMSR
UF4 molecule in a liquid fluoride mixture intrinsically oxidizes to dissolve Cr as the most vulnerable constitution of the specifically developed structural material Hastelloy N to result in CrF2 and to form UF3 molecule. This challenge to be addressed for a UF4-fueled molten salt reactor was overcome by keeping U(IV)/U(III) ratio no less than 100 with constant monitoring of CrF2 concentration [22].
From 1965 to 1969, a successful operation of the MSRE proved that the fission of 235UF4 as well as of 233UF4 made the fuel salt moderately oxidizing as previously suggested and proven that the absence of metallic uranium deposition or uranium carbide formation incidence due to successive fissioning. The U(IV)/U(III) ratio could be maintained within the projected range by periodic dissolution of beryllium metal bar suspended in the pump bowl. During the post-MSRE work, it was found that the significant intergranular cracks due to the presence of fission product tellurium could be suppressed by adjusting the U(IV)/U(III) ratio no higher than 70 [22].
In 1968, Thoma [19] described that no significant differences were believed to exist in the yield or chemistry of the principal species of fission products which would result from the incorporation of PuF3 in MSR fuels and then the use of a tri-fluoride solute should result in a cation excess and should cause the fuel solution to generate a mild reducing potential, because he had confirmed that the fission of 235UF4 fuel consuming ∼0.8 is equivalent to UF3 per gram atom of fissioned uranium.
In 1994 Toth [23] ratified Thoma’s perception [19] made in 1968 regarding the effect of PuF3 fission on redox potential of the fuel salt however with strong warning that further investigations should be required if Pu fuels were used in future designs.
In November 2017, the ORNL has made an official presentation to the US-NRC staff [24] that the fission of PuF3 releases three fluorine ions, while the fission products require more than three, and thus there will be a fluorine ion deficit with net reducing conditions without showing fission product yield data or chemical status of fission products. The ORNL traditionally has ignored the fact in which fission of 239Pu yields much more rare metals and much less zirconium than those of 235U or 233U which could decrease the required fluorine ions substantially.
The author solicited Dr. Shimazu [25] to take a positive approach to certify the new redox potential control paradigm using the newest computation practice and elucidated free fluorine yield data for 233UF4, 235UF4, and 239PuF3 per unit fission as well as per unit power output under both thermal neutron (MSRE) and fast neutron (FFMSR) environment assuming that the chemical behavior of fission product in molten fluoride environment is identical as evaluated for 235U fission by Baes [26] as shown in Table 7.
Fissionable Materials
Mole-F/Fission
Mole-F/MWt-y
Fast
Thermal
Fast
Thermal
233UF4
0.65
0.80
1.13
1.14
235UF4
0.80
0.80
1.35
1.36
239PuF3
0.60
0.60
1.02
1.09
Table 7.
Free fluorine production rate per fissioning in liquid fluoride fuel [25].
It was informed by the study [27] with molten LiF-BeF2-ThF4 (75-5-20 mol%) salt mixture fueled by 2 mol% of UF4 and containing additives of Cr3Te4, including 250-h tests with exposure of nickel-based alloy specimens at temperatures from 700 to 750oС and under mechanical loading, that there were no traces of tellurium intergranular cracking on specimens in the fuel salt with [U(IV)]/[U(III)] ratio from 20 to 70 and no nickel-uranium intermetallic film on the specimens with fuel salts characterized by the ratio larger than 3, as shown by the acceptable redox voltage range in Figure 5 [27, 28].
Figure 5.
Dependence of the redox potential on UF4/UF3 ratio [27, 28].
NaF-KF-UF4 compound might be less Lewis basic than LiF-BeF2-ThF4; however it will require to make the [U(IV)]/[U(III)] ratio at least 20. This means that UF3 has to be kept as the redox buffer at 1.33 mol% while total uranium fluoride at 28.1 mol%.
2.6 Operational behavior of FFMSR
2.6.1 Effect of U inventory on reactor physical properties
Neutronic calculations were made taking originally proposed configurations of the reactor (core height/radius ratio, 1.85; core volume, 21.2 m3; primary circuit volume, 31.8 m3) and the power output (3.2GWth) the same as Ref. [7], but other factors, such as the actinide isotopic composition (45,000MWD/t-U in BWR, 5 years cooling), neutron leakage (with 30 cm steel reflector), the fuel temperature (627°C), the salt cleanup and makeup condition, etc., were discretely specified to give verified number of heavy element masses and concentrations in the fuel salt to give designated reactivity (keff = 1.007) from the start up to the equilibrium state (40 years).
Operational features are characterized by annual feed/breed balance of fissile material as TRU over four zones under a constant U inventory which can be maintained by an appropriate makeup. The effect of U inventory in three levels on TRU feed/breed balance is evaluated in which fuel salt cleaning started after 300 effective full power days (EFPD) with an interval of 300 EFPD and illustrated in Figure 6. The larger inventory of U requires larger amount of initial fissile inventory but smaller amount of supplement; however the peak annual supplement is less dependent on the initial U charge. U inventory of 61.4 tons is the lowest threshold limit to make breeding break-even possible, while that of 71.5 tons can provide as much as 100 kg TRU of annual breeding; however it is the highest threshold limit by U content acceptable by a relevant fuel salt.
Figure 6.
Effect of initial U charge on the feed/breed balance.
2.6.2 Effect of fuel salt cleaning interval on reactor physical properties
Three hundred EFPD and 1500 EFPD of the fuel salt cleaning interval are evaluated both for an identical initial charge of the fuel salt composition (U: 71 t) as shown in Figure 7. No chemical cleaning but only makeup of TRU was made during the designated initial interval. The longer interval requires larger amount of fissile material supplement; however the peak annual supplement is less dependent on the extension of cleaning interval. A longer interval makes the cleaning volume smaller but nevertheless total makeup larger; however the cost of facility is specifically determined by the peak annual makeup value.
Figure 7.
Effect of fuel salt cleaning interval on the feed/breed balance.
The operation of an FFMSR with 1500 EFPD of fuel salt cleaning interval is assumed as barely providing a steady and sustaining operation with an appreciable breeding (10 kg TRU/year) in equilibrium.
2.6.3 Effect of initial fissile isotope composition
The effect of isotopic composition of initial feed TRU was evaluated for BWR-UOx fuel and ABWR-MOX fuel as shown in Figure 8. The isotopic compositions of each feed TRU are shown in Table 8.
Figure 8.
Effect of initial fissile isotope composition on the feed/breed balance.
Source of TRU
Np/Pu/Am/Cm (wt.%)
238/239/240/241/242Pu (wt.%)
BWR-UOX-45GWd/t-U
5.19/89.22/4.90/0.69
2.80/51.77/25.98/11.07/8.38
ABWR-MOX-33GWd/t-HM
0.35/91.69/7.11/0.85
2.62/38.17/35.33/13.49/10.39
Table 8.
Isotopic composition of initial feed TRU.
It is revealed that the breeding performance of an FFMSR applied on the ABWR-MOX spent fuel is much better than that on the BWR-UOX spent fuel though they can be comparable after the equilibrium state.
What is more drastic is the capability of accumulated TRU to support deployment of the FFMSR. It is assumed that a 3.3 GWt (1.0 GWe) BWR yields annually 20.4 t of spent nuclear fuel (SNF) (50 GWd/t-U) containing 0.27 t of TRU; meanwhile a 3.93 GWt (1.38 GWe) full MOX ABWR yields annually 34.8 t of SNF (33 GWd/t-HM) containing 1.28 t of TRU. The accumulated SNF from a BWR for 54.6 years will support an FFMSR-UOX, and that of an ABWR’s SNF for 17.8 years will support an FFMSR-MOX, with equivalent power output the same as the respective reactor. This means that a full MOX ABWR can be a breeding reactor with 17.8 years doubling time by the combination of FFMSR deployment.
2.7 Evolution of TRU constitution
The TRU inventory is almost kept at a constant through FFMSR operation with specific trends of isotopic evolution as shown in Figures 9 and 10.
Figure 9.
Evolution of TRU isotopic composition during burnup (BWR-UOX).
Figure 10.
Evolution of TRU isotopic composition during burnup (ABWR-MOX).
The high content of Np is distinct in the TRU from LWR; however it is transmuted effectively. The content of Pu isotopes is getting saturated in both cases. Am isotopes are slowly decreasing until 40 years. The buildup of Cm is over a factor of 3.5; however it tends to be saturated after 20 years. This is a characteristic feature compared with the case of MOSART [29] in which non-fissionable Cm isotopes build up remarkably. Generally favorable features of fast neutron irradiation are represented, though further assessments for several hundred years are inevitable.
2.8 Freezing behavior of fuel salt
The molten salt reactor is feasible as long as the liquidus temperature of the fuel salt is kept at least 50°C lower than the reactor core inlet temperature. According to the classic design principle of molten salt reactors, the fuel salt should be composed of a single eutectic mixture, and all components of the fuel salt should congruously solidify at the eutectic point.
In the case of the FFMSR, the phase change is incongruous manner as the fuel salt should be composed of a pair of independent eutectic mixtures. It should be qualified by freezing behavior down to the solidus temperature in order to justify any engineering effort particular to the molten salt reactor such as the freeze valve, the fuel drain tank, and the reactor safety evaluation.
The freezing of NaF-KF-UF4-PuF3 system is dictated by the eutectic point of fissile salt (605°C) to give eutectic of NaF-KF-PuF3 irrespective of the concentration of UF4 as shown in Table 9. These values of liquidus temperature are substantially higher than that of the classic fuel salt such as 0.72LiF-0.16BeF2-0.12ThF4 (500°C) for thermal neutron molten salt reactors based upon the Hastelloy N technology however near to that of the revised MSFR (594°C) [30].
Table 9.
Liquid and solid components of fuel salt during freezing.
The solidified fuel salt eventually produces a specific stratified structure, a lighter fissile salt on a heavier fertile salt. The density of solidified salt is assumed as 8% higher than that of liquid at the same temperature.
Feasibility of the freeze valve can be controversial because it has originally been developed on the assumption that the fuel salt was a single eutectic mixture which solidified congruously.
2.9 Effect of burnup and tri-fluorides on freezing behavior
If the U(IV)/U(III) ratio in the system is fixed at 20 as a redox buffer medium, 71.4 tons-U (300,000 moles) of the total U inventory should consist of 285,700 moles of UF4 and 14,300 moles of UF3. The concentration of UF3 is 1.33 mol% when that of PuF3 is 8.10 mol%. Meanwhile, UF4 inventory is reduced to a factor of 0.952 by chemical reduction to UF3.
It has been suggested thermodynamically that tri-fluorides of fission product lanthanide behave as PuF3 as well as those of minor actinide in the phase relationship and would interfere the freezing behavior.
Calculations are made to evaluate the effect of reduction of UF4 to UF3 and buildup of fission product lanthanide tri-fluorides in NaF-KF-0.281UF4-0.081PuF3 fuel salt according to chemical processing intervals for two cases of fissile salt arrangement and shown in Tables 10 and 11.
Table 10.
Option (a): to keep eutectic freezing at 605°C of fuel salt, 0.053NaF-0.607KF-0.340PuF3.
It is revealed that the effect of UF4 reduction to UF3 does not affect liquidus temperature of fuel salt meaningfully irrespective of fissile salt.
The buildup of lanthanide tri-fluorides does affect the liquidus temperature of fertile salt up to 625°C for the case (a); meanwhile it does not exceed 610°C using the fissile salt (b).
Option (a) should allow 900 EFPD of the chemical process interval if the liquidus temperature of fertile salt at 610°C is acceptable.
Option (b) should allow 1500 EFPD of the chemical process interval if the liquidus temperature of fertile salt at 610°C is acceptable. Option (b) however is against the rule in which no free fissile material is deposited before eutectic freezing. The choice of alternatives is depending upon less than 3% of difference of designated molar composition of tri-fluoride in the fissile salt. Not only the phase behavior of stable tri-fluoride such as PuF3 and LnF3 but also that of fluctuated UF3 should be examined carefully.
3. Chemical processing
3.1 How fission product stream be free from TRU
It has been evaluated that the radiotoxicity of the PWR-UOX-SNF of 50GWd/t-U decreases to the reference level represented by that of annually transmuted natural uranium (7.83 t-Unat.) after 130,000 years from discharge. If the HLW contains absolutely no TRU, the radiotoxicity decreases to the reference after 270 years mainly dominated by that of alkali and alkali earth elements (FPalk: Rb, Cs, Sr., Ba) as shown in Figure 11 [31].
Figure 11.
Ingestion radiotoxicity of 1 t of spent nuclear fuel [31].
The radiotoxicity of HLW from a reprocessing of UOX fuel with a nominal Pu loss rate of 0.5% and with removing minor actinides (MA; viz., Am and Cm) with a loss rate of 1% will decrease at the reference level in 500 years. It is assumed that the period will decrease to 370 years if Pu and MA are removed simultaneously from the HLW as TRU at the overall loss rate of 0.5%. This represents that the permissible TRU content in the finally disposed fission product (FPalk: Rb, Cs, Sr., Ba) is 65.9 g-TRU/8461 g-FPalk (0.78%) as shown in Table 12.
Burnup at the end of the first 1500 EFPD and thereafter.
The nuclear fuel of a 3.2 GWt FFMSR supported by 93.6 t-HM reaches the burnup of 51.3 GWd/t-HM in 1500 EFPD by consuming depleted uranium (4.33 t-Udep./50 GWd/t-HM), which might have been discarded as a radioactive waste somehow. If the radiotoxicity of 4.33 t-U instead that of 7.83 t-U is assumed as the reference for the HLW of FFMSR, the period to decrease to the revised reference value might be extended to 500 years after discharge. In order to keep TRU/FPalk at 0.78%, the permissible loss rate of the TRU into the FPalk should be less than 0.036% due to the specific TRU concentration in an FFMSR fuel as high as in an equivalent LMFBR fuel, as shown in Table 11. The required loss rate is far less than 0.1% of the target to be achieved by the pyro-processes such as electrochemical refining or liquid metal extraction currently under development [31].
The chemical processing in the FFMSR should be efficient to remove fuel material from the fission product streams but not necessarily efficient to remove fission products to become as neutron poisons if it were operated under the thermal neutron from the fuel stream.
To perform this new and perpetual mission, a processing interval of 1500 EFPD is sufficiently long and provides a small throughput in other words. The online chemical processing facility of α-β-γ-n remote operable capability collocated with the FFMSR would be the most expensive auxiliary part of the plant to be constructed as well as to be operated. Such cost should be depending upon the nature of process, i.e., process complexity, material compatibility, process wastes, and capacity in particular.
3.2 Requirements to be concerned
The crucial point in the fuel cleanup process is not the complete removal of neutron-absorbing material such as lanthanides from the fuel but keeping any leak of actinides into waste streams as low as possible. This could justify the use of the selective oxide precipitation process as an absolutely simple choice compared with other pyro-processes such as the electrochemical or the reductive extraction [32].
The fluoride volatile process of UF6 had been perceived as the most practical since the successful operation in MSRE during switch over the fissile from 235U to 233U; however it has been overlooked the fact that metallic Zr scrap in addition to the fuel should be followed by a prolonged H2 sparge to remove metallic corrosion products (Ni, Fe, Cr) caused by F2 treatment. The presence of a certain amount of Pu should require applying a reducing process from PuF4 to PuF3 in order to avoid accidental precipitation of PuO2 and severe material corrosion. Any absence of such treatment after the final removal of 233UF6 might have resulted MSRE remediation in a fruitless and endless trouble by undisclosed reasons of line clogging of the fuel drain tank.
3.3 Selective oxide precipitation process
In the very early stage of the Molten-Salt Reactor Program (MSR Program) started at ORNL, experimental studies on selective precipitation of oxides had been carried out because it might have been a suitable scheme for the reprocessing of molten salt reactor fuels, though it was abandoned after the discovery of the reductive extraction and metal transfer process associated with the UF6 volatile process, which, though complex and material incompatible, involved handling only liquids and gases. However the ultimately small throughput may allow us to select a solid handling process if the process is simple, fast, and material compatible.
A successful attempt was made to precipitate mixed uranium, plutonium, minor actinides, and rare earths from LiF-NaF molten salt solution by fluor-oxide exchange with other oxides (e.g., CaO, Al2O3) at temperatures 700–800°C. It was found that the following order of precipitation in the system is U-Pu-Am-Ln-Ca. Essentially all U and TRU were recovered from the molten salt till to rest concentration 5 × 10−4%, when 5–10 mol% of rare earths are still concentrated in solution [33, 34].
An optional process to be applied to the DMSR fuel was suggested as follows. Treat the melt with a strong oxidant to convert UF3 to UF4, PaF4 to PaF5, and PuF3 to PuF4. Precipitate the insoluble oxides using water vapor diluted in helium. The oxides UO2, Pa2O5, PuO2, CeO2, probably NpO2, and possibly AmO2 and CmO2 should be obtained. Recover the oxides by decantation and filtration. Hydrofluorinate the oxides into the purified melt of LiF-BeF2-ThF4, and reduce the melt with H2 and reconstitute fuel with the desired UF4/UF3 ratio [35].
This could justify the use of the selective oxide precipitation process as an absolutely simple choice compared with other pyro-processes such as the electrochemical or the reductive extraction [36].
3.4 Customization of the process
Based upon the survey, it is concluded that the application of the selective oxide precipitation process with alkali or alkali earth metal oxides (K2O2; melt at 490°C and CaO; solid) as the oxidizer can be feasible under special cautions about selectivity to the FFMSR technology relying on NaF and KF as major constitutes of fuel solvent, as shown in Figure 12.
Figure 12.
Process flowsheet of the oxide selective precipitation.
If it can reduce TRU concentration to 5 × 10−4 mol% in liquid phase from 8 mol%, the available loss rate will be 6.25 × 10−5. The permissible loss rate of 3.6 × 10−4 is six times larger than the available loss rate.
Intense increase of liquidus temperature should be taken into account during actinide removal treatment from 605°C up to 800°C. Using K2O2 as a precipitator can modify Na/K ratio from 0.55/0.45 to nearly 0.40/0.60 to give eutectic mixture at 710°C.
Elemental fluorine freed from UO2 precipitation reaction would react with TRUF3 to oxidize them into TRUF4 which can be eventually precipitated as TRUO2 by succeeding the use of CaO as a precipitator no more than ca. 20 mol% which may give stable ternary eutectic at ca. 700°C of the final waste salt.
As actinides are extremely abundant than lanthanides, the separation efficiency of actinides from lanthanides should not be good enough in a practical application; repeated treatments might be required to reduce actinide concentration in the lanthanide stream until permissible level is attained, even though moderate amount of lanthanides are permitted in the actinide stream. Up to 10% of lanthanides would be allowed to leave in the fuel salt stream, but lower than 0.01% of actinide leak into the waste stream is anticipated.
The process is a small batch scale (e.g., 21.2 l/day) in a pure Ni-made vessel facilitated to eliminate solid handling but performed by liquid phase handling only.The relevant fuel batch contains 12.9 kg of TRU which substantially exceed the significant mass of 8 kg; however it is always accompanied with 47 kg of chemically inseparable uranium. It is anticipated that the heat generation rate of a fuel batch will be 13.4 kW and the radioactivity will be 6MCi at 2 days after being drained.
The process is incorporated with He sparge to purge rare gases and halogens as well as noble and semi-noble metal fission products and electroreductive removal of zirconium developed for the MSRE remediation [37] as shown in Figure 13. Accumulation of fission product zirconium tetrafluoride in the fuel system would give an adverse effect in the fuel storage tank due to its reducible nature under gamma radiation as well as sublimation. Some detail process parameters are shown in Table 13.
Figure 13.
Online chemical process in a typical 3.2 GWt FFMSR.
Table 13.
Process parameters of oxide selective precipitation.
4. Chemical engineering of FFMSR
4.1 Initial fuel charge
An institutional restriction imposed to our task is the fact that no separated plutonium is tolerable in Japan to secure proliferation resistance under the international agreement. Japanese reprocessing plant cannot produce anything but U-Pu mixed oxide.
In the case of the FFMSR, the preparation work of initial charge does not require a high gamma facility if the source materials come from a conventional reprocessing plant. The oxide precipitation process incorporated with the hydro-fluorination process makes solid mixed oxide as makeup material feasible.
A typical 3.2 GWt FFMSR requires U-21.23% TRU mixed compound of 90 tons for the initial charge and 3.41 kg-U/EFPD (1245 kg-U/EFPY) of makeup in the equilibrium state compared with the 47.8 kg-U/EFPD of projected throughput of the chemical processing.
The FFMSR requires several tons of TRU supplement according to the nuclear characteristics until it reaches to equilibrium. This system is capable of making up 0.92 kg-TRU/EFPD (336 kg-TRU/EFPY), if the same U-TRU mixed compound as the initial charge is applied.
According to the specific nucleonic characteristics, the minimum U makeup is 1115 kg-U/EFPY, and the peak TRU supplement is 720 kg-TRU/EFPY. This means that as high as 39.2% U-TRU mixed compound should be temporally required in this occasion.
4.2 Redox buffer control and burnup effect
The nuclear reaction in the FFMSR consists of transformation of UF4 into TRUF3 and fission of TRUF3 into fission products. The annual free fluorine production of 3.2 GWth FFMSR at the equilibrium is 1308 moles (0.25/0.238 mol/kg-U × 1245 kg-U/EFPY) from the transmutation of UF4 and 3264 moles from the fission of TRUF3 based on 1.02 mole-F/MWt/y times 3200 according to Table 6. The annual consumption of UF3 is 4572 moles (1088 kg-U). This can be compensated by dissolution of 1524 moles uranium metal (363 kg-U) in the fuel salt containing UF4 as a part of annual U makeup (1245 kg-U), though any side stream hydro-fluorination is also available.
Taking into account uranium inventory as much as 71.65 tons (28 mol%), assumed U[IV]/U[III] = 20 ratio represents 3.41 tons of U[III] inventory and 1.33 mol% of UF3 concentration. Since the daily supply of U[III] is 3 kg/EFPD, very stable control of U[IV]/U[III] ratio is available. On the other hand, steadiness of UF3 concentration as high as 1.33 mol% represents 26.67 mol% of the UF4 and 9.33 mol% of the total tri-fluoride concentration instead of 8.0 mol% of TRUF3.
It should be assumed that the inventory of fission product lanthanide tri-fluoride at the burnup of 50,000 MWd/t-HM is 6.9% (0.55 mol%) of TRU tri-fluorides. Any effect of fluctuation as high as ∼1.33 mol% in UF4 or ∼1.88 mol% in total tri-fluoride upon the liquidus temperature of fuel salt should be carefully examined.
4.3 Back-end process and radioactive wastes
In the FFMSR, the inventory ratio of fission products to that of TRU is the key factor to guarantee an effectively low concentration of TRU in the waste stream with a given TRU leak rate. The inventory of fission product is equal to that of accumulation during 1500 EFPD (51GWd/t-HM).
The waste stream consists of gases (He, Kr, Xe, and 3H), spent charcoal filter absorbing I, solid elements (Zr, rare metals, and semi-rare metals such as Zn, Ga, Ge, As, Se, Nb, Mo, Ru, Rh, Pd, Ag, Tc, Cd, In, Sn, Sb, and Te), lanthanide oxides, and NaF-KF-CaF2 matrix salt containing alkali/alkali earth fission product fluorides.
Storage of fission product gases in high-pressure cylinders and then transfer to the repository was a standard practice in the MSBR design; however it is impractical in Japan, because of regulative requirement of annual pressure proof test of high-pressure cylinders.
Though the fission yield of 85Kr from the FFMSR system is assumed as about 1/3 of that from the graphite-moderated thorium molten salt reactors, special attention was suggested such as underground disposal by geological hydro-fracturing should be paid for radioactive Kr [38] if releasing from a high stack as currently applied in the spent fuel reprocessing plant will not be allowed in the future.
The spent iodine filter such as silver-impregnated matrix is a universal issue in every molten salt reactor as well as in spent solid fuel reprocessing plants.
Zr is electrochemically separated from the fuel salt prior to the oxide precipitation. Zr compounds are not desirable in the waste salt tank because of their reducibility in addition to sublimation capability [34].
Rare and semi-rare metals could possibly be industrially utilized after appropriately separated because they are virtually alpha activity free. They include various very long-lived fission products, such as 99Tc, 126Sn, 79Se, and 107Pd, which are to be disposed in a very compact form.
NaF-KF mixture containing soluble and major heat-generating fission product fluorides (CsF, SrF2, etc.) and the process reagent (KF and CaF2) is the main process waste as far as the online chemical processing is concerned.
Composition of fuel salt is assumed as 0.348NaF-0.284KF-0.280UF4–0.082TRUF3-0.006LnF3 (Tliq. = 605°C), and that of waste salt is assumed as 0.356NaF-0.580KF-0.060CaF2-0.004FPF1.5 (Tliq = 700°C).
Storage of the waste salt as liquid phase at higher than 700°C should be unpractical. It might be cooled to solidify in a tank shortly after being transferred.
The inventories are assumed as fuel salt, 147.87 tons; HM fluoride, 120.54 tons; and matrix salt, 27.33 tons. The high-level waste salt originated from a 1.5 GWe FFMSR system for 1500 EFPD operation (51.3 GWd/t-HM) is 46.26 tons (20.12 m3 at 2.3 g/cc of density), and the radiotoxicity of this amount of waste is equivalent to 405 tons of depleted uranium after 500 years cooling.
The throughput of high-level waste salt mixture from the vitrified high-level waste of 1.5 GWe PWR (50 GWd/t-U) after 99.5% Pu by reprocessing and 99% MA removal by P&T is probably 59 tons, and the radiotoxicity of this amount of waste is equivalent to 1163 tons of natural uranium after 500 years cooling.
The selection of the fuel matrix without 7Li economically allows a direct disposal of the waste matrix salt without recycle; nevertheless the bulk mass is comparable to that of vitrified waste of LWR though public utilization of decay heat before immobilization of cooled waste salt might be feasible.
Furthermore the incomparably favorable fact that the FFMSR system does not produce any fuel cycle-associated wastes, starting from uranium mine tailing all through to alpha-contaminated HEPA filters of MOX fuel fabrication plant, should be taken into account.
The characteristic capability of the oxide selective separation process enables to retrieve alpha contamination-free metals as well as lanthanide oxides without elaborating partitioning processes. Effective technologies to utilize such recovered resources are sincerely expected.
Full deployment of the FFMSR should make the entire fuel cycle infrastructures from the uranium mining to the spent fuel reprocessing including P&T needless except the HLW disposal site.
4.4 Contingency plan
The annual loss of TRU due to fuel salt chemical cleaning is 6 kg based upon the assumption 1500 EFPD of interval and 0.1% of nominal loss rate for 22.6 tons-TRU inventory. This can be accounted for in the equilibrium phase indefinitely because the annual TRU surplus is 10 kg. However if a flushing procedure should be required at the maintenance work according to 0.43% of the transfer rate in the MSRE operation experience [34], 97 kg of TRU may be transferred to the flushing salt even if it will be recovered efficiently later. How much TRU should have been given as a dowry at the deployment of a stand-alone FFMSR is a question. The reactivity swing by the chemical process unit outage (halt of the makeup and FP separation) should also be evaluated.
4.5 Dedicated front-end process for the ABWR
The dedicated front-end plant might produce U-TRU mixed fluoride from the MOX spent fuel of ABWR for which the Rokkasho Reprocessing Plant cannot deal with technical reasons as shown in Figure 14.
Figure 14.
Dedicated front-end process for the ABWR-MOX fuel.
The original fluoride volatility process converts all components into volatile fluorides by using fluorine flame reactor and then separates them into fractions according to their properties [39]. However we were rather interested in the recently developed innovative process using NF3 as a thermally sensitive reagent; it would react with different compounds at different temperatures [40]. For example, NF3 reacts with Tc and Mo oxide near 300°C and Ru and Rh near 400°C, while U oxides required near 500°C to form a volatile fluoride. This process eventually yields the nonvolatile fraction containing all TRU fluorides. Then we intended to apply the oxide selective precipitation process, to provide TRU stream not so much cleaned from fission products but to result very clean fission product stream from TRU contamination.
The distinguished feature of this process is the capability to separate useful metallic fission products as well as lanthanide oxides free from alpha contamination from other residual materials of fluorination process effectively, without laborious partitioning.
A suite of processes are shown as the flowsheet specifically for the ABWR spent fuel processing; however it can be reasonably modified to the original LWR spent fuel or LWR-MOX spent fuel.
5. Experimental test plans
5.1 Clarify phase relationship in NaF-KF-UF4-UF3-PuF3 system for the FFMSR
It is perceived that experimental confirmation of density assessment procedure of molten salt mixtures is inevitable to establish any MSR technology. The liquid fuel of the FFMSR contains UF4, UF3, and PuF3. Currently any performance of experimental activity on the specimens containing Pu as the special nuclear material is not available other than in the Russian Research Laboratories.
We plan the experimental procedure using NaF-KF-nat.UF4 containing in situ prepared nat.UF3 to simulate NaF-KF-nat.UF4-PuF3 taking advantage of identical crystal structure as well as similarity of density between PuF3 and UF3.
Furthermore, the phase relationship (freezing behavior) will be experimentally evaluated in order to justify that the feasibility of the phase structure should be understood.
The plan includes:
Confirmation of synthetic process of heavy element fluoride.
Confirmation of recovery process of heavy element as UO2.
Confirmation of synthetic process of NaF-KF-UF4-UF3.
Density measurement of liquid NaF-KF-UF4-UF3 to clarify the dependency of heavy element content with different solid densities on density of the liquefied salt.
Investigation of the phase diagrams of NaF-KF-UF4-UF3 to clarify the dependency of UF3 collocation in the NaF-KF-UF4 phase diagram using the solubility measuring practice. Effect of trivalent fission products on the phase diagram using CeF3 as a surrogate of UF3 and PuF3.
5.2 Experimental confirmation of chemical effects of TRU fissioning
The chemical effects of UF4 fissioning in a fluoride molten salt reactor were confirmed by the successful operation of the MSRE during the end of the 1960s. However any experimental confirmation of the chemical effect of PuF3 fissioning in a fluoride molten salt reactor has not yet been undertaken in spite of a strong warning made by the ORNL scientist in the end of the last century [23].
In spite of the continued effort by the author to try to stimulate academic discussion on the chemical effect of TRU fissioning controversial against the ORNL since 2015, it seems to the author to become “an inconvenient truth” for which no one dares to discuss. The author seriously concerns that the present situation might jeopardize the technological development of plutonium burning technology in the immediate future.
The author plans to propose a capsule irradiation test of NaF-KF-TRUF3 specimens under the fast neutron flux (3.9 × 1019 m−1 s−1) during liquid Na cooling in an experimental fast reactor (JYOYO) located in Oharai, Japan. It plans to measure the freed fluorine ions per a fission of fissile Pu and compare with that of 235U by the weight loss of the pure Zirconium metal specimen immersed in the fuel salt.
The proposed specimens are:
0.053NaF-0.608KF-0.340TRUF3 eutectic mixture (liquidus: 605°C) 2.56 g-TRU/cc as the subject.
0.053NaF-0.608KF-0.340CeF3 eutectic mixture (liquidus: 605°C) as the reference.
0.528NaF-0.285KF-0.188235UF4 eutectic mixture (liquidus: 490°C) 2.52 g-U/cc as the comparative.
The nominal sample temperature in the test region is at least 600°C; however it is assumed that the gamma heat of capsule structure should enable to heat the specimen up to 750°C.
6. Conclusions
The study on our FFMSR was started from the review of the reference technology and based upon the comprehension of immaturity of the TRU burning technologies using the MSR due to the prejudice of the original design principle of ORNL in which the use of PuF3 had been an exclusively temporary issue.
The various aspects but restricted in chemical technology discussed in this work should be taken into account and reviewed carefully in the imminent future activity although they are in limited scope and hypothetical nature to be verified experimentally. The present neutron physical calculations are preliminary nature in which the direct fission fraction of 238U is not quantified, taking for instances. The system has not yet been optimized, in various factors.
FFMSR should provide us with a tool to stimulate immediate use of existing LWR by making values to the spent fuel as well as to the depleted uranium and to create nuclear fission energy not relying on the existing fuel cycle infrastructure with the ultimate safety owing to the absence of and eliminating fuel cycle wastes and the simplicity for an indefinitely long term.
One of a price in return for these efforts is exclusive challenges to overcome increased reactor core inlet temperature up to 660°C (50°C higher than the liquidus temperature of fuel) however it might deserve.
Acknowledgments
The author would like to express his thanks to Prof. Dr. Koshi Mitachi and Prof. Dr. Yoichiro Shimazu for their volunteer dedication to the entire physical calculations in this work, Prof. Dr. L.I. Ponomarev for the courtesy of personally introducing his work, and Standard Power, Co. Ltd. for publishing this chapter. He would like to dedicate this paper to the late Prof. Dr. Yoich Takashima for his guidance in initiating the work associated with MSR technology.
\n',keywords:"fast-spectrum fluoride molten salt reactor, high-level radioactive waste, structure of fuel salt, density of fuel salt, redox potential control, freezing behavior of fuel salt, selective oxide precipitation process, front-end processing dedicated to the MOX spent fuel, nuclear fuel cycle and associated wastes",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71264.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71264.xml",downloadPdfUrl:"/chapter/pdf-download/71264",previewPdfUrl:"/chapter/pdf-preview/71264",totalDownloads:241,totalViews:0,totalCrossrefCites:1,dateSubmitted:"November 13th 2019",dateReviewed:"December 23rd 2019",datePrePublished:"February 27th 2020",datePublished:"February 24th 2021",dateFinished:"February 27th 2020",readingETA:"0",abstract:"A mixture of NaF-KF-UF4 eutectic and NaF-KF-TRUF3 eutectic containing heavy elements as much as 2.8 g/cc makes a fast-spectrum molten salt reactor based upon the U-Pu cycle available without a blanket. It does not object breeding but a stable operation without fissile makeup under practical contingencies. It is highly integrated with online dry chemical processes based on “selective oxide precipitation” to create a U-Pu cycle to provide as low as 0.01% leakage of TRU and nominated as the FFMSR. This certifies that the radiotoxicity of HLW for 1500 effective full power days (EFPD) operation can be equivalent to 405 tons of depleted uranium after 500 years cooling without Partition and Transmutation (P&T). A certain amount of U-TRU mixture recovered from LWR spent fuel is loaded after the initial criticality until U-Pu equilibrium but the fixed amount of 238U only thereafter. The TRU inventory in an FFMSR stays at an equilibrium perpetually. Accumulation of spent fuel of an LWR for 55 years should afford to start up the identical thermal capacity of FFMSR and to keep operation hypothetically until running out of 238U. Full deployment of the FFMSR should make the entire fuel cycle infrastructures needless except the HLW disposal site.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71264",risUrl:"/chapter/ris/71264",signatures:"Yasuo Hirose",book:{id:"9888",title:"Nuclear Power Plants",subtitle:"The Processes from the Cradle to the Grave",fullTitle:"Nuclear Power Plants - The Processes from the Cradle to the Grave",slug:"nuclear-power-plants-the-processes-from-the-cradle-to-the-grave",publishedDate:"February 24th 2021",bookSignature:"Nasser Awwad",coverURL:"https://cdn.intechopen.com/books/images_new/9888.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"145209",title:"Prof.",name:"Nasser",middleName:"S",surname:"Awwad",slug:"nasser-awwad",fullName:"Nasser Awwad"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"315264",title:"Dr.",name:"Yasuo",middleName:null,surname:"Hirose",fullName:"Yasuo Hirose",slug:"yasuo-hirose",email:"yahirose@mint.ocn.ne.jp",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Preliminary survey and study",level:"1"},{id:"sec_2_2",title:"2.1 Is FLiNaK the best choice as the matrix for a liquid fuel?",level:"2"},{id:"sec_3_2",title:"2.2 Alternative choice to prepare the liquid fuel",level:"2"},{id:"sec_4_2",title:"2.3 Density of alkali fluoride mixture with heavy metal fluoride",level:"2"},{id:"sec_5_2",title:"2.4 Implication of density of the liquid fuel in the feasibility of reactor",level:"2"},{id:"sec_5_3",title:"Table 6.",level:"3"},{id:"sec_6_3",title:"2.4.2 Deviation of density due to UF3 formation",level:"3"},{id:"sec_8_2",title:"2.5 Challenges for realization of FFMSR",level:"2"},{id:"sec_8_3",title:"2.5.1 Characteristic arrangement for the unmoderated MSR",level:"3"},{id:"sec_9_3",title:"Table 7.",level:"3"},{id:"sec_11_2",title:"2.6 Operational behavior of FFMSR",level:"2"},{id:"sec_11_3",title:"2.6.1 Effect of U inventory on reactor physical properties",level:"3"},{id:"sec_12_3",title:"2.6.2 Effect of fuel salt cleaning interval on reactor physical properties",level:"3"},{id:"sec_13_3",title:"Table 8.",level:"3"},{id:"sec_15_2",title:"2.7 Evolution of TRU constitution",level:"2"},{id:"sec_16_2",title:"2.8 Freezing behavior of fuel salt",level:"2"},{id:"sec_17_2",title:"2.9 Effect of burnup and tri-fluorides on freezing behavior",level:"2"},{id:"sec_19",title:"3. Chemical processing",level:"1"},{id:"sec_19_2",title:"3.1 How fission product stream be free from TRU",level:"2"},{id:"sec_20_2",title:"3.2 Requirements to be concerned",level:"2"},{id:"sec_21_2",title:"3.3 Selective oxide precipitation process",level:"2"},{id:"sec_22_2",title:"3.4 Customization of the process",level:"2"},{id:"sec_24",title:"4. Chemical engineering of FFMSR",level:"1"},{id:"sec_24_2",title:"4.1 Initial fuel charge",level:"2"},{id:"sec_25_2",title:"4.2 Redox buffer control and burnup effect",level:"2"},{id:"sec_26_2",title:"4.3 Back-end process and radioactive wastes",level:"2"},{id:"sec_27_2",title:"4.4 Contingency plan",level:"2"},{id:"sec_28_2",title:"4.5 Dedicated front-end process for the ABWR",level:"2"},{id:"sec_30",title:"5. Experimental test plans",level:"1"},{id:"sec_30_2",title:"5.1 Clarify phase relationship in NaF-KF-UF4-UF3-PuF3 system for the FFMSR",level:"2"},{id:"sec_31_2",title:"5.2 Experimental confirmation of chemical effects of TRU fissioning",level:"2"},{id:"sec_33",title:"6. Conclusions",level:"1"},{id:"sec_34",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Mourogov A, Bokov P. Potentialities of the fast spectrum molten salt reactor concept: REBUS-3700. Energy Conversion and Management. 2006;47:2761-2771'},{id:"B2",body:'Benes O, Cabet C, Deloech S, Hosnedl P, Ignatiev V, Kornings R, et al. Review report on liquid salts for various applications. In: ALISIA Project. 2009. p. 15/64'},{id:"B3",body:'Lizin A, Tomilin S, Gnevashov O, Gazizov A, Osipenko A, Kormilitsin V. PuF3, AmF3, CeF3, NdF3 solubility in LiF_NaF_KF melt. Atomic Energy. 2013;115(1):11-17'},{id:"B4",body:'Lizin A, Tomilin S, Gnevashov O, Gazizov A, Osipenko A, Kormilitsin M. 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Identification and evaluation of alternatives for the disposition of fluoride fuel and flush salts from the MSRE at ORNL. In: ORNL-ER-380. 1996'},{id:"B38",body:'Messenger S, Forsberg C, Massie M. Gaseous fission product management for molten salt reactors and vented fuel system. In: ICAPP-2012, Chicago, USA, June 24–28. 2012. p. 12097'},{id:"B39",body:'Uhlir J, Marecek M. Fluoride volatility method for reprocessing of LWR and FR fuels. Journal of Fluorine Chemistry. 2009;130:89-93'},{id:"B40",body:'McNamara B, Casella A, Scheele R, Kozelisky A. Nitrogen trifluoride-based fluoride-volatility separations process: Initial studies. In: PNNL-20775. 2011'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Yasuo Hirose",address:"yahirose@mint.ocn.ne.jp",affiliation:'
Standard Power, Inc., Tokyo, Japan
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