Provenance of HMAC component materials.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 179 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 252 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
\n'}],latestNews:[{slug:"intechopen-authors-included-in-the-highly-cited-researchers-list-for-2020-20210121",title:"IntechOpen Authors Included in the Highly Cited Researchers List for 2020"},{slug:"intechopen-maintains-position-as-the-world-s-largest-oa-book-publisher-20201218",title:"IntechOpen Maintains Position as the World’s Largest OA Book Publisher"},{slug:"all-intechopen-books-available-on-perlego-20201215",title:"All IntechOpen Books Available on Perlego"},{slug:"oiv-awards-recognizes-intechopen-s-editors-20201127",title:"OIV Awards Recognizes IntechOpen's Editors"},{slug:"intechopen-joins-crossref-s-initiative-for-open-abstracts-i4oa-to-boost-the-discovery-of-research-20201005",title:"IntechOpen joins Crossref's Initiative for Open Abstracts (I4OA) to Boost the Discovery of Research"},{slug:"intechopen-hits-milestone-5-000-open-access-books-published-20200908",title:"IntechOpen hits milestone: 5,000 Open Access books published!"},{slug:"intechopen-books-hosted-on-the-mathworks-book-program-20200819",title:"IntechOpen Books Hosted on the MathWorks Book Program"},{slug:"intechopen-s-chapter-awarded-the-guenther-von-pannewitz-preis-2020-20200715",title:"IntechOpen's Chapter Awarded the Günther-von-Pannewitz-Preis 2020"}]},book:{item:{type:"book",id:"5921",leadTitle:null,fullTitle:"Textiles for Advanced Applications",title:"Textiles for Advanced Applications",subtitle:null,reviewType:"peer-reviewed",abstract:"This book presents a global view of the development and applications of technical textiles with the description of materials, structures, properties, characterizations, functions and relevant production technologies, case studies, challenges, and opportunities. 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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].
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].
\nBecker 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].
\nNa,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].
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].
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].
\nHIFs 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].
\nProlyl 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].
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].
\nSimilarly, 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].
\nIn 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].
\nEndothelial-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].
\nIn 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).
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.
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.
\nEmigration 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).
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.
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].
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].
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].
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].
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].
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.
Industries annually generate millions of metric tons of solid by-products, and most of these materials have been landfilled at considerable cost since. Modern society has been developing beneficial reuse of industrial by-products in a variety of applications [1, 2, 3]. Recycling of waste construction materials saves natural resources, saves energy, reduces solid waste, reduces air and water pollutants and reduces greenhouse gases [4, 5]. The transportation, construction and environmental industries have the greatest potential for reuse because they use vast quantities of earthen materials annually. Replacement of natural soils, aggregates and cements with solid industrial by-products is highly desirable [1, 2].
The steel industry produces a myriad of metal components for industrial chains such as the automobile industry, which in turn generates mineral discarded sand moulds (waste foundry sand/WFS) that end up occupying large volumes in landfills [6]. The major portion of the WFS is considered as non-hazardous waste and is currently deposited in a special WFS landfill that is remote from areas of settlement [7, 8, 9, 10].
The metal casting industry annually discards about 10% of foundry sand for production, i.e. approximately an estimated 9–10 million tons of WFS each year, in the USA [5, 10, 11]. Generally speaking, approximately 1 ton of foundry sand is needed to produce 1 ton of metal casting [8, 12]. WFS can be used as an alternative material (fine aggregate in asphalt mixtures) in highway constructions allowing the increasing of the lifespan of landfills [13].
This work analyses the physical and mechanical behaviour of asphalt mixtures, using the WFS as a mineral filler in asphalt concrete, in 5% (in mass) of maximum replacement to conventional Portland cement (CP). The waste was obtained from an industry located in the free-trade zone of Manaus city, Amazon State, Brazil. The results showed that the addition of industrial WFS in asphalt mixture resulted in adequate performance of the mixtures.
Waste foundry sand is generated by industries that use sands, binders and additives to form moulds and cores for castings. Sands are chosen for several reasons; they are readily available everywhere, inexpensive, highly refractory and readily bonded by clays or other inorganic and organic materials [8, 9, 14]. The mould forms the outside of the castings; the core forms the internal shape. When the part to be made has deep recesses or hollow portions, sand cores must be provided in the mould [3]. The material to be used to form moulds and cores in a foundry should have cohesiveness and porosity properties at the same time. Adding binder (bentonite, resins, cement, sodium silicate and oils) will improve the cohesiveness of the sand grains but will tend to reduce porosity. Additives are those materials which are added to the bonded sands to improve properties, either during the moulding process or during the casting process or both [8]. The moulding processes which involve sand are (1) green sand moulding (or clay-bonded sand, [12]), (2) chemically bonded process and (3) shell moulding process [3, 5, 8, 9]. The most commonly used process is green sand moulding [15]. Green sand is composed of four major materials. Sand comprises 85–95% of the green sand mixture. Most often the sand is inert silica, but olivine and zircon sand are also used [8, 15, 16, 17]. Approximately, 4–10% of the mixture is made of some form of clay, e.g. bentonite. The clay acts as a binder for the green sand and provides strength and plasticity. Combustible additives like sea coal, cereal, fuel oil and wood flour typically make up from 2 to 10% of the green sand mixture. The final additive of green sand is water which is usually added in small percentages (2–5% by weight) [5, 8]. Chemically bonded sands are those that use furan, phenolic urethane and acid cured no-bake systems, as well as alkyd and phenolic urethane cold box processes. Shell moulding uses a mixture of sand and thermosetting resin (usually phenol formaldehyde) to form the mould [8, 17].
The physical, chemical and mechanical characteristics of virgin sand make it a popular material for construction engineering, but after several reuses in moulds and cores, it becomes WFS [7]. The grain size distribution of WFS is quite uniform, with a majority of the sizes (85–95%) falling within a narrow range between 0.6 and 0.15 mm, and 5–12% is smaller than 0.075 mm [5, 8, 10] or between 1 and 16.5% [14]. According to Tikalsky et al. [17], more than 80% of the particles by mass are concentrated by size between 0.15 and 0.70 mm, compared to 0.30–4.75 mm for conventional fine aggregate. Most of the WFS materials reported are found to be medium to fine sand. WFS have been found to be too fine to satisfy the specifications for general fine aggregate [8, 10, 12]. WFS has uniform equidimensional subangular to rounded grains, and a few has rounded grains [8, 10, 17, 18].
For density and unit weight, the values found for the WFS were very close to conventional aggregate [13]. The bulk specific gravities reported in the literature on WFS ranged from 1.985 to 2.722 [8, 17]. In most of the cases WFS have been reported to be almost dry. The moisture content as received for WFS were reported to be in the range of 0.0–4.85% [8, 17, 18]. Concerning absorption, the values are relatively higher than those obtained for the natural aggregate, due to the presence of organic matter [6, 8]. The percentage absorption values on WFS samples have been reported to vary between 0.3 and 6.2% [3, 8, 17].
Over the past three decades, there have been several studies around the world on the use of WFS in engineering works, in different areas: base and subbase layers of highway construction [19, 20, 21], embankments [22, 23], hydraulic barriers [24], asphalt mixtures [3, 7, 16, 25, 26], etc.
Highway subbase layers using WFS have been shown to resist winter conditions (freeze–thaw cycles) better than specimens of reference materials [5, 17, 19]. If a subbase layer stabilised with WFS is compacted in field at dry of optimum content then it will have an increase in its strength [19, 20, 27].
It has been mentioned in the literature that the fines of WFS affect the properties of asphalt concrete negatively [7, 28]. The amount of WFS used in an asphalt mixture depends largely on the amount of fines in the WFS [5, 12, 14, 29]. Studies have recommended that WFS should replace successfully as much as 15% (in mass) of the conventional sand (fine) content in asphalt concrete [3, 9]; 8–10, 10–20 and 10%, respectively, in engineering practice in Pennsylvania, Michigan and Tennessee States [5]; 35% [30]; 15% [26]; 10% [7, 13]; 15% [10, 31]; 35% [27, 32]; and 15–30% [14].
Concerning physical characteristics, the densities of the mixtures decreased as the percentage of WFS in the asphalt concrete increased [7, 9, 10, 12, 13, 17, 32]. Percentage of air voids and voids in the mineral aggregate (VMA) were found to increase with blending of increased quantities of WFS [8, 9]. The optimum asphalt content (4.9–6.8%) for HMA mixtures containing various amounts of foundry sand is comparable to the content of mixes not containing foundry sand [14, 17]. The OAC increases with increase in the WFS percentage [13], although Miller et al. [14] found lower values for mixtures containing WFS, in relation to control ones. According to this author, the mixtures obtain the higher percentage of OAC with the WFS with the higher amount of particles passing the #200 sieve. This happens due to the fineness properties of material and increase of surface area [10, 32].
Regarding the mechanical characteristics, the Marshall stability of the asphalt concrete samples containing WFS decreases as the quantity of WFS is increased [3, 6, 7, 8, 10, 12, 29, 32]. The flow values of mixtures decreased with increasing percentage of WFS in the asphalt concrete mixtures [7, 8, 9, 10, 13]. The indirect tensile strengths of the asphalt cement mixtures decreased as the percentage of WFS material was increased [7, 8, 9, 10, 12, 13, 32]. However, Abdulsattar and Mohammed [25] found that all the WFS mixtures that they analysed showed higher tensile strength than the control mixture. According to Tikalsky et al. [17], the level of air voids and saturation greatly influenced the indirect tension values.
In relation to moisture susceptibility, WFS has little effect on top-down fatigue cracking resistance and moisture susceptibility of the mixtures [32]. When WFS replacement is higher than 15%, asphalt mix may become more sensitive to moisture damage (i.e. stripping) due to the presence of silica [10, 27]. WFS, on average, decreases the unconditioned tensile strength and thus the durability of asphalt mixtures; on the other hand, WFS do not necessarily increase or decrease a mixture’s rutting potential but do improve fatigue performance [17].
The experimental procedure of this research contemplates the dosage and physical and mechanical tests on five hot-mixed asphalt concrete (HMAC) mixtures using the conventional Portland cement filler (as reference) and four other mixtures using WFS, replacing the cement gradually in proportions of 25%. This residue was produced by the foundry industrial process of a company located in free-trade zone of Manaus city, Amazon State, Brazil, which produces clutch assembly lines (pressure and friction plates, discs, outer housing, etc.) for the motorcycle industry. Figure 1a shows one of the several kinds of pieces that are produced in that industry, while Figure 1b presents the WFS studied. The annual production of WFS in that industry was about 1500 tons in 2014 (SUFRAMA, 2016). The coarse aggregate (natural pebble) came from the “Japurá” River (an Amazon River affluent) riverbeds and was extracted by dredging, but it was acquired in the local market. The fine aggregate (clean sand) came from mining extraction in the vicinity of the city (about 30–50 km), but it was acquired in the local market as well. The mineral filler used was Portland cement II-Z-32 type. Finally, asphalt cement (AC) 50/70 grading was used, produced by the oil refinery of Manaus (REMAN). The materials used in this research and their respective origins are listed in Table 1.
(a) A piece (to be deburred) produced at the trade zone of Manaus city industry. (b) WFS to be tested.
Material | Origin |
---|---|
Sand | Market of Manaus |
Pebble | Market of Manaus |
Portland cement (PC) II-Z-32 (mineral filler) | Market of Manaus |
Asphalt cement (AC) (50/70 grading) | Oil refinery of Manaus (REMAN) |
Waste foundry sand (WFS) | Industry of free-trade zone of Manaus |
Provenance of HMAC component materials.
All mineral aggregates used in the asphalt mixtures were tested according to the standards described in Table 2, mainly by the Brazilian highway standards, which are most similar to known international standards. In relation to the asphalt cement (AC—50/70 penetrating grading), it was submitted to complete characterisation according to standards shown in Table 3.
Material | Brazilian standard | Title | Acceptance parameters (Brazilian standard) | Similar international standard |
---|---|---|---|---|
Pebble | NBR NM 53/2009 | Coarse aggregate—determination of the bulk specific gravity, apparent specific gravity and water absorption | Greater than 0.88 and 2.00 g/cm3; less than 18%, respectively | ASTM-T-85 |
Pebble | NBR NM 51/2001 | Coarse aggregate—test method for resistance to degradation by Los Angeles machine | Less than 50% | AASHTO-T-96 |
Pebble, Sand, Fillers | NBR NM 248/2003 | Aggregates—sieve analysis of fine and coarse aggregates | Within granulometric range | ASTM-C136/C136M-14 |
Pebble | NBR 12583/1992 | Coarse aggregate—coating to bituminous binder | Qualitative test (visual analysis) | — |
Sand | NBR NM 52/2009 | Fine aggregate—determination of the bulk specific gravity and apparent specific gravity | Greater than 1.60 and 2.60 g/cm3, respectively | ASTM-C128–01 |
Fillers | NBR NM 23/2001 | Portland cement and other powdered materials—determination of density | Greater than 3.00 g/cm3 | ASTM-C188–09 |
WFS | NBR 16137/2010 | Non-destructive testing—material identification by spot test, X-ray fluorescence spectrometry and optical emission spectrometry | — | ASTM-C114–15 |
WFS | — | Wavelength dispersive X-ray fluorescence spectrometry | — | ASTM-C1365 |
Aggregate characterisation tests.
Brazilian standard | Test | Unity | Similar international standard | AC 50/75 |
---|---|---|---|---|
NBR 14756 | Apparent specific gravity, 25°C | g/cm3 | AASHTO T 228 | 1.010 |
NBR 6576 | Penetration, 25°C, 100 g, 5 s | 0.1 mm | AASHTO T 49 | 58 |
NBR 14950 | SSF viscosity, 135°C | s | AASHTO T 72 | 160 |
NBR 15184 | Brookfield viscosity, 135°C, sp21, rpm 20 | cP | AASHTO T 316 | 286 |
NBR 6560 | Softening point | °C | AASHTO T 53 | 53 |
NBR 6293 | Ductility, 25°C | cm | AASHTO T 51 | >120 |
Properties of asphalt cement (AC—50/70 penetrating grading) used in the mixtures.
In order to avoid the presence of impurities, the residue was washed in sieves Nos. 200, 300 and 400, before subjected to characterisation tests and used in asphalt mixtures. The WFS filler was subjected to chemical analysis (XRF) made by an X-Ray spectrometer equipment (720 energy dispersive, Shimadzu), through drying and subsequently pressing the sample in a disc form. The equipment can perform analyses from sodium to uranium, has a rhodium tube and is cooling by liquid nitrogen. Besides that, the WFS filler was also submitted to the X-Ray diffraction (XRD) in order to be characterised its crystalline phases. The equipment used in the analysis was the D8 Focus-Bruker diffractometer, with monochromatic cuprum radiation (CuKα, λ = 1.5418 Å), operating at 35 kV and 40 mA. A laser particle size analyser was used to determine with precision the particle size of both mineral fillers (PC and WFS).
Since the tests were performed 10 years ago, asphalt concrete studies were developed through the traditional Marshall method and not by current Superior Performing Asphalt Pavements (Superpave) methodology. After the characterisation of all components of asphalt concrete, the materials were classified in the “C” granulometric range limits of Brazilian highway specifications following the Marshall dosage method, as shown in Figure 2. The curves obtained fitted in the area defined by the two curve limits of the “C” range, minimum and maximum. After fixing the particle size distribution of aggregates of the mixture, the probable optimum asphalt content (OAC) was estimated by the expression derived from the work of Duriez (1950) based on the specific surface of the aggregates:
XRD analysis for WFS filler.
where S is the specific surface area of aggregate (m2/kg), G is the percentage retained on sieve 9.5 mm, g is the percentage passing on sieve #9.5 mm e retained on sieve 4.8 mm, A is the percentage passing on sieve #4.8 mm e retained on sieve 0.3 mm, a is the percentage passing on sieve #0.3 mm e retained on sieve 0.074 mm and f is the percentage passing on sieve 0.074 mm.
Then, the probable OAC was calculated, using the following expression:
where Tca is the OAC in relation to the mass of the aggregates (%) and m is the richness modulus of AC, varying from 3.75 (wearing course with high stiffness) to 4.00 (wearing course with low stiffness).
If the mean bulk specific gravity of the total aggregate is less than 2.60 or greater than 2.70, then the content obtained in the previous item should be corrected by the following expression:
where T′ca is the corrected OAC in relation to the mass of the aggregates (%) and δam is the mean bulk specific gravity of the total aggregate.
Finally, the OAC is calculated in relation to the entire mixture:
where Pca is the final value of OAC in relation to the total mixture (%).
From that OAC value were adopted two points below it (each 0.5%) and two points above it (each 0.5%).
Five HMAC mixtures were analysed whose grain size proportions are shown inTable 4. The mixture 1 was used as reference, for 100% of Portland cement as mineral filler. The other mixtures used WFS as mineral filler, replacing Portland cement in gradual proportions each 25%. At the end, the results were compared between the mixtures with and without WFS according to the physical and mechanical tests performed.
Oxide | SiO2 | Al2O3 | SO3 | Fe2O3 |
---|---|---|---|---|
Content (%) | 93.68 | 3.97 | 1.66 | 0.41 |
Composition of oxides present in WFS filler.
The experimental procedures were defined as follows, for each mixture [33]: (i) determination of the AC working temperatures from Saybolt-Furol viscosity test in the range of 85 ± 10 and 140 ± 15 SSF for mixing and compaction, respectively; (ii) the components (aggregates + AC) were mixed at a temperature of 146°C for approximately 2 min; (iii) the mix was placed in the Marshall mould and compacted mechanically with 75 blows on each side of the specimen; (iv) the specimen were left at rest for 24 h at room temperature; (v) after that, the specimens were left in a water bath at 60°C for 2 h; (vi) finally, they were placed in the compression mould and submitted to compression in order to determine the rupture load and flow value. Thus, all physical and mechanical parameters of HMAC mixtures were determined by the Marshall method.
From Eq. 4, an initial OAC value of 6.15% for mixture 1 was adopted, with m = 3.75. Nevertheless, the mixture showed excessive fluid, with AC in excess. Hence, OAC = 4.5% was considered. It is noteworthy that three specimens were cast for each AC content to find the final OAC of each the mixture (mixtures 1–5), whose range varied from 3.5 to 5.5%, at each interval of 0.5%. Figure 3a presents the results of OAC for each mixture.
Marshall physical and mechanical characteristics of studied mixtures: (a) optimum asphalt content, (b) bulk specific gravity, (c) air void volume, (d) asphalt-void ratio, (e) Marshall stability and (f) flow value.
After the tests, the Marshall parameters of the mixtures were determined: bulk specific gravity (BSG), theoretical maximum specific gravity (TMG), air void volume (AVV), voids in the mineral aggregate (VMA), voids filled with asphalt (VFA), asphalt-void ratio (AVR), Marshall stability (STA) and flow value (FLV). The optimum contents of AC adopted were those with an AVV value of 4%.
Three samples with cylindrical forms were moulded for the determination of the static indirect tensile strength (ITS) by diametrical compression for each type of mixture, at each OAC. The ITS individual value was obtained through the expression
where σt is the individual static ITS (kPa), T is the static rupture load (kN), r is the sample radius (m) and h is the sample height (m).
Three samples were moulded for determining the resilient modulus (RM) of each mixture. This mixture was then placed in the mould and compacted mechanically with 75 blows on each side of the sample. Then, the specimen were submitted to a repeatedly vertical compression load F at a maximum stress level less than or equal to 20% of the ITS. The RM adopted was the arithmetical mean value determined at 300, 400 and 500 load application F.
Hence, the value of the RM was determined by the expression [33]
where RM is the individual resilient modulus (MPa), F is the cyclic vertical load diametrically applied on specimen (N), δ is the elastic strain recorded for 200, 400 and 500 load applications (mm), h is the sample height (mm) and μ is Poisson’s ratio.
The fatigue test was performed to define the number of loading repetitions as a function of controlled stresses in diametrical compression samples with the load applied at a frequency of 1 Hz, with 0.10 s of repeated loading duration through the same resilient modulus equipment, increasing in tensile strain until the specimen is completely disrupted at a constant temperature of 25°C. The fatigue curve was determined in seven stress levels (7.5, 10, 15, 20, 25, 30 and 40% of the static ITS) with two specimens per level. The fatigue resistance was evaluated according to the fatigue curves generated by testing, which introduces the relationship between fatigue strength and fatigue life. The fatigue equation in this study was calculated using the formula given in the following equation [34]:
where Nf is the fatigue life (in cycles) and σf is the fatigue stress (MPa), i.e. the tension stress applied during the test. The equation provides a linear relationship between them using a bilogarithmic scale, in which “n” is the gradient and “k” is the intercept.
The study of permanent deformation was made using the static creep test applying a static and continuous compression load on a specimen moulded according to the Marshall methodology. The specimen was placed in the axial position and then was subjected to an applied tension of 0.1 MPa, distributed over the entire contact surface of the specimen for a period of 60 min at a temperature of 40°C. The permanent deformations were measured continuously along that time, and then the specimen was discharged, waiting for 15 min for the stabilisation of the viscous deformations, which were measured continuously too. The total strain (Dt) after the recovery period can be obtained as:
where Δh75 is the specimen height change after the final recovery period, i.e. 75 min after the start of the test load (mm), and ho is the specimen initial height taken in the axial direction of loading (mm). Table 5 shows the mechanical tests performed on HMAC mixtures, while Figure 4 presents all tests carried out on components and mixtures.
Brazilian standard | Title | Acceptance parameter (Brazilian standard) | Similar international standard |
---|---|---|---|
DNER-ME 043/1995 | Asphalt mixtures—Marshall test | OAC ≥ 6% STA ≥ 5 kN 3% < AVV < 5% | ASTM D5581-07a |
NBR 16018/2011 | Asphalt mixture—stiffness determination by repeated load indirect tension test | — | ASTM D4123–82 |
NBR 15087/2012 | Asphalt mixtures—determination of tensile strength by diametrical compression | ≥0.65 MPa | ASTM D 6931–17 |
DNER-ME (provisional standard)/2017 | Hot-mixed asphalt concrete—fatigue under repeated loading, constant tension, using the indirect tension test | — | FHWA-Protocol P07/2001 |
— | Standard test methods for tensile, compressive and flexural creep and creep rupture of plastics | Dt ≤ 0.02 mm/mm in 75 min | ASTM D 2990–09 |
Mechanical characterisation tests carried out on HMAC mixtures.
Flowchart of the laboratory tests.
Figure 2 indicates the result of XRD analysis for WFS filler. As shown in the figure, WFS is essentially formed by quartz mineral, as expected. Table 4 shows the composition of the main oxides present in the WFS filler obtained by XRF analysis. The high percentage of silica confirms the XRD analysis of the material [8, 16, 17].Table 6 indicates the physical characteristics of the aggregates. WFS aggregate apparent specific gravity of WFS is very close to conventional aggregates (pebble and sand) [7, 9, 10, 13] each other except for PC. Pebble had a Los Angeles abrasion loss below the maximum allowed by the Brazilian standard, which is 50%. The WFS had 76.25% of its particle sizes passing at #200 sieve and are slightly larger than that of Portland cement, i.e. it is too fine to replace part of the fine aggregate of the asphalt mixes [8, 10, 12], thus demonstrating that the residue could only replace part or total filler fraction.
Aggregate | Apparent specific gravity (g/cm3) | Absorption (%) | Los Angeles abrasion loss (%) | d90 (mm) | d50 (mm) | d10 (mm) |
---|---|---|---|---|---|---|
Pebble | 2.66 | 1.92 | 40.0 | 12.0 | 7.0 | 2.5 |
Sand | 2.63 | — | — | 1.5 | 0.35 | 0.12 |
Filler (PC) | 3.03 | — | — | 0.063 | 0.020 | 0.004 |
Filler (WFS) | 2.65 | — | — | 0.133 | 0.040 | 0.004 |
Physical characteristics of aggregates.
Notes: d90, d50 and d10 are the particle size for which 90, 50 and 10% of the all particles, in mass, are finer than it.
Table 7 shows the resulting granulometric composition of the mineral aggregates with and without the addition of WFS. It is observed that all the mixtures were composed with the same amount of aggregates, varying only the proportion between the two types of the filler fraction. Conventional mixture 1 used PC exclusively, while mixture 2 used WFS as filler exclusively. The other mixtures had variations between permutations of PC and WFS proportions. The grain size distribution of the mineral aggregates, the “C” range maximum and minimum limits of the Brazilian highway specification and the resulting aggregates of mixtures 1 and 2 are shown in Figure 5.
Aggregate | Mixture designation | ||||
---|---|---|---|---|---|
1 (%) | 2 (%) | 3 (%) | 4 (%) | 5 (%) | |
Pebble | 62.0 | 62.0 | 62.0 | 62.0 | 62.0 |
Sand | 33.0 | 33.0 | 33.0 | 33.0 | 33.0 |
Filler (cement) | 5.0 | 0.0 | 3.75 | 2.5 | 1.25 |
Filler (WFS) | 0.0 | 5.0 | 1.250 | 2.5 | 3.75 |
% Total | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 |
Granulometric composition of mineral aggregate mixtures with and without WFS addition.
Grain size distribution and limit curves of mineral aggregates.
Figure 3 shows the main physical parameters of the mixtures, obtained through the Marshall methodology. OAC values of the mixtures containing WFS are comparable to the control in mixture 1 [14, 17]. Mixture 1 obtained the lowest OAC (4.5%), whereas mixtures with WFS had little bit higher OAC values, whose contents increased as WFS proportions were increased too [13]. This reason probably is due to the absorption characteristics of this residue, and not due to the grain size [10, 32], since CP has larger particle size and therefore smaller surface area and thus should consume less AC, at the same proportion of WFS.
It was observed that all five mixtures met the Brazilian standards regarding the physical Marshall parameters (OAC, AVV, VMA and AVR). Mixture 1 had a higher GMB values than all other mixtures with WFS and was therefore the densest. The other mixtures maintained a slight decrease of this parameter, when the proportion of WFS in the mixture was increased [7, 9, 13]. Mixture 2 (100% WFS filler) had the highest amount of AVV and the second largest AVR among all mixtures. AVV values increased when WFS content were increased in the mixtures [8, 9, 10, 32].
High amounts of AVV and AVR tend to negatively influence STA and FLV values, given the viscous characteristic of AC. Thus, mixture 1 showed the best performance, with the highest STA and lowest FLV values. Among the mixtures using WFS, mixture 5 (one fourth WFS + three fourths PC) was the one that presented the highest value of GMB, thus being the densest, and also presented the highest value of STA; however, it had the highest FLV value too. The FLV values of the WFS blends were higher than the PC blends, which characterises a higher AC consumption of these blends. In summary, the use of WFS decreased the stability of blends [6, 8, 10, 12, 32] while increasing their fluency. This latter is in disagreement with that observed by the author cited previously. Even so, all mixtures showed STA values higher than the minimum required (>5 kN).
There was a certain tendency that static ITS values will decrease as WFS content increased [7, 9, 10, 13, 32]. Mixtures 3 and 5 presented higher values of this parameter than control mixture 1 [25]. All asphalt mixtures presented values above the minimum value of the Brazilian standard (>0.65 MPa). This is a good indication for durability of the mixtures since fatigue life is a function of ITS. There was not an apparent correlation between AVV and static ITS values (Figure 6).
Mechanical characteristics of studied mixtures: (a) static indirect tensile strength, (b) resilient modulus, (c) RM/ITS ratio and (d) total strain (static creep).
The use of WFS decreased the RM values. Mixture 1 presented the highest value, followed by mixture 2. In Brazil, the relationship between RM and static ITS (RM/ITS) has been used as an analysis parameter to evaluate the behaviour of asphalt mixtures related to fatigue life. As a rule, mixtures with RM/ITS ratio around 3000 exhibit good structural behaviour because they allow the use of thinner asphalt wearing layers for the same fatigue life; that is, they characterise mixtures that are not susceptible to early development of permanent deformations because they are not rigid enough. In this sense, mixture 3 was the only one that met this criterion. On the other hand, the conventional mixture 1 presented the highest value of this ratio, thus indicating a more rigid behaviour.
Figure 7 shows the comparison between asphalt mixtures in relation to the stress-controlled fatigue test. For the acquisition of fatigue curves, the average value of the RM and the static ITS of each mixture were used. Between Mixtures 1 and 4, the best-fitting straight lines were very close to each other, with a parallelism between the line slopes, and both mixtures can be considered to have practically the same fatigue life. Mixture 2 presented the shortest fatigue life, while mixture 5 presented the longest fatigue life, standing out among the others. For applied stress differences up to 0.4 MPa, Mixtures 1, 2 and 4 behave similarly.
Fatigue life for the mixtures with and without WFS content.
It should be noted that mixture 5 presented the second best ITS result and the second closest value of the RM/ITS ratio around 3000, thus justifying the use of this parameter as a quantitative indicator of fatigue life of asphalt mixtures. The fatigue life test on mixture 3 was not performed.
Regarding the permanent deformation, Mixtures 2 and 3 presented lower values than mixture 1, while mixture 5 presented the highest value among the others. There was no direct relationship with AVV, since, of all of them, mixture 5 presented the lowest value of voids. Mixture 3 presented the lowest value of permanent deformation, confirming again the good indicative of the RM/ITS ratio around 3000 in predicting the behaviour of asphalt mixtures for fatigue and permanent deformations. All mixtures presented permanent deformation values below the conventional criterion of 0.020 mm/mm and do not have the tendency to be susceptible to premature permanent deformations.
This work analysed five asphalt mixtures, one using 100% CP as a filler and the other four using WFS, with a maximum proportion of 5% (by weight) of the total aggregate. The WFS residue used consisted of almost 94% silica, without organic compounds, with apparent specific gravity similar to clean sand and slightly coarser than CP.
All mixtures with WFS residue presented physical and mechanical parameters within the Brazilian standards, following the Marshall methodology, although with lower STA and higher FLV values. The use of WFS increased static ITS values, while decreased MR values. The mixtures with WFS showed total permanent deformation values less than 2% after 75 min of the test. The RM/ITS ratio around 3000 proved to be a good indication of mixtures with better performance against fatigue life and permanent deformation.
Finally, the use of WFS as a mineral filer in asphalt mixtures proved to be adequate, meeting the criteria of Brazilian standards in physical and mechanical tests.
The authors would like to thank Prof. Dr. Laura Maria Goretti da Mota, from Pavement Laboratory of COPPE/Federal University of Rio de Janeiro (UFRJ), for some laboratorial tests carried out in that place. This work was supported by the CNPq [grant number 620244/2008-9]; FAPEAM [scholarship].
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\n\nWhat isn't covered by the Open Access Publishing Fee?
\n\nIf your manuscript:
\n\nYour Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\nOpen Access Funding
\n\nTo explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at oapf@intechopen.com for further details or assistance.
\n\nFor Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\nAdded Value of Publishing with IntechOpen
\n\nChoosing to publish with IntechOpen ensures the following benefits:
\n\nBenefits of Publishing with IntechOpen
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