\r\n\tBoth diagnosis and clinical manipulation of the patient with vasospasm is a unique and challenging situation. Multi-clinical approach is extremely mandatory. The patient must be treated in a center, which requires a experienced team with both neurological surgeons, interventional radiologists, neurologists and neuroanesthesiologists. Moreover, a well-equiped, isolated neurointensive care is needed for all patients suffering form subarachnoid hemorraghe. \r\n\tIn their daily practice, both neurological surgeons, interventional radiologists, neurologists, neuroanesthesiologists, and even intensive care providers have to deal and challenge of vasospasm. Numerous studies relevant to pathophysiological mechanisms underlying vasospasm had been published, but we still know little about the exact mechanisms causing vasospasm. In the last decades of modern medical era, despite the technological developments concerning the neurological care of the patients with vasospasm, we still have no effective treatment and preventive care of this devastating entity. \r\n\tThe aim of this book project is to provide in detailed knowledge to both physicians and scientists dealing with cerebral vasospasm. This book will attract interest of both students, residents, specialists and academics of neurological sciences.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"1a824e678bcab74178b208a6bb6f6bb5",bookSignature:"Dr. Bora Gürer",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/9448.jpg",keywords:"vasospasm, cellular responses, vascular tone, blood breakdown products, biogenic amins, electrolytes, transcranial doppler, digital subtraction angiography, cerebral blood flow studies, nitrovasodilators, free radical scavengers, calcium channel blockers, endothelin based approaches, balloon angioplasty, medical angioplasty, microneurosurgery, intraoperative manipulations",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"August 19th 2019",dateEndSecondStepPublish:"September 9th 2019",dateEndThirdStepPublish:"November 8th 2019",dateEndFourthStepPublish:"January 27th 2020",dateEndFifthStepPublish:"March 27th 2020",remainingDaysToSecondStep:"a year",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"95341",title:"Dr.",name:"Bora",middleName:null,surname:"Gürer",slug:"bora-gurer",fullName:"Bora Gürer",profilePictureURL:"https://mts.intechopen.com/storage/users/95341/images/system/95341.jpg",biography:"Bora Gurer is currently affiliated to Department of Neurosurgery, University of Health Sciences, Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey. 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1. Introduction
The onset of leaf senescence is a highly regulated developmental program that is controlled by both genetics and the environment. Multiple stresses in plants induce programmed cell death, and the underlying regulatory mechanisms are often associated with molecular links of developmentally programmed senescence. The transcriptome changes induced by different environmental stressors are not entirely overlapping, but functional analysis of genes commonly induced as shared responses can give clues on signaling integration. This approach has been used to select for overlapping genes as candidate regulatory components that integrate the ER stress and osmotic stress responses, which were shown later to participate also in natural leaf senescence. Among genes identified as components of the ER and osmotic stress shared response, the developmental and cell death (DCD) domain-containing asparagine-rich proteins (NRP-A and NRP-B) were the first ones to be characterized as cell death-promoting proteins, and hence this multiple stress-integrating signaling was designated as stress-induced DCD/NRP-mediated cell death response. Further characterization of the cell death pathway implicated in the discovery of the signaling module ERD15/NRPs/GmNAC81:GmNAC30/VPE that also has been shown to operate in developmentally programmed leaf senescence. This plant-specific cell death signaling module, which operates in both stress-induced and natural leaf senescence, constitutes the primary focus of this chapter.
2. Modest overlapping of ER stress and osmotic stress response identifies NRPs and NACs as cell death-promoting genes
2.1 Osmotic stress responses
Organisms, in general, are continually adapting to internal and external stimuli, which activate sensor proteins to subsequently transmit the signal to downstream effectors responsible for the assembly of adaptive cellular responses [1]. Abiotic stresses consist of a set of adverse environmental conditions that limits plant development. Cold, high temperature, salinity, water availability (drought or overflow), radiation, pollution, and chemical exposure are the most common examples of types of abiotic stresses [2].
Generally, a signaling sensor network connects internal and external stimuli to adaptive responses leading to molecular modifications that allow physiological adjustments, which ultimately cause susceptibility or tolerance to the exposed conditions. Molecular responses to abiotic stress conditions in plants are crucial for survival and productivity as these stresses often limit yield. Among abiotic stresses, drought and excess salinity conditions induce sophisticated adaptive responses in plants to cope with or acclimate to these adverse environmental conditions [3, 4]. Some types of abiotic stress responses are better understood than others. In plants, for example, the molecular mechanisms of perception and responses to drought, high salinity, and endoplasmic reticulum stress are well characterized, and many stress-related cell signaling pathways are completely elucidated, revealing some convergence points between them.
The osmotic stress in plants, caused by water deprivation or high salinity, for example, undergoes a set of characteristic morphological, molecular, and physiological changes. One of the most notorious symptoms in plants under low water availability is the ABA-mediated stomatal closure [5]. This hormone-mediated morphological change affects plant physiology. The stomatal closure prevents the evapotranspiration, optimizing the cell water use, but it also compromises carbon dioxide uptake, causing imbalances on photosynthetic apparatus, which culminates on reactive oxygen species (ROS) production [6, 7]. The ROS accumulation acts as a signal to the cell, which triggers mechanisms of ROS-associated detoxification, including upregulation of antioxidant enzymes, osmolyte, and electron-carrier synthesis [8]. There is evidence that osmotic stress and temperature changes are capable of generating lipid-derived signal transducers, including the phosphatidic acid, phosphoinositides, sphingolipids, lysophospholipids, oxylipins, N-acylethanolamines, and others. Water deprivation causes a collapse on the organization of membrane lipids, disrupting its permeability and some significant molecular interactions between lipids and proteins, which act as a cell signal to stress-mediated physiological changes. The mechanisms of how stress responses are connected with membrane lipid transducer generation are still unclear, but lipid messengers can alter protein and enzymatic functions [9].
2.2 ER stress responses
The endoplasmic reticulum is one of the most dynamics organelles in cell machinery. It is the gateway for the synthesis of secretory proteins and contains the necessary apparatus to ensure quality protein synthesis, protein maturation, and secretion in eukaryotic cells [10]. Furthermore, the ER can modulate some chronic stress-related pathways, promoting oxidative stress, autophagy, and apoptotic cell death in mammals and plant cells [11, 12, 13].
Several adverse environmental conditions can affect the ER quality control machinery, causing unfolded/misfolded protein accumulation in the ER lumen. The secretory proteins are synthesized in ER membrane-bound polysomes, and, as soon as they enter the organelle, they are processed by the ER processing machinery. Under normal conditions, there is a perfect balance between the rate of protein synthesis and ER processing capacity. Any conditions that disrupt this balance promote unfolded/misfolded protein accumulation in the ER lumen. As a consequence, the perturbation on ER function triggers a sophisticated and coordinated signal cascade, perceived by ER membrane-associated sensors, which activate the expression of ER-resident chaperones, foldases, and components of the ER quality control machinery. Collectively, these cytoprotective mechanisms are known as the unfolded protein response pathway (UPR, Figure 1) [14].
Figure 1.
The endoplasmic reticulum stress response in Arabidopsis. The secretory proteins are synthesized in ER-bound polysomes (1) attached to the ER membrane through the interaction of signal recognition particle (SRP) and membrane receptor. As soon as they enter the lumen of the organelle, they are bound to a series of molecular chaperones, including BiP, to assist correct folding (2). Upon ER stress, the accumulation of unfolded protein (UP) activates a protective signaling cascade, designated as unfolded protein response, which allows communication of ER with the nucleus via a bipartite signaling module: the bZIP28/bZIP17 and IRE1a/IRE1b-bZiP60 signaling modules. Under normal conditions, BiP is bound to bZIP28/17, keeping the transducer in an inactive configuration (4). Upon ER stress, UP causes the dissociation of BiP from bZIP28/bZIP17, which is, then, translocated to the Golgi (5), where it is proteolytically cleaved to release the bZIP28/bZIP17 domain from the membrane that, in turn, is translocated to the nucleus (6). UP accumulation also causes the oligomerization of IRE1a/IRE1b, subsequent activation of its kinase domain by phosphorylation, and the endonuclease activity (6). The activated IRE1a/IRE1b endonuclease domain promotes unconventional splicing of bZIP60 mRNA to remove a transmembrane motif-encoding fragment, generating bZIP60 spliced mRNA that is translated into a soluble bZIP60 protein (bZIP60s) (7), which otherwise would be translated into the membrane-associated bZIP60us as it occurs under normal conditions. bZIP60s is, then, translocated to the nucleus (8), where it cooperates with bZIP28/bZIP17 to upregulate UPR genes and ERAD-related genes, increasing the ER protein processing capacity under ER stress to promote recovery (9). However, if the stress persists, and ER homeostasis cannot be restored, cell death signaling pathways are activated. among them, the DCD/NRP-mediated cell death signaling is initiated with activation of AtNRP1 (10) that leads to the induction of AtNRP2 and activation of a signaling cascade that culminates with the induction of ANAC36 that binds to the VPE promoter (11) and induces the expression of VPE, the executioner of the cell death program via collapse of the vacuole. These ER stress signaling pathways are conserved in other plant species.
The detection of ER stress is mediated by membrane-associated sensors, identified both in mammals and plants. In mammals, there are three of these sensors: kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK) [15], which are regulated by the ER-resident molecular chaperone BiP (binding protein). The ER sensors initiate the UPR to restore ER homeostasis under stress condition. If the adverse physiological status is prolonged, they can initiate some alternative routes leading to cell death.
Under normal conditions, BiP is bound to the luminal domain of these receptors, keeping them inactive. With the stress progression and consequent misfolded protein accumulation, the BiP molecular chaperone function is required to prevent aggregation of the unfolded proteins. Therefore, under these stress conditions, BiP is released from the ER receptors, which leads to their activation. The three ER signal transducers act in different ways, but in convergent stress-responsive pathways. IRE1 (IRE1a and IRE1b) displays a dual biochemical activity. It harbors a ribonuclease and kinase activity at the C-terminus, responsible for the unconventional spliceosome-independent splicing of X-box binding protein 1 (XBP1) mRNA. Stress-mediated BiP release from the IRE1 N-terminus promotes IRE1 homodimerization, which sequentially activates its kinase via autophosphorylation and endoribonuclease activity, culminating on spliceosome-independent splicing of XBP1, a bZIP transcriptional factor. Under normal conditions, the XBP1u (unspliced form) is constitutively translated into a low-functional transcription factor, which is rapidly degraded by the proteasome and does not effectively activate UPR. The IRE1-mediated mRNA splicing removes an unconventional intron of 26 nucleotides, which causes a shifting frame in XBP1 mRNA translation, generating a protein of 376 amino acids instead of 261 amino acids when unprocessed. This unconventional splicing seems to prevent the degradation of XBP1s (spliced form) product by the proteasome and increase its transactivation activity, causing activation of UPR-related genes [16, 17]. Thus, the XBP1s is a soluble and functional transcription factor, which is reallocated to the cell nucleus to activate genes involved in cytoprotective pathways, such as some members of ER quality control or programmed cell death-related genes, including the apoptotic signaling kinase 1 (ASK1) and Jun-N-terminal kinase (JNK) [16, 17, 18, 19].
The ER signal transducer ATF6 is anchored to the ER membrane and harbors an N-terminal sensor domain facing the ER lumen and a C-terminal bZIP domain facing the cytosolic side. Under normal conditions, ATF6 is inactivated by BiP binding to the ER stress sensor domain. ER stress conditions promote the BiP disassociation and reallocation of ATF6 to the Golgi apparatus, where it is specifically processed by SP1 and SP2 proteolytic enzymes. The limited proteolysis of ATF6 transmembrane domain allows that the bZIP domain of ATF6 be directed to the nucleus, where it acts in concert with XBP1 to induce genes involved in ER protein processing, ER quality control, and ER-associated protein degradation (ERAD) pathway. Finally, the PERK activation upon BiP release by stress conditions promotes global translation suppression through the phosphorylation of the translation initiation factor IF2α [20]. PERK also activates the transcription factor CHOP, involved in the regulation of apoptosis-related genes [10, 21].
In plants, the UPR pathway has, at least, two arms (Figure 1). The first one activates IRE1 (IRE1a–AT2G17520 and IRE1b–AT5G24360, in Arabidopsis thaliana), and the other is transduced through bZIP membrane-associated transcription factors (bZIP17–AT2G40950 and bZIP28–AT3G10800, in Arabidopsis thaliana) [22, 23]. In the first arm of plant UPR, like in mammals, the accumulation of misfolded proteins leads to the activation of IRE1, which promotes unconventional cytosolic splicing of bZIP60 mRNA [24]. The unspliced bZIP60 mRNA, called bZIP60us, is translated into an ER membrane-associated transcription factor and does not exhibit transcriptional activity. Upon IRE1 activation by UPR, the spliced bZIP60 mRNA, called bZIP60s, does not display the transmembrane domain coding region, and its translation generates an active transcription factor, which is reallocated to the nucleus to activate UPR and cytoprotective genes, such as BiP3, CNX (calnexin), CRT (calreticulin), etc. [24, 25, 26]. This mechanism is conserved among plants, as the rice (Oryza sativa) bZIP60 orthologs, OsbZIP74 or OsbZIP50, display similar IRE-mediated mRNA splicing to render the activation of ER stress-inducible promoters [27, 28]. Likewise, in maize (Zea mays), ZmbZIP60 mRNA splicing leads to the activation of ER stress-inducible promoters [29], and, in soybean (Glycine max), the ZIP60 ortholog GmbZIP68 harbors a canonical site for IRE1 endonuclease activity and is efficiently spliced under ER stress conditions to activate UPR genes [30].
The second arm of plant UPR pathway is mediated by posttranslational modification of bZIP17 and bZIP28 transcription factors, the functional analogs of ATF6. Both bZIP17 and bZIP28 display a canonical SP1 site in their C-terminal domain, facing the ER lumen [31]. Upon stress conditions, BIP is released from the bZIP28 and bZIP17 ER sensor domain, and the transcription factors are reallocated from the ER to the Golgi apparatus, where they are processed by SP1 and SP2 proteases. These proteases remove the transmembrane domain of bZIP17 and bZIP28, exposing their cytosolic regions, which will activate UPR-related genes in the nucleus [31, 32, 33, 34]. Like the IRE1/bZIP60 signaling module of plant UPR, the bZIP28/bZIP17 arm triggers the evolutionarily conservative UPR but also accommodates cross-talk with several other adaptive signaling responses [24, 30, 31]. In summary, upon ER stress, bZIP60s and bZIP28 use a different mechanism to be translocated to the nucleus where they act in concert to induce the expression of UPR genes and ERAD-related genes to increase the ER protein processing capacity for recovery from stress.
2.3 Convergence of ER stress and osmotic stress responses into a cell death signaling pathway
At a physiological level, the UPR encompasses three protective mechanisms: (i) global translation suppression by PERK-mediated IF2α phosphorylation; (ii) upregulation of ER-resident molecular chaperones, and (iii) proteasome-mediated protein degradation by ERAD pathway. However, if the stress conditions are sustained and the UPR pathway fails to restore ER homeostasis, apoptotic pathways are triggered as an ultimate attempt to survive. In plants, there is a specific branch of ER stress that integrates the osmotic stress and leads to programmed cell death (PCD), the development and cell death domain-containing N-rich protein (DCD/NRP)-mediated cell death signaling (Figure 1) [12]. This cell death pathway was first identified via genome-wide and expression profiling approaches, which revealed a modest overlapping between ER and osmotic stress-induced transcriptomes of soybean seedlings treated with PEG (an osmotic stress inducer) and tunicamycin and AZC (ER stress inducers). Several genes displayed similar kinetics and a synergistic induction under combined ER and osmotic stresses, indicating that the ER stress response integrates the osmotic signal to potentiate transcription of shared target genes. Among them, two plant-specific DCD/N-rich proteins, NRP-A and NRP-B, an ubiquitin-associated protein homolog (UBA), and a NAC domain-containing protein, GmNAC81, displayed the most robust synergistic upregulation by the combination of both stresses [35]. Transient expression of NRPs or GmNAC81 in soybean protoplasts and Nicotiana benthamiana leaves demonstrated that they are critical mediators of ER stress- and osmotic stress-induced cell death in plants [36, 37, 38].
The NRP-A and NRP-B display a highly conserved DCD domain at their C-terminal protein region and a high number of asparagine residues at their more divergent N-terminus (Figure 2) [39]. Consistent with the presence of a DCD domain, overexpression of NRPs in soybean protoplasts induces caspase-3-like activity and promotes extensive DNA fragmentation. Furthermore, transient expression of NRPs in planta causes leaf yellowing, chlorophyll loss, malondialdehyde production, ethylene evolution, and induction of the senescence marker genes, which are hallmarks of leaf senescence and cell death [36, 38, 40]. The cell death response mediated by NRPs resembles a programmed cell death event. Because NRPs were the first components of the ER stress and osmotic stress-integrating cell death response to be characterized, this signaling pathway is commonly referred to as the DCD/NRP-mediated cell death response.
Figure 2.
Schematic representation of the cell death pathway components. The predicted domains of each protein are highlighted. The indicated domains are delimited by the amino acid positions in the primary structure shown by the numbers. For ERD-15, PAM2 is a PABP-interacting motif, PAE2 is PAM2-associated element 1 motif, DEDEKERKEGKEV is a conserved sequence representing a putative motif of ssDNA-binding transcriptional regulators, and QPR is a highly conserved C-terminal QPR motif. As for GmNAC81, GmNAC30, and ANAC36, the N-terminal NAC domain is subdivided into five conserved motifs (A to E) as indicated. In the AtNRP1, AtNRP2, NRP-A, and NRP-B schemes, DCD is development and cell death domain.
Similar to NRPs, GmNAC81 (Glycine max NAC81, formerly designated as GmNAC6) is another target of the ER stress- and osmotic stress-integrating pathway that induces a senescence-like response in planta and cell death in soybean protoplasts [37, 41]. GmNAC81 belongs to the plant-specific transcriptional factor superfamily of domain-containing proteins, represented by 111 members in Arabidopsis, 151 in rice, 152 in maize, and 180 in soybean [42, 43]. Members of this family function in development and stress response. The NAC transcriptional factors display a highly conserved N-terminal domain, called NAC domain, responsible for recognition of cis-regulatory elements on target promoters and DNA binding (Figure 2). The C-terminal domain is more divergent in sequence but is undoubtedly responsible for transcriptional activity [44, 45]. In addition, a subset of NAC proteins, which also exhibits protein binding activity, harbors an additional transmembrane domain present in the membrane-tethered NAC proteins [43, 46, 47].
NRPs and GmNAC81 are induced by several different abiotic and biotic stresses in a coordinated manner, but induction of NRPs precedes the upregulation of GmNAC81. This early induction kinetics of NRPs is consistent with its capacity to activate the promoter and induce the expression of GmNAC81. These data placed GmNAC81 downstream of NRPs in the ER and osmotic stress-induced cell death pathway [37]. More recently, using reverse genetics in Arabidopsis, NRPs were confirmed to be upstream of ANAC36, the Arabidopsis ortholog of GmNAC81, in the DCD/NRP-mediated cell death signaling [40].
3. Early dehydration responsive gene 15, ERD15-like, controls NRP expression
The early dehydration responsive (ERD) genes were first identified due to their rapid induction in response to drought stress. The ERD genes (ERD1 to ERD16) encode a set of proteins that differ in biological functions and cell localization [48]. Among them, ERD15 is a small acidic and hydrophilic protein that belongs to the PAM2 domain-containing protein family (Figure 2). The PAM2 domain is a well-characterized protein–protein interaction domain, which allows ERD15 to interact with polyA-binding proteins (PABP) regulating mRNA stability and protein translation [49]. In addition to PAM2, ERD15 contains two other domains with unknown function, designated as PAM2-associated element 1 (PAE1) and QPR.
ERD15 is a multiple stress-responsive gene that is involved in adaptation to abiotic and biotic stress. Light treatment, cold stress, and high salinity trigger ERD15 expression [50, 51]. ERD15 functions as a negative regulator of the abscisic acid (ABA)-mediated response and a positive regulator of the salicylic acid (SA)-dependent defense pathway. ERD15-overexpressing transgenic lines are less sensitive to ABA and display enhanced salicylic acid-dependent defense pathway, which was associated with increased resistance to the bacterial Erwinia carotovora of the transgenic lines [52].
Consistent with the multiple stress-responsive expression profiles, the soybean ERD15 ortholog (GmERD15) is also induced by ER and osmotic stress. GmERD15was identified using one hybrid screening that targeted the NRP-B promoter in yeast. As an upstream member of the NRP-mediated cell death response, GmERD15 binds the NRP-B promoter region in vivo and in vitro and induces the NRP-B expression [53]. Despite its role as a transcription factor, GmERD15 does not harbor a typical DNA-binding motif, but instead, it contains a conserved sequence of 13 amino acids at positions 71–83 (DEDEKERKEgKEv), which is a part of a tripartite motif domain derived from ssDNA-binding transcriptional regulators [54]. Accordingly, the GmERD15 binding site was mapped to a 12-bp palindromic sequence −511AGCAnnnnnTGCT−500 on the NRP-B promotor in both single-stranded and double-stranded configurations [53].
4. The stress-induced NRP/NAC081/VPE module transduces a cell death signal
As components of the DCD/NPR-mediated cell death signaling, NRPs and GmNAC81 are critical mediators of cell death derived from ER stress and osmotic stress signals. More recent progress toward deciphering this branch of stress-induced cell death signaling includes the identification of two additional downstream components, the NAC transcriptional factor (GmNAC30) and the vacuolar processing enzyme (VPE) [55].
GmNAC30 was identified as a nuclear partner of GmNAC81 via two-hybrid screening using GmNAC81 as a bait. GmNAC30 and GmNAC81 exhibit similar expression profiles and cell death activity. They are upregulated by ER stress, osmotic stress, and by the cell death-inducer cycloheximide. Consistently, GmNAC30 promotes cell death when transiently expressed in soybean protoplasts and, as a downstream component of the cell death signaling, is induced by expression of NRP-A and NRP-B.
GmNAC30 interacts with GmNAC81 in vitro and in vivo, the complex formed binds to common cis-regulatory sequences in target promoters and synergistically regulates hydrolytic enzyme promoters, including the caspase-1-like vacuolar processing enzyme (VPE) gene, which is involved in PCD in plants [55]. Consistent with their transcriptional function as a heterodimer, GmNAC81 and GmNAC30 display overlapping and coordinate expression profiles in response to multiple environmental and developmental stimuli. Therefore, the stress-induced GmNAC30 cooperates with GmNAC81 to activate PCD through the upregulation of the cell death executioner VPE.
VPE is a vacuole-localized cysteine protease that exhibits caspase-1-like activity and hydrolyzes a peptide bond at the C-terminal side of aspartate and asparagine residues [56]. It is synthesized as an inactive preprotein precursor, which is self-catalytically converted into the active mature form, under a processing step that resembles the activation of caspase 1 (Figure 2). It has been associated with Tobacco mosaic virus-induced hypersensitive cell death and developmental PCD [57, 58]. As an executioner of a cell death program, VPE is self-activated by hydrolytic cleavage and, in turn, mediates the initial activation of vacuolar enzymes, which degrade the vacuolar membrane and initiate the proteolytic cascade leading to PCD. Therefore, VPE activation may result in vacuolar collapse-mediated cell death, a type of plant-specific programmed cell death.
The discovery of VPE as a downstream target of the coordinate action of GmNAC81 and GmNAC30 underlies a mechanism for the execution of the ER and osmotic stress-induced cell death program (Figure 1). This model holds that prolonged ER and osmotic stresses induce the expression of the transcriptional activator GmERD15 to target the NRP promoter. The upregulation of NRPs initiates a transduction signaling that leads to the induction of GmNAC81 and GmNAC30, which cooperate to activate the VPE promoter and expression. Activation of VPE promotes the disintegration of vacuoles, initiating the proteolytic cascade in plant PCD. As vacuole-triggered PCD is unique to plants, the regulatory circuit linking the stress signal to activation of VPE is fundamentally composed of plant-specific signaling components.
The DCD/NRP-mediated programmed cell death pathway is conserved and operates with similar regulatory mechanisms in plants [40]. Soybean prototypes of each component of the cell death pathway were used to search for orthologs in the Arabidopsis genome (Figure 3) [30]. Arabidopsis AtNRP1 is most closely related to GmNRP-A and GmNRP-B, whereas a third homolog GmNRP-C was related to AtNRP-2. GmNAC81 and its paralog share sequence conservation with the Arabidopsis ortholog ANAC36 (At2G17040), whereas the predicted Arabidopsis ortholog of soybean VPE was identified as At4G32940/γVPE. Transient expression of the selected Arabidopsis orthologs of pathway components (AtNRP-1, AtNRP-2, ANAC36, and γVPE) induces cell death in Nicotiana benthamiana leaves with the appearance of hallmarks of PCD and leaf senescence, including DNA fragmentation, leaf yellowing, chlorophyll loss, and lipid peroxidation [38]. In addition, knockout lines for each one of pathway genes in Arabidopsis display enhanced tolerance to ER stress-mediated cell death induction. Very importantly, the stress induction of AtNRP2, ANAC36, and γVPE was dependent on the AtNRP1 function, confirming the upstream position of AtNRP1 in the cell death pathway. Therefore, in Arabidopsis, the execution of the cell death program has been proposed to occur through AtNRP1-mediated induction of the AtNRP2-ANAC36-γVPE signaling module. Nevertheless, functional information about the GmERD15 and GmNAC30 orthologs in Arabidopsis is lacking, and these pathway components have not been identified yet in Arabidopsis. Both in soybean and Arabidopsis, the DCD/NRP-mediated cell death pathway is modulated by the ER-resident molecular chaperone BiP, which negatively regulates the gene expression and activity of these cell death-inducing genes [13, 40].
Figure 3.
Integration of developmental signal and stress signals into the DCD/NRP-mediated cell death response. Leaf senescence, ER stress, and osmotic stress induce the expression of ERD15-regulated NRP-A that in turn upregulates NRP-B to initiate a signaling cascade that culminates with the induction of GmNAC30 and GmNAC81 expression. The NAC transcription factors form a heterodimer to fully induce the activation of VPE promoter, which leads to VPE upregulation and subsequent execution of a cell death program. The ER-resident molecular chaperone BiP acts as a negative regulator of cell death by modulating the expression and activity of the cell death pathway components. The DCD/NRP-mediated cell death signaling is conserved in other plant species, and the Arabidopsis orthologs are shown on the right.
5. A negative regulator of the NRP/NAC081/VPE signaling module confers tolerance to drought
Plants can negatively modulate the NRP/DCD-mediated cell death response to suit the cellular balance during the stress conditions. Moreover, this modulation improves the cellular stableness and consequently increases the plant tolerance to stress conditions in an essential process that is required for plant acclimatization and development. The molecular chaperone BiP plays a crucial role as a negative regulator of NRP/DCD-mediated cell death response. BiP belongs to the HSP70 family, which is essential to protect the cells against environmental stresses and to restore the cell homeostasis [59].
The molecular chaperone BiP has a catalytic site at the amino-terminal region and a substrate-binding site at the carboxy-terminal region [60]. BiP is involved in the regulation of several processes in the endoplasmic reticulum, a critical organelle that is related to responses to abiotic and biotic stress in plants. In the ER, BiP acts as a sensor that responds to quantitative and qualitative changes in the ER by regulating the activity of ER stress transducers [61]. Furthermore, BiP coordinately regulates the cell death signaling, which connects the signals from osmotic and ER stress in a DCD/NRP-dependent manner [35, 36, 38].
BiP attenuates the NRP/DCD-mediated cell death signal propagation by the modulation of expression and activity of the pathway signaling components (Figure 3). BiP overexpression in soybean attenuates ER stress- and osmotic stress-mediated cell death, a phenotype that is linked to a delay in the induction of GmNRP-A, GmNRP-B, and GmNAC81 under ER stress and osmotic stress [38]. Furthermore, enhanced accumulation of BiP in tobacco (Nicotiana tabacum) prevents the GmNRP- and GmNAC81-mediated induction of cell death-associated physiological and molecular markers, whereas silencing of endogenous BiP enhances the cell death response.
In addition to alleviating ER and osmotic stress-mediated cell death, the BiP overexpression in plants has also been shown to increase their tolerance to water deficits [62, 63, 64]. Enhanced accumulation of BiP in soybean, tobacco, and Arabidopsis promotes a delay in drought-induced senescence and wilting of leaves leading to a higher survival rate of overexpressing lines under water-deficit regimes [12, 38, 40, 63, 64]. The BiP-mediated tolerance mechanism is not associated with conventional mechanisms of drought tolerance and avoidance, as the BiP-overexpressing lines do not display lower photosynthesis and transpiration rates than untransformed lines under drought, and the stomata closure and root growth are not stimulated under water deprivation. Furthermore, the BiP-overexpressing lines exhibit a lower induction of drought-related genes than WT under water-deficit conditions, and the abscisic acid content in BiP-overexpressing plants is similar to untransformed lines, indicating that the BiP-mediated drought tolerance mechanism is independent on ABA [59, 64, 65]. Under drought conditions, the only variations observed in BiP-overexpressing lines are a delay in drought-induced leaf senescence and an attenuation in the drought induction of PCD-associated marker genes, which is associated with the protective function of BiP as a negative modulator of the DCD/NRP-mediated cell death response. A metabolomic approach was used to detect the metabolite profile of BiP-overexpressing lines under drought conditions [65]. Due to a higher osmolyte accumulation, mainly amino acids, the BiP-overexpressing plants can maintain the leaf turgidity upon drought stress, which is a phenotypic hallmark of the BiP-mediated tolerance to drought. The BiP-overexpressing lines also display a higher accumulation of salicylic acid and upregulation of SA-responsive genes, which is associated with accelerated hypersensitive response triggered by Pseudomonas syringae pv tomato in soybean and tobacco [59, 65]. The SA signaling also activates the antioxidative metabolism, which may be linked to the BiP protective function to drought. Very importantly, the BiP modulation of the DCD/NRP-mediated cell death response does not impair the plant growth and development.
6. The stress-induced DCD/NRP-mediated cell death signaling positively regulates leaf senescence
Leaf senescence is a natural process in plant development, which begins with a physiological transition between active photosynthetic leaves to degenerative and nutrient-recycling leaves. The classical age senescence-related symptom is the leaf yellowing caused by generalized chlorophyll loss. The age-induced senescence or naturally programmed leaf senescence, hereafter referred to as leaf senescence, occurs by plant aging and is precisely regulated by senescence-associated genes (SAGs) [66, 67].
Many SAGs are environmental- and stress-responsive genes, integrating a convergent regulatory cascade between natural plant development and stress-induced PCD [68]. At the molecular level, the onset of senescence is accompanied by a massive reprogramming of gene expression, probably controlled by senescence-associated transcription factors. Among these, several NAC transcription factors have been associated with senescence regulation based on high-resolution temporal expression profiles [69].
In soybean, a transcriptomic analysis of senescing leaves reveals that 44% of the GmNAC genes were differentially expressed at the onset of leaf senescence. The most representative subfamilies of soybean senescence-associated NAC genes were the abiotic stress-induced SNAC-A (ATAF) subfamily, in which 90% of the members were differentially expressed during senescence, followed by the biotic stress-induced TERN subfamily, displaying 80% of the members differentially expressed during leaf senescence [43]. GmNAC30 and GmNAC81, which belong to the SNAC-A and TERN subfamilies, respectively, are among the upregulated genes by leaf senescence [43, 59]. These results raise the hypotheses that the (i) DCD-NRP/NAC/VPE signaling module may integrate stress-induced with natural leaf senescence and (ii) other NAC genes may be involved in integrated circuits between age- and stress-induced cell death pathways.
Regarding the first hypothesis, several lines of evidence indicate that the regulatory circuit NRPs/GmNAC81:GmNAC30/VPE integrates osmotic stress- and ER stress-induced PCD response with natural leaf senescence. First, not only GmNAC30 and GmNAC81 but also the other cell death pathway components, NRP-A, NRP-B, and VPE, are induced by leaf senescence [43, 59, 70]. Second, the activity of VPE is also induced during the onset of leaf senescence [59]. Third, transient expression of the soybean components of ER stress- and osmotic stress-induced cell death response, NRP-A, NRP-B, GmNAC81, and GmNAC30, as well as the Arabidopsis orthologs AtNRP1, AtNRP2, ANAC36, and γVPE, in protoplasts and in planta induce a cell death response bearing the hallmarks of leaf senescence and PCD. These symptoms include the induction of caspase 1-like activity and DNA fragmentation, chlorophyll loss, protein degradation, enhanced lipid peroxidation, and the induction of senescence-associated marker genes [36, 37, 38, 40, 55]. Fourth, enhanced accumulation of BiP, which negatively regulates the NRPs/GmNAC81:GmNAC30/VPE signaling module, also promotes a delay in leaf senescence in transgenic plants [59]. Finally, GmNAC81 is a positive regulator of naturally programmed leaf senescence [70]. Although leaf senescence is genetically programmed in an age-dependent manner, it can be triggered by environmental cues and is also positively and negatively regulated by various plant hormones. GmNAC81 and GmNAC30 are induced by the phytohormones ABA, jasmonic acid (JA) and salicylic acid (SA), which are positive regulators of senescence, and GmNAC81-overexpressing lines display high levels of ABA, mimicking the enhanced endogenous levels of this hormone during leaf senescence [70, 71]. Consistent with a role in leaf senescence, the overexpression of GmNAC81 in soybean plants accelerates leaf senescence, a phenotype associated with extensive leaf yellowing, increased chlorophyll loss, faster photosynthetic decay, and enhanced expression and activity of the GmNAC81 direct target VPE, than untransformed, wild-type plants. Conversely, suppressing GmNAC81 expression delays leaf senescence and decreases the expression of GmNAC81 direct target genes, including VPE [70]. Therefore, GmNAC81 is involved in developmentally programmed leaf senescence. Furthermore, ER stress- and osmotic stress-induced PCD is integrated with natural leaf senescence through the NRPs/NACs/VPE regulatory circuit.
7. Conclusion
Since the discovery of the ER stress- and osmotic stress-induced DCD/NRP-mediated cell death response, considerable progress has been achieved toward deciphering the components and regulation of the pathway (Figure 3). We now know that the combination of multiple stresses synergistically activates a plant-specific PCD response that is initiated by induction of the stress-responsive transcription factor GmERD15, which, in turn, binds and activates the DCD/NRP promoter. Induction of the DCD/NRP genes NRP-A and NRP-B leads to the activation of a signal cascade that culminates with the upregulation of the transcription factors GmNAC81 and GmNAC30. The NAC transcription factors form a heterodimer to activate the expression of hydrolytic enzymes, including VPE, an executioner of vacuole-triggered programmed cell death. The stress-induced DCD/NRP-mediated cell death response is conserved in plants with similar regulatory mechanisms and represents a shared response to multiple stress signals. As a negative regulator of the stress-induced DCD/NRP-mediated cell death response, overexpression of the ER-resident molecular chaperone BiP delays drought-induced senescence in tobacco and soybean plants and confers the increased adaptation of these transgenic lines under water deprivation conditions. This DCD/NNP-mediated stress-induced cell death program is also activated during age-dependent leaf senescence and contributes positively for the progression of the developmentally programmed senescence. Therefore, the plant-specific NRPs/NACs/VPE signaling module represents a regulatory circuit integrating stress-induced with natural leaf senescence.
Acknowledgments
We thank the Brazilian government agencies, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), for financial support.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"senescence, stress, NRP, DCD, BiP, NAC, VPE, ER, osmotic stress, drought",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/70467.pdf",chapterXML:"https://mts.intechopen.com/source/xml/70467.xml",downloadPdfUrl:"/chapter/pdf-download/70467",previewPdfUrl:"/chapter/pdf-preview/70467",totalDownloads:234,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"June 7th 2019",dateReviewed:"September 3rd 2019",datePrePublished:"December 14th 2019",datePublished:"May 13th 2020",dateFinished:null,readingETA:"0",abstract:"Any condition that disrupts the ER homeostasis activates a cytoprotective signaling cascade, designated as the unfolded protein response (UPR), which is transduced in plant cells by a bipartite signaling module. Activation of IRE1/bZIP60 and bZIP28/bZIP17, which represent the bipartite signaling arms and serve as ER stress sensors and transducers, results in the upregulation of ER protein processing machinery-related genes to recover from stress. However, if the ER stress persists and the cell is unable to restore ER homeostasis, programmed cell death signaling pathways are activated for survival. Here, we describe an ER stress-induced plant-specific cell death program, which is a shared response to multiple stress signals. This signaling pathway was first identified through genome-wide expression profile of differentially expressed genes in response to combined ER stress and osmotic stress. Among them, the development and cell death domain-containing N-rich proteins (DCD/NRPs), NRP-A and NRP-B, and the transcriptional factor GmNAC81 were selected as mediators of cell death in plants. These genes were used as targets to identify additional components of the cell death pathway, which is described here as a regulatory circuit that integrates a stress-induced cell death program with leaf senescence via the NRP-A/NRP-B/GmNAC81:GmNAC30/VPE signaling module.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/70467",risUrl:"/chapter/ris/70467",book:{slug:"plant-science-structure-anatomy-and-physiology-in-plants-cultured-in-vivo-and-in-vitro"},signatures:"Otto Teixeira Fraga, Bruno Paes de Melo, Luiz Fernando de Camargos, Debora Pellanda Fagundes, Celio Cabral Oliveira, Eduardo Bassi Simoni, Pedro Augusto Braga dos Reis and Elizabeth Pacheco Batista Fontes",authors:[{id:"21426",title:"Prof.",name:"Elizabeth",middleName:null,surname:"Fontes",fullName:"Elizabeth Fontes",slug:"elizabeth-fontes",email:"bbfontes@ufv.br",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Modest overlapping of ER stress and osmotic stress response identifies NRPs and NACs as cell death-promoting genes",level:"1"},{id:"sec_2_2",title:"2.1 Osmotic stress responses",level:"2"},{id:"sec_3_2",title:"2.2 ER stress responses",level:"2"},{id:"sec_4_2",title:"2.3 Convergence of ER stress and osmotic stress responses into a cell death signaling pathway",level:"2"},{id:"sec_6",title:"3. Early dehydration responsive gene 15, ERD15-like, controls NRP expression",level:"1"},{id:"sec_7",title:"4. The stress-induced NRP/NAC081/VPE module transduces a cell death signal",level:"1"},{id:"sec_8",title:"5. A negative regulator of the NRP/NAC081/VPE signaling module confers tolerance to drought",level:"1"},{id:"sec_9",title:"6. The stress-induced DCD/NRP-mediated cell death signaling positively regulates leaf senescence",level:"1"},{id:"sec_10",title:"7. 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Frontiers in Plant Science. 2018;9:1864. DOI: 10.3389/fpls.2018.01864'},{id:"B44",body:'Olsen AN, Ernst HA, Leggio LL, Skriver K. NAC transcription factors: Structurally distinct, functionally diverse. Trends in Plant Science. 2005;10:79-87. DOI: 10.1016/j.tplants.2004.12.010'},{id:"B45",body:'Nakashima K, Takasaki H, Mizoi J, Shinozaki K, Yamaguchi-Shinozaki K. NAC transcription factors in plant abiotic stress responses. Biochimica et Biophysica Acta. 2012;1819:97-103. DOI: 10.1016/j.bbagrm.2011.10.005'},{id:"B46",body:'Tran LSP, Quach TN, Guttikonda SK, Aldrich DL, Kumar R, Neelakandan A, et al. Molecular characterization of stress-inducible GmNAC genes in soybean. Molecular Genetics and Genomics. 2009;281:647-664. DOI: 0.1007/s00438-009-0436-8'},{id:"B47",body:'Seo PJ, Kim MJ, Park JY, Kim SY, Jeon J, Lee YH, et al. Cold activation of a plasma membrane-tethered NAC transcription factor induces a pathogen resistance response in Arabidopsis. Plant Journal. 2010;61:661-671. DOI: 10.1111/j.1365-313X.2009.04091.x'},{id:"B48",body:'Kiyosue T, Yamaguchi-Shinozaki K, Shinozaki K. Cloning of cDNAs for genes that are early-responsive to dehydration stress (ERDs) in Arabidopsis thaliana L.: Identification of three ERDs as HSP cognate genes. Plant Molecular Biology. 1994;25:791-798. DOI: 10.1007/bf00028874'},{id:"B49",body:'Wang X, Grumet R. Identification and characterization of proteins that interact with the carboxy terminus of poly(A)-binding protein and inhibit translation in vitro. Plant Molecular Biology. 2004;54:85-98. DOI: 10.1023/B:PLAN.0000028771.70969.6b'},{id:"B50",body:'Dunaeva M, Adamska I. Identification of genes expressed in response to light stress in leaves of Arabidopsis thaliana using RNA differential display. European Journal of Biochemistry. 2001;268:5521-5529. DOI: 10.1046/j.1432-1033.2001.02471.x'},{id:"B51",body:'Park MY, Chung MS, Koh HS, Lee DJ, Ahn SJ, Kim CS. Isolation and functional characterization of the Arabidopsis salt-tolerance 32 (AtSAT32) gene associated with salt tolerance and ABA signaling. Physiologia Plantarum. 2009;135:426-435. DOI: 10.1111/j.1399-3054.2008.01202.x'},{id:"B52",body:'Kariola T, Brader G, Helenius E, Li J, Heino P, Palva ET. Early responsive to dehydration 15, a negative regulator of abscisic acid responses in Arabidopsis. Plant Physiology. 2006;142:1559-1573. DOI: 10.1104/pp.106.086223'},{id:"B53",body:'Alves MS, Reis PAB, Dadalto SP, Faria JAQA, Fontes EPB, Fietto LG. A novel transcription factor, ERD15 (early responsive to dehydration 15), connects endoplasmic reticulum stress with an osmotic stress-induced cell death signal. The Journal of Biological Chemistry. 2011;286:20020-20030. DOI: 10.1074/jbc.M111.233494'},{id:"B54",body:'Desveaux D, Allard J, Brisson N, Sygusch J. A new family of plant transcription factors displays a novel ssDNA-binding surface. Nature Structural and Molecular Biology. 2002;9:512-517. DOI: 10.1038/nsb814'},{id:"B55",body:'Mendes GC, Reis PAB, Calil IP, Carvalho HH, Aragao FJL, Fontes EPB. GmNAC30 and GmNAC81 integrate the endoplasmic reticulum stress- and osmotic stress-induced cell death responses through a vacuolar processing enzyme. Proceedings of the National Academy of Sciences of the United States of America. 2013;110:19627-19632. DOI: 10.1073/pnas.1311729110'},{id:"B56",body:'Hara-Nishimura I, Hatsugai N, Nakaune S, Kuroyanagi M, Nishimura M. Vacuolar processing enzyme: An executor of plant cell death. Current Opinion in Plant Biology. 2005;8:404-408. DOI: 10.1016/j.pbi.2005.05.016'},{id:"B57",body:'Hatsugai N, Kuroyanagi M, Yamada K, Meshi T, Tsuda S, Kondo M, et al. A plant vacuolar protease, VPE, mediates virus-induced hypersensitive cell death. Science. 2004;305:855-858. DOI: 10.1126/science.1099859'},{id:"B58",body:'Hatsugai N, Yamada K, Goto-Yamada S, Hara-Nishimura I. Vacuolar processing enzyme in plant programmed cell death. Frontiers in Plant Science. 2015;6:234. DOI: 10.3389/fpls.2015.00234'},{id:"B59",body:'Carvalho HH, Silva PA, Mendes GC, Brustolini OJB, Pimenta MR, Gouveia BC, et al. The endoplasmic reticulum binding protein BiP displays dual function in modulating cell death events. Plant Physiology. 2014;164:654-670. DOI: 10.1104/pp.113.231928'},{id:"B60",body:'DB MK. Structure and mechanism of 70-kDa heat-shock-related proteins. Advances in Protein Chemistry. 1993;44:67-98. DOI: 10.1016/S0065-3233(08)60564-1'},{id:"B61",body:'Srivastava R, Deng Y, Shah S, Rao AG, Howell SH. Binding protein is a master regulator of the endoplasmic reticulum stress sensor/transducer bZIP28 in Arabidopsis. The Plant Cell. 2013;25:1416-1429. DOI: 10.1105/tpc.113.110684'},{id:"B62",body:'Cascardo JCM, Almeida RS, Buzeli RAA, Carolino SMB, Otoni WC, Fontes EPB. The phosphorylation state and expression of soybean BiP isoforms are differentially regulated following abiotic stresses. The Journal of Biological Chemistry. 2000;275:14494-14500. DOI: 10.1074/jbc.275.19.14494'},{id:"B63",body:'Alvim FC, Carolino SMB, Cascardo JCM, Nunes CC, Martinez CA, Otoni WC, et al. Enhanced accumulation of BiP in transgenic plants confers tolerance to water stress. Plant Physiology. 2001;126:1042-1054. DOI: 10.1104/pp.126.3.1042'},{id:"B64",body:'Valente MAS, Faria JAQA, Soares-Ramos JRL, Reis PAB, Pinheiro GL, Piovesan ND, et al. The ER luminal binding protein (BiP) mediates an increase in drought tolerance in soybean and delays drought-induced leaf senescence in soybean and tobacco. Journal of Experimental Botany. 2009;60:533-546. DOI: 10.1093/jxb/ern296'},{id:"B65",body:'Coutinho FS, dos Santos DS, Lima LL, Vital CE, Santos LA, Pimenta MR, et al. Mechanism of the drought tolerance of a transgenic soybean overexpressing the molecular chaperone BiP. Physiology and Molecular Biology of Plants. 2019;25:457-472. DOI: 10.1007/s12298-019-00643-x'},{id:"B66",body:'Yoshida S. Molecular regulation of leaf senescence. Current Opinion in Chemical Biology. 2003;6:79-84. DOI: 10.1016/S1369526602000092'},{id:"B67",body:'Lim PO, Kim HJ, Nam HG. Leaf senescence. Annual Review of Plant Biology. 2007;58:115-136. DOI: 10.1146/annurev.arplant.57.032905.105316'},{id:"B68",body:'Balazadeh S, Siddqui H, Allu AD, Matallana-Ramirez LP, Caldana C, Mehrnia M, et al. A gene regulatory network controlled by the NAC transcription factor ANAC092/AtNAC2/ORE1 during salt promoted senescence. Plant Journal. 2010;62:250-264. DOI: 10.1111/j.1365-313X.2010.04151.x'},{id:"B69",body:'Breeze E, Harrison E, McHattie S, Hughes L, Hickman R, Hill C, et al. High-resolution temporal profiling of transcripts during Arabidopsis leaf senescence reveals a distinct chronology of processes and regulation. The Plant Cell. 2011;23:873-894. DOI: 10.1105/tpc.111.083345'},{id:"B70",body:'Pimenta MR, Silva PA, Mendes GC, Alves JR, Caetano HDN, Machado JPB, et al. The stress-induced soybean NAC transcription factor GmNAC81 plays a positive role in developmentally programmed leaf senescence. Plant and Cell Physiology. 2016;57:1098-1114. DOI: 10.1093/pcp/pcw059'},{id:"B71",body:'Zhang H, Zhou C. Signal transduction in leaf senescence. Plant Molecular Biology. 2013;82:539-545. DOI: 10.1007/s11103-012-9980-4'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Otto Teixeira Fraga",address:null,affiliation:'
National Institute of Science and Technology in Plant-Pest Interactions, Bioagro, Universidade Federal de Viçosa, Brazil
Department of Biochemistry and Molecular Biology/BIOAGRO, Universidade Federal de Viçosa, Brazil
'},{corresp:null,contributorFullName:"Bruno Paes de Melo",address:null,affiliation:'
National Institute of Science and Technology in Plant-Pest Interactions, Bioagro, Universidade Federal de Viçosa, Brazil
Department of Biochemistry and Molecular Biology/BIOAGRO, Universidade Federal de Viçosa, Brazil
'},{corresp:null,contributorFullName:"Luiz Fernando de Camargos",address:null,affiliation:'
National Institute of Science and Technology in Plant-Pest Interactions, Bioagro, Universidade Federal de Viçosa, Brazil
Department of Biochemistry and Molecular Biology/BIOAGRO, Universidade Federal de Viçosa, Brazil
National Institute of Science and Technology in Plant-Pest Interactions, Bioagro, Universidade Federal de Viçosa, Brazil
Department of Biochemistry and Molecular Biology/BIOAGRO, Universidade Federal de Viçosa, Brazil
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\n
1. Introduction
\n
Most of the gastrointestinal (GI) bleeding occurs from the upper and lower gastrointestinal tract. Mid-gastrointestinal (GI) bleeding refers to small bowel bleed anywhere from the ampulla of Vater to the ileocecal valve [1]. It occurs in 5–10% of all cases of gastrointestinal bleeding [2]. It is the most common cause of obscure GI bleeding, i.e., when the source of bleeding cannot be identified anywhere in the gastrointestinal tract [3, 4]. Management of mid-GI bleeding can be challenging to a gastroenterologist although various diagnostic and therapeutic tools are now available to evaluate and treat mid-GI bleeding. Despite the availability of various endoscopies and imaging studies, the exact cause of mid-GI bleeding can be still elusive in about one third of cases [5]. The etiology, clinical presentation, evaluation, investigations, and management of mid-GI bleeding will be discussed in this chapter.
\n
\n
\n
2. Etiology
\n
There are various etiologies of mid-GI bleeding, but their frequency depends on patient’s age and underlying comorbidities [6]. Below the age of 40, the most common causes include Crohn’s disease, Dieulafoy’s lesion, small bowel tumors, Meckel’s diverticulum, and polyposis syndrome. Small bowel tumors could be benign or malignant [7]. Benign ones include small gastrointestinal stromal tumors (GIST), benign neuroendocrine tumors (particularly small carcinoid), hemangioma, adenoma, leiomyoma, lipoma, and neurofibroma. Malignant ones include large GIST, adenocarcinoma, lymphoma, malignant neuroendocrine tumors, leiomyosarcoma, and metastatic tumor from melanoma, lung, or breast [8, 9, 10, 11]. Rarely, polyposis syndromes involving the small bowel may present with mid-GI bleeding. These include familial adenomatous polyposis, Peutz-Jeghers syndrome, and generalized juvenile polyposis. Over the age of 40, the most common causes of mid-GI bleeding include angioectasia, nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers, Dieulafoy’s lesion, and small bowel tumors. On rare occasions, other small bowel lesions can cause gastrointestinal bleeding. These include small intestinal diverticuli, small intestinal varices, hereditary hemorrhagic telangiectasia, Kaposi sarcoma, intestinal tuberculosis, blue rubber bleb nevus syndrome, hematobilia, hemosuccus entericus, aortoenteric fistula, infectious enteritis, radiation enteritis, ulcerative jejunoileitis due to celiac disease, cryptogenic multifocal ulcerous stenosing enteritis [12], amyloidosis, Behcet’s disease, pseudoxanthoma elasticum, and Ehlers-Danlos syndrome [13]. The incidence of small bowel neuroendocrine tumors (SBNET) has been increasing over the last few decades, and they are now considered as the most common primary malignancy of small bowel. Adenocarcinomas are generally seen in the proximal small bowel, whereas SBNET and lymphoma are commonly located in the distal small bowel. Sarcomas (GIST and non-GIST mesenchymal tumors: leiomyosarcoma, liposarcoma, fibrosarcoma, Kaposi’s sarcoma, angiosarcoma) are evenly located throughout the small bowel.
\n
\n
\n
3. Clinical presentation
\n
Patients with mid-GI bleeding generally present with melena, occult gastrointestinal bleeding (anemia with heme-positive stool), or iron deficiency anemia. Sometimes, they may present with hematochezia as well when there is brisk mid-gut bleeding. Hematemesis is rare but can happen if bleeding occurs proximal to the ligament of Treitz. Patients can have abdominal pain, constipation, diarrhea, or constitutional symptoms like fever, anorexia, or weight loss depending on the underlying etiology. Symptoms (fatigue, shortness of breath, dysphagia due to esophageal web) and signs (pallor of conjunctiva, atrophic glossitis, and koilonychia) can be present depending on the severity and chronicity of iron deficiency anemia [14]. Patients may give history of receiving multiple blood transfusions acutely, subacutely, or chronically despite having multiple endoscopies, colonoscopies, and imaging studies.
\n
\n
\n
4. Clinical evaluation
\n
A thorough history and physical examination are essential in the evaluation of mid-GI bleeding. Besides the symptoms and signs mentioned above, there are certain clinical clues which may direct us to suspect the underlying etiology of mid-GI bleeding:
Drug history: NSAIDs.
Personal history: aortic stenosis (suspecting Heyde syndrome), cancer, melanoma, lymphoma, immunosuppressive state including human immunodeficiency virus (HIV) infection, celiac disease, radiation, polyposis syndrome.
Family history: early colorectal cancer or endometrial cancer (suspecting Lynch syndrome).
Hyperpigmentation around the mouth and on the lips, fingers, or toes may suggest Peutz-Jeghers syndrome.
Telangiectasia on the lips and tongue may suggest hereditary hemorrhagic telangiectasia.
Itchy blistering rash on the extensor aspect of the elbows, knees, buttocks, back, and scalp may suggest dermatitis herpetiformis.
Cutaneous Kaposi’s sarcoma.
Oral aphthous ulcers, genital ulcers, and uveitis may suggest Behcet’s syndrome.
Cutaneous manifestations of pseudoxanthoma elasticum and Ehlers-Danlos syndrome.
\n
\n
\n
5. Investigations
\n
The various investigations used for management of mid-GI bleeding include wireless video capsule endoscopy (VCE), push enteroscopy, device-assisted enteroscopy (DAE), multiphasic CT enterography (CTE), magnetic resonance enterography (MRE), bleeding scan, Meckel’s scan, angiography, and rarely laparoscopy with intraoperative enteroscopy [15, 16, 17, 18].
\n
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5.1 VCE
\n
VCE has revolutionized the visualization of the entire mucosa of the small bowel. It was approved by the US Food and Drug Administration (FDA) in 2001. The video capsule (size: 13 × 27.9 mm) takes 2 pictures per second with a total of approximately 57,600 color pictures wirelessly over a period of 8 hours [19]. It can detect subtle mucosal changes which cannot be detected by imaging studies. VCE is very useful not only in patients with chronic or intermittent mid-GI bleeding but also in acute overt mid-GI bleeding. VCE should be done as soon as possible after the bleeding episode ideally within 14 days in the case of chronic or recurrent overt mid-GI bleeding and within 24–72 hours of acute overt mid-GI bleeding for maximal diagnostic yield [20]. The European Society of Gastrointestinal Endoscopy (ESGE) recommends that patients should take 2 L of polyethylene glycol (PEG) and simethicone (80–200 mg) prior to VCE. Prokinetic drugs (metoclopramide or domperidone) should be given if the video capsule stays in the stomach for more than 30–60 minutes as shown by real-time VCE viewer [21, 22]. Ideally video capsule should be placed endoscopically into the small bowel by using a capsule endoscope delivery device in patients with dysphagia or abnormal gastrointestinal anatomy or delayed gastric emptying where there will be increased risk of incomplete VCE study [23]. It is safe to perform VCE in patients with cardiac pacemaker, automatic implantable cardioverter-defibrillator (AICD), and left ventricular assist device [24].
\n
\n
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5.2 Push enteroscopy
\n
Push enteroscopy is a very useful tool in the evaluation of lesion seen in the proximal part of the small bowel by VCE. Push enteroscopy is generally done by a dedicated push enteroscope (250 cm long) or a pediatric or standard colonoscope. Gastric looping and duodenal angulation prevent advancement of the scope. An overtube back-loaded on to the scope or a stiffening wire through the biopsy channel of the scope helps prevent loop formation of the scope allowing deeper intubation of the small bowel. The actual depth of insertion of small bowel by push enteroscopy is difficult to measure but varies (120–180 cm beyond the ligament of Treitz) among endoscopists and patients [25]. Push enteroscopy has both diagnostic and therapeutic potential including biopsy, hemostasis, and tattooing [26].
\n
\n
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5.3 DAE
\n
DAE includes balloon-assisted enteroscopy (single balloon and double balloon) and spiral enteroscopy.
\n
Single-balloon enteroscopy (SBE) and double-balloon enteroscopy (DBE) were developed in 2006 and 2001, respectively, to examine the entire small bowel mucosa. Both procedures are bidirectional, i.e., the enteroscope is introduced anterogradely through the mouth and retrogradely through the anus, and the midway point is marked by tattooing or endoclipping [27]. Although the rate of complete visualization of the small bowel is three times (66 vs. 22%) higher with DBE than that with SBE [28], the diagnostic and therapeutic yields of these two procedures do not differ significantly [29]. In spiral enteroscopy (SE), the small bowel is pleated on the enteroscope by a screw operated by a machine, and the rotational force is converted into a linear force. In one study, complete enteroscopy was successful in 92% of cases of bidirectional DBE and 8% of cases of SE, although the diagnostic and therapeutic outcomes were not statistically different [30].
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5.4 CTE
\n
CTE is a useful tool in the evaluation of mid-GI bleed due to vascular lesion. Characteristic enhancement of the vascular lesion can be seen [31]. They are classified as angioectasia, arterial lesions (Dieulafoy’s lesion and arteriovenous malformation), and venous lesions (vascular lesion with unusual morphology). Active bleeding is evidenced by progressive accumulation of contrast material over the three phases on the dependent surface of the intestine or distributed over a wide area by peristalsis. CT enterography is also useful in the detection of inflammatory and neoplastic condition of the small bowel [32].
\n
\n
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5.5 MRE
\n
MRE is a noninvasive radiation-free method of evaluating the entire small bowel. It can detect the mural thickening (>4 mm) and mass lesion of the small bowel. These lesions could be secondary to inflammatory and benign conditions (like Crohn’s disease, adenoma, lipoma, fibroepithelial polyps) or malignant conditions (like neuroendocrine tumors, GIST, adenocarcinoma, lymphoma, and Peutz-Jeghers syndrome) [33, 34].
\n
\n
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5.6 Bleeding scan
\n
Bleeding scan is a nuclear medicine test performed by injecting 99 m technetium-labeled red blood cells (RBC). It can detect extravasation of tagged RBC if the bleeding rate is 0.1 ml/minute or more. It is a highly sensitive test in detecting active bleeding in the gastrointestinal tract and can localize the site of bleeding accurately in 52% of cases [35].
\n
\n
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5.7 Meckel’s scan
\n
Meckel’s scan is also a nuclear medicine test performed by injecting 99 m technetium pertechnetate which has affinity for the gastric mucosa. It is positive in patients with Meckel’s diverticulum with heterotopic/ectopic gastric mucosa. Acid secretion from the gastric mucosa can cause ulceration and bleeding near or adjacent to the diverticulum. In children, Meckel’s scan is performed early, whereas in adults, it is generally performed late in the evaluation of mid-GI bleeding.
\n
\n
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5.8 CT angiography (CTA)
\n
CTA is increasingly being done in patients with less brisk mid-GI bleeding. CTA can detect the bleeding site if the bleeding rate is 0.3 ml/minute or more [36]. However, CTA exposes the patient to ionizing radiation, and intravenous contrast is required. So patients with contrast allergy, renal failure, and pregnancy should avoid CTA.
\n
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5.9 Conventional mesenteric angiography (CMA)
\n
CMA is rarely done in the evaluation of mid-GI bleeding unless there is ongoing significant bleeding and patient had hemodynamic instability, positive CTE, or bleeding scan; and embolization is considered to stop the bleeding. However, there is risk of bowel wall infarction following embolization therapy. CMA can also detect small bowel varices in patients with portal hypertension and Meckel’s diverticulum by the finding of an anomalous long branch of superior mesenteric artery traversing the mesentery toward the right lower quadrant and supplying the diverticulum.
\n
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5.10 Gallium-68 dotatate PET/CT scan
\n
Gallium-68 dotatate PET/CT scan is now considered as the best scan for detecting SBNET as 70–90% of them have somatostatin receptors. It has much better imaging quality and can detect more lesions than Octreoscan [37]. But it does not replace CTE or MRE for those SBNET which are not somatostatin receptor positive.
\n
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5.11 Intraoperative enteroscopy
\n
Intraoperative enteroscopy is done in the operating room when other modalities of investigations fail to detect the source of bleeding. The scope is introduced through the mouth or through an enterotomy, and whole small bowel can be evaluated. It is diagnostic as well as therapeutic in achieving hemostasis in about 70% of cases.
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6. Management
\n
A systematic approach is essential to manage mid-GI successfully. Mid-GI bleeding is generally established when no source of potential bleeding is found in the upper or lower gastrointestinal tract after doing bidirectional endoscopy, i.e., upper endoscopy (including examination with a side-viewing duodenoscope) and ileocolonoscopy. Second-look bidirectional endoscopy should be done considering substantial initial endoscopic miss rates [38]. Next step to evaluate is whether the patient is hemodynamically stable or unstable and whether the patient is having occult or overt GI bleeding. The first investigation to evaluate mid-GI bleeding in a hemodynamically stable patient is VCE unless there are contraindications like small bowel obstruction [39]. On the other hand, in a hemodynamically unstable patient, the first investigation will be angiography for both diagnostic and therapeutic purposes [40].
\n
Depending on the location of bleeding lesion in VCE, push enteroscopy or DAE should be done, i.e., push enteroscopy for lesion in the proximal part of the small bowel and DAE for lesion in the mid or distal part of the small bowel. If the VCE is negative, the next step will depend on whether the patient has ongoing blood loss, the rate of blood loss, and the presence of comorbidities:
If the patient has ongoing blood loss without significant comorbidities, DAE, CTE/MRE, or even laparoscopy with intraoperative enteroscopy should be considered to stop the bleeding.
If the patient does not have ongoing blood loss, further evaluation can be stopped.
If the patient has significant comorbidities and slow rate of blood loss, further investigation could be reasonably stopped. Patient should be observed with periodic monitoring of complete blood count (CBC), and iron supplementation and/or blood transfusion should be given as necessary basis.
\n
Definitive therapy should be given according to the findings seen in the above investigations. Treatment modalities of some of the common conditions are listed below:
Small bowel angioectasia: it is by far the commonest cause of mid-GI bleeding. Endoscopic ablation is the treatment of choice. Sometimes patients may present with recurrent anemia due to bleeding from widespread or inaccessible angioectasia, and endoscopic treatment is risky because of patients’ comorbidities or old age. Pharmacologic treatment is generally offered in those cases. Thalidomide prevents angiogenesis by inhibiting vascular endothelial growth factor (VEGF). One study showed that thalidomide was effective in reducing the rate of recurrent small bowel bleeding due to vascular malformations [41]. Octreotide decreases mesenteric blood flow, inhibits angiogenesis, and improves platelet aggregation. One meta-analysis showed that octreotide therapy reduced the transfusion requirement in patients with recurrent bleeding from gastrointestinal vascular malformations [42]. Other treatment modalities for different conditions include:
Isolated jejunal and ileal bleeding ulcers due to NSAIDs: hold NSAIDs, endoscopic treatment, and/or embolization. In rat model, proton pump inhibitors were found to worsen NSAID-induced small bowel injury by inducing dysbiosis [43].
Dieulafoy’s lesion: endoscopic (argon plasma coagulation, hemoclip, injection therapy) or angiographic intervention (embolization) or surgery if those interventions fail [44].
Small bowel varices: endoscopic treatment if within reach of endoscope. Angiography, transjugular intrahepatic portosystemic shunt (TIPS) placement, or surgery if endoscopic hemostasis fails or is beyond the reach of endoscope [45].
SBNET: surgical resection is the treatment of choice for locoregional disease. Long-acting somatostatin analogs are given for functional and nonfunctional metastatic SBNET because of their antiproliferative effects and ability to control carcinoid symptoms [46].
Adenocarcinoma of small bowel: surgery, chemotherapy, and checkpoint inhibitors.
GIST: surgery and tyrosine kinase inhibitors.
Non-GIST mesenchymal tumors: surgery.
Benign tumors:
Adenoma: endoscopic resection.
Lipoma, leiomyoma, and hamartomas: segmental resection.
Peutz-Jeghers syndrome: segmental resection or endoscopic resection. Because some patients are young with widespread polyps, endoscopic treatment should be preferred [47].
Metastatic tumor to the small bowel: palliative treatment.
Meckel’s diverticulum: surgery.
Crohn’s disease: endoscopic treatment, embolization, corticosteroid, 5-aminosalicylic acid, 6-mercaptopurine/azathioprine, infliximab, and surgery [48].
Ulcerative jejunoileitis due to celiac disease: surgical resection of the ulcerated segment, corticosteroid, elimination diet, and total parenteral nutrition.
\n
\n
\n
7. Prognosis
\n
Prognosis depends on the etiology of the lesion causing mid-GI bleeding. Vascular lesions carry a good prognosis if they can be successfully treated endoscopically, radiologically, or surgically. Most of the time, vascular lesions can be managed endoscopically. Surgical intervention is required if the bleeding cannot be managed endoscopically or by interventional radiology. Surgery is also required for benign and malignant small bowel tumors, ulcerative jejunoileitis due to celiac disease, and refractory bleeding Crohn’s ulcers. Sometimes, patients’ comorbidities or old age do not allow invasive procedures or surgery. Symptomatic and palliative treatments are offered in those cases. Sometimes, mid-GI bleeding remains obscure. Patients end up getting multiple hospitalizations, multiple diagnostic tests, and multiple blood transfusions.
\n
\n
\n
8. Conclusion
\n
Mid-GI bleeding is common in our day-to-day clinical practice. Capsule endoscopy and imaging studies have made the diagnostic evaluations much easier than before. Balloon-assisted enteroscopy and spiral enteroscopy are generally done for therapeutic interventions. Interventional radiology and surgery are required if there is massive bleeding or endoscopic therapeutic interventions fail. After hemostasis is obtained, treatment of the underlying condition should be done. Patient’s age, comorbidities, pros and cons of the procedures, and radiological and surgical interventions should be considered.
\n
\n\n',keywords:"small bowel bleed, occult gastrointestinal bleed, obscure gastrointestinal bleed, capsule endoscopy and gastrointestinal bleed, small bowel angioectasia",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/69303.pdf",chapterXML:"https://mts.intechopen.com/source/xml/69303.xml",downloadPdfUrl:"/chapter/pdf-download/69303",previewPdfUrl:"/chapter/pdf-preview/69303",totalDownloads:318,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 4th 2019",dateReviewed:"August 25th 2019",datePrePublished:"September 28th 2019",datePublished:"January 8th 2020",dateFinished:null,readingETA:"0",abstract:"Mid-gastrointestinal bleeding constitutes a small proportion of all cases of gastrointestinal bleeding. It is more difficult to manage mid-gastrointestinal bleeding than upper or lower gastrointestinal bleeding. The etiology differs in younger and older age groups. The clinical presentation, investigations, and management are also different. Capsule endoscopy has improved the diagnostic accuracy to a great extent. Device-assisted enteroscopies (balloon-assisted enteroscopies and spiral enteroscopy) have both diagnostic and therapeutic potentials. Most of the time, patients present with obscure gastrointestinal bleeding which could be overt or occult. Another common presentation is iron deficiency anemia. A stepwise approach is essential to accurately diagnose and manage mid-gastrointestinal bleeding.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/69303",risUrl:"/chapter/ris/69303",signatures:"Monjur Ahmed",book:{id:"7959",title:"Digestive System",subtitle:"Recent Advances",fullTitle:"Digestive System - Recent Advances",slug:"digestive-system-recent-advances",publishedDate:"January 8th 2020",bookSignature:"Xingshun Qi and Sam Koruth",coverURL:"https://cdn.intechopen.com/books/images_new/7959.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"197501",title:"Dr.",name:"Xingshun",middleName:null,surname:"Qi",slug:"xingshun-qi",fullName:"Xingshun Qi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"206355",title:"Associate Prof.",name:"Monjur",middleName:null,surname:"Ahmed",fullName:"Monjur Ahmed",slug:"monjur-ahmed",email:"monjur.ahmed@jefferson.edu",position:null,institution:{name:"Thomas Jefferson University",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Etiology",level:"1"},{id:"sec_3",title:"3. Clinical presentation",level:"1"},{id:"sec_4",title:"4. Clinical evaluation",level:"1"},{id:"sec_5",title:"5. Investigations",level:"1"},{id:"sec_5_2",title:"5.1 VCE",level:"2"},{id:"sec_6_2",title:"5.2 Push enteroscopy",level:"2"},{id:"sec_7_2",title:"5.3 DAE",level:"2"},{id:"sec_8_2",title:"5.4 CTE",level:"2"},{id:"sec_9_2",title:"5.5 MRE",level:"2"},{id:"sec_10_2",title:"5.6 Bleeding scan",level:"2"},{id:"sec_11_2",title:"5.7 Meckel’s scan",level:"2"},{id:"sec_12_2",title:"5.8 CT angiography (CTA)",level:"2"},{id:"sec_13_2",title:"5.9 Conventional mesenteric angiography (CMA)",level:"2"},{id:"sec_14_2",title:"5.10 Gallium-68 dotatate PET/CT scan",level:"2"},{id:"sec_15_2",title:"5.11 Intraoperative enteroscopy",level:"2"},{id:"sec_17",title:"6. Management",level:"1"},{id:"sec_18",title:"7. Prognosis",level:"1"},{id:"sec_19",title:"8. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Ell C, May A. Mid-gastrointestinal bleeding: Capsule endoscopy and push-and-pull enteroscopy give rise to a new medical term. Endoscopy. 2006;38(1):73-75\n'},{id:"B2",body:'Murphy B, Winter DC, Kavanagh DO. Small bowel gastrointestinal bleeding diagnosis and management–A narrative review. Frontiers in Surgery. 2019;6:25\n'},{id:"B3",body:'Gunjan D, Sharma V, Rana SS, Bhasin DK. Small bowel bleeding: A comprehensive review. Gastroenterology Report. 2014;2(4):262-275\n'},{id:"B4",body:'Gerson LB, Fidler JL, Cave DR, Leighton JA. ACG clinical guideline: Diagnosis and management of small bowel bleeding. The American Journal of Gastroenterology. 2015;110(9):1265-1287\n'},{id:"B5",body:'Song JH, Hong SN, Kyung Chang D, Ran Jeon S, Kim JO, Kim J, et al. The etiology of potential small-bowel bleeding depending on patient’s age and gender. United European Gastroenterology Journal. 2018;6(8):1169-1178\n'},{id:"B6",body:'Katz LB. 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American Gastroenterological Association (AGA) institute technical review on obscure gastrointestinal bleeding. Gastroenterology. 2007;133(5):1697-1717\n'},{id:"B20",body:'Pennazio M, Spada C, Eliakim R, Keuchel M, May A, Mulder CJ, et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) clinical guideline. Endoscopy. 2015;47(4):352-376\n'},{id:"B21",body:'Koulaouzidis A, Giannakou A, Yung DE, Dabos KJ, Plevris JN. Do prokinetics influence the completion rate in small-bowel capsule endoscopy? A systematic review and meta-analysis. Current Medical Research and Opinion. 2013;29(9):1171-1185\n'},{id:"B22",body:'Lai LH, Wong GL, Lau JY, Sung JJ, Leung WK. Initial experience of real-time capsule endoscopy in monitoring progress of the videocapsule through the upper GI tract. Gastrointestinal Endoscopy. 2007;66(6):1211-1214\n'},{id:"B23",body:'Holden JP, Dureja P, Pfau PR, Schwartz DC, Reichelderfer M, Judd RH, et al. Endoscopic placement of the small-bowel video capsule by using a capsule endoscope delivery device. Gastrointestinal Endoscopy. 2007;65(6):842-847\n'},{id:"B24",body:'Rondonotti E, Spada C, Adler S, May A, Despott EJ, Koulaouzidis A, et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) technical review. Endoscopy. 2018;50(4):423-446\n'},{id:"B25",body:'Barth B. Capsule endoscopy and small bowel enteroscopy. In: Wyllie R, Hyams JS, editors. Pediatric Gastrointestinal and Liver Disease. 4th ed. Philadelphia: Elsevier; 2011. pp. 679-685.e2. ISBN: 978-1-4377-0774-8. https://doi.org/10.1016/C2009-0-53242-4\n\n'},{id:"B26",body:'Kovacs TO. Small bowel bleeding. Current Treatment Options in Gastroenterology. 2005;8(1):31-38\n'},{id:"B27",body:'Kawamura T, Uno K, Tanaka K, Yasuda K. Current status of single-balloon enteroscopy: Insertability and clinical applications. World Journal of Gastrointestinal Endoscopy. 2015;7(1):59-65\n'},{id:"B28",body:'May A, Färber M, Aschmoneit I, Pohl J, Manner H, Lotterer E, et al. Prospective multicenter trial comparing push-and-pull enteroscopy with the single- and double-balloon techniques in patients with small-bowel disorders. The American Journal of Gastroenterology. 2010;105(3):575-581\n'},{id:"B29",body:'Prachayakul V, Deesomsak M, Aswakul P, Leelakusolvong S. The utility of single-balloon enteroscopy for the diagnosis and management of small bowel disorders according to their clinical manifestations: A retrospective review. BMC Gastroenterology. 2013;13:103\n'},{id:"B30",body:'Akerman PA. Spiral enteroscopy versus double-balloon enteroscopy: Choosing the right tool for the job. Gastrointestinal Endoscopy. 2013;77(2):252-254\n'},{id:"B31",body:'Huprich JE, Barlow JM, Hansel SL, Alexander JA, Fidler JL. Multiphase CT enterography evaluation of small-bowel vascular lesions. AJR. American Journal of Roentgenology. 2013;201(1):65-72\n'},{id:"B32",body:'Masselli G. Small bowel imaging: Clinical applications of the different imaging modalities—A comprehensive review. ISRN Pathology. 2013;2013:419542, 13 p. DOI: 10.1155/2013/419542\n'},{id:"B33",body:'Cengic I, Tureli D, Aydin H, Bugdayci O, Imeryuz N, Tuney D. Magnetic resonance enterography in refractory iron deficiency anemia: A pictorial overview. World Journal of Gastroenterology. 2014;20(38):14004-14009\n'},{id:"B34",body:'Kumar AS, Coralic J, Vegeler R, Kolli K, Liang J, Estep A, et al. Magnetic resonance enterography: The test of choice in diagnosing intestinal “zebras”. Case Reports in Gastrointestinal Medicine. 2015;2015:206469\n'},{id:"B35",body:'Bentley DE, Richardson JD. The role of tagged red blood cell imaging in the localization of gastrointestinal bleeding. Archives of Surgery. 1991;126(7):821-824\n'},{id:"B36",body:'García-Blázquez V, Vicente-Bártulos A, Olavarria-Delgado A, Plana MN, van der Winden D, Zamora J, et al. Accuracy of CT angiography in the diagnosis of acute gastrointestinal bleeding: Systematic review and meta-analysis. European Radiology. 2013;23(5):1181-1190\n'},{id:"B37",body:'Mojtahedi A, Thamake S, Tworowska I, Ranganathan D, Delpassand ES. The value of (68)Ga-DOTATATE PET/CT in diagnosis and management of neuroendocrine tumors compared to current FDA approved imaging modalities: A review of literature. American Journal of Nuclear Medicine and Molecular Imaging. 2014;4(5):426-434. eCollection 2014\n'},{id:"B38",body:'Fry LC, Bellutti M, Neumann H, Malfertheiner P, Mönkemüller K. Incidence of bleeding lesions within reach of conventional upper and lower endoscopes in patients undergoing double-balloon enteroscopy for obscure gastrointestinal bleeding. Alimentary Pharmacology & Therapeutics. 2009;29(3):342-349\n'},{id:"B39",body:'Leung WK, Ho SS, Suen BY, Lai LH, Yu S, Ng EK, et al. Capsule endoscopy or angiography in patients with acute overt obscure gastrointestinal bleeding: A prospective randomized study with long-term follow-up. The American Journal of Gastroenterology. 2012;107(9):1370\n'},{id:"B40",body:'Walker TG, Salazar GM, Waltman AC. Angiographic evaluation and management of acute gastrointestinal hemorrhage. World Journal of Gastroenterology. 2012;18(11):1191-1201\n'},{id:"B41",body:'Ge ZZ, Chen HM, Gao YJ, Liu WZ, Xu CH, Tan HH, et al. Efficacy of thalidomide for refractory gastrointestinal bleeding from vascular malformation. Gastroenterology. 2011;141(5):1629-37.e1-4\n'},{id:"B42",body:'Brown C, Subramanian V, Wilcox CM, Peter S. Somatostatin analogues in the treatment of recurrent bleeding from gastrointestinal vascular malformations: An overview and systematic review of prospective observational studies. Digestive Diseases and Sciences. 2010;55(8):2129-2134\n'},{id:"B43",body:'Wallace JL, Syer S, Denou E, de Palma G, Vong L, McKnight W, et al. Proton pump inhibitors exacerbate NSAID-induced small intestinal injury by inducing dysbiosis. Gastroenterology. 2011;141(4):1314-1322, 1322.e1-5\n'},{id:"B44",body:'Baxter M, Aly EH. Dieulafoy’s lesion: Current trends in diagnosis and management. Annals of the Royal College of Surgeons of England. 2010;92(7):548-554\n'},{id:"B45",body:'Norton ID, Andrews JC, Kamath PS. Management of ectopic varices. Hepatology. 1998;28(4):1154-1158\n'},{id:"B46",body:'Scott AT, Howe JR. Management of small bowel neuroendocrine tumors. Journal of Oncology Practice. 2018;14(8):471-482\n'},{id:"B47",body:'Wang R, Qi X, Shao X, Guo X. A large intracolonic mass in a patient with Peutz-Jeghers syndrome. Middle East Journal of Digestive Diseases. 2017;9(3):173-175\n'},{id:"B48",body:'Podugu A, Tandon K, Castro FJ. Crohn’s disease presenting as acute gastrointestinal hemorrhage. World Journal of Gastroenterology. 2016;22(16):4073-4078\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Monjur Ahmed",address:"monjur.ahmed@jefferson.edu",affiliation:'
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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
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