FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2072100897> ?p ?o ?g. }

• W2072100897 endingPage "1352" @default.
• W2072100897 startingPage "1350" @default.
• W2072100897 abstract "Olson TS, Reuter BK, Scott KG, Morris MA, Wang XM, Hancock LN, Burcin TL, Cohn SM, Ernst PB, Cominelli F, Meddings JB, Ley K, Pizarro TT (University of Virginia Health System, Charlottesville, Virginia). The primary defect in experimental ileitis originates from a nonhematopoietic source. J Exp Med 2006;203:541–552. The primary defect in genetically susceptible individuals that initiates the inflammatory response that characterizes Crohn’s disease is largely unknown. In this study, Olson et al demonstrate epithelial barrier dysfunction as a potential initiating event in the senescence accelerated mouse P-1 (SAMP-1/YitFC) model of ileitis. The SAMP mouse model exhibits chronic intestinal inflammation restricted to the ileum driven by primarily Th1 immune responses with some contribution by Th2 cytokines (J Clin Invest 2001;107:695–702, Eur J Immunol 2004;34:1561–1569). This mouse strain derived from brother–sister breeding of the inbred wild-type AKR strain exhibits spontaneous ileal inflammation developing at 10 weeks of age (Gastroenterology 2003;124:972–982) and resembles human Crohn’s disease in many respects, including spontaneous development of ileal inflammation that is chronic, transmural, and granulomatous in nature (Gut 1998;43:71–78). The etiology of Crohn’s disease is thought to result from an inappropriate and exaggerated mucosal immune response driven by constituents of the normal mucosal microflora that is in part genetically determined. Therefore, inciting events leading to Crohn’s disease could involve genetic, immunologic, and/or environmental factors. Using SAMP mice, the investigators systematically addressed the inciting event that precedes colitis in these mice. The investigators first determined the role of hematopoietic versus nonhematopoietic cells in the development of ileitis using bone marrow (BM) chimeras between AKR and SAMP mice. AKR BM → SAMP mice exhibited ileitis of comparable severity and histopathology as native SAMP mice with mesenteric lymph node (MLN) pathogenicity, as determined by increased production of tumor necrosis factor (TNF)-α, interferon-γ, interleukin (IL)-2, IL-4, and IL-5 by CD4+ T cells, and MLN composition resembling that of SAMP mice. SAMP BM → AKR mice showed mild or no inflammation with MLN composition and pathogenicity resembling that seen in AKR mice. These results suggest that ileitis in SAMP mice originates from a nonhematopoietic source and that the size and inflammatory potential of MLN populations is determined by inflammatory status of the recipient. Having determined that ileitis originates from a nonhematopoietic source in SAMP mice, the investigators next assessed epithelial barrier function of the BM chimeric mice. Ilea from AKR BM → SAMP mice exhibited decreased transepithelial electrical resistance (TEER) after 1 hour of culture similar to native SAMP ilea. SAMP BM → AKR and wild-type AKR ilea maintained baseline TEER levels while in culture. Native SAMP and AKR BM → SAMP mice also showed increased epithelial permeability in the small intestine compared with SAMP BM → AKR and wild-type AKR mice. These results suggest that epithelial dysfunction in SAMP mice does not depend on hematopoietic cells because BM from SAMP mice transplanted into AKR mice maintains epithelial barrier function similar to wild-type AKR mice. Interestingly, noninflamed intestinal segments from BM transplant recipient groups did not exhibit decreased TEER (jejunum) or increased permeability (colon). The authors therefore assessed whether increased epithelial permeability precedes the onset of inflammation. Intestinal permeability was measured in native SAMP and AKR mice from 3–20 weeks of age. SAMP mice showed increased small intestinal permeability compared to ARK mice throughout the time course including the earliest time point. However, inflammatory scores and myeloperoxidase (MPO) activity were not greater in SAMP mice compared with AKR mice until after 6 weeks of age. No difference in permeability, inflammatory score, or MPO activity was evident in colon of SAMP or AKR mice. These results indicate that increased epithelial permeability precedes the development of inflammation in SAMP mice. The investigators next determined if bacterial colonization is necessary for increased epithelial permeability in SAMP mice. Small intestinal permeability of 3-week-old germ-free SAMP mice was comparable to that of age-matched specific pathogen-free SAMP mice, but greater than specific pathogen-free AKR mice. Inflammatory scores and bowel histology for all mice were normal. Therefore, increased epithelial permeability in SAMP mice does not depend on colonization with commensal bacteria. Finally, the investigators studied expression of tight junction proteins as a potential underlying mechanism of the epithelial permeability defect in SAMP mice. Claudin-1, -3, and -4 mRNA expression and ZO-1 immunohistochemical staining showed no differences between SAMP and AKR ileum. Previous studies using immunohistochemistry have shown that claudin-1 and ZO-1 expression are decreased in epithelial cells adjacent to transmigrating immune cells in inflammatory bowel disease (IBD) mucosa (Am J Pathol 2001;159:2001–2009). Claudin-2 mRNA was increased in epithelial cells isolated from SAMP ileum but not colon compared with AKR ileum. It is known that increased claudin-2 expression increases epithelial permeability in vitro (J Cell Biol 2001;153:263–272). Occludin mRNA was decreased in ileal and colonic epithelial cells of SAMP mice. Decreased occludin expression in CD patients, as found by immunohistochemical staining and Western and Northern blotting (Am J Pathol 2001;159:2001–2009), increases epithelial permeability in vitro (Cell Microbiol 2000; 2:305–315). These results indicate that the combination of increased claudin-2 and decreased occludin expression in the ileum, but not colon, leads to increased epithelial permeability in ileum of SAMP mice. The authors conclude that the primary susceptibility leading to the development of ileitis in SAMP mice is derived from a nonhematopoietic source. The epithelium may be responsible for ileitis susceptibility given that epithelial barrier dysfunction is evident in AKR BM → SAMP mice, precedes inflammation, and is independent of commensal bacterial colonization. Moreover, epithelial dysfunction in SAMP mice is associated with altered expression and regulation of tight junction proteins. The intestinal epithelium constitutes the body’s largest interface between self and hostile luminal contents and a healthy epithelium forms a highly effective barrier that limits inappropriate activation of immune responses to luminal antigens. It has long been suggested that a defective intestinal mucosal barrier that allows antigens to come into direct contact with lamina propria immune cells may initiate, perpetuate, and accelerate the inflammatory process (Gastroenterol Clin North Am 2002;31:41–62). Host susceptibility factors that establish mucosal barrier function or immune response are involved in determining the chronicity of inflammation (Gut 1988;26:1621–1624). However, definitive evidence of the involvement of epithelial barrier defects as an initiating factor has not been established. Barrier dysfunction involvement in the etiology of IBD is supported by multiple observations. IBD is associated with increased permeability of the intestinal epithelium (Ann N Y Acad Sci 2000;915:333–338, Gastroenterology 1989;97:927–931, Proc Soc Exp Biol Med 1997;214:318–327). Increased permeability precedes and predicts relapse for Crohn’s disease patients (Lancet 1993;341:1437–1439) and increased intestinal permeability is evident in first-degree relatives of Crohn’s disease patients compared with the general population (Ann Intern Med 1986:105:883–885, Gastroenterology 1993;104:1627–1632). Both chemically induced (DSS, TNBS) as well as genetically altered (IL-10−/−) rodent models of colitis are also associated with increased epithelial permeability (Lab Invest 1999;79:49–57, Scand J Gastroenterol 2000;35:1053–1059). The development of severe inflammation in animal models of colitis tends to locate beneath the permeability defect (Nat Rev Immunol 2003;3:521–533). Finally, transgenic animals that exhibit intestinal hyperpermeability consequently show symptoms of mucosal inflammation (Science 1995;270:1203–1207). Although it is clear that intestinal inflammation is associated with barrier dysfunction, it is not known whether barrier dysfunction causes the inflammatory response by allowing antigens to come into direct contact with lamina propria immune cells or if barrier dysfunction results from the inflammatory response. Certainly, there is ample evidence for the latter. For example, several studies have shown that cytokines can impair barrier function. IL-13, which is up-regulated in ulcerative colitis, alters epithelial tight junction protein expression and apoptosis (Gastroenterology 2005;129:550–564). TNF-α, which plays a large role in the pathogenesis of Crohn’s disease, dissembles tight junctions and increases permeability (J Surg Res 2004;116:14–18). Moreover, TNF-α antibody treatment leads to barrier repair in active Crohn’s disease (Gut 2004;53:1295–1302). The work presented by Olson et al provide several lines of evidence that demonstrate barrier dysfunction as the causative event in the SAMP model of ileitis. Consistent with the original observation made by Hollander et al in human disease (Ann Intern Med 1986:105:883–885), barrier dysfunction in SAMP mice is seen early (as early as 3 weeks of age) and precedes objective evidence of inflammation, including histology and MPO assay. Interestingly, permeability defects in SAMP mice are seen only in the ileum where subsequent inflammation ensues but not in the colon or jejunum, which are devoid of inflammation. This is a novel finding that localizes the barrier defect for the first time to the affected area. Surprisingly, the barrier defect seems independent of bacterial colonization in the SAMP model. This is in contrast to the observations made in some animal models of colitis such as IL-10−/− mice in which bacterial colonization is required for barrier defects and subsequent inflammation (Cell 1993:75;263–274). Multiple reasons including genetic manipulations could underlie the discrepancy in the role of bacteria as the underlying cause of barrier dysfunction or inflammatory response in the SAMP versus other models. Nevertheless, data presented in this systematic study using a mouse model that develops spontaneous colitis are convincing for a permeability defect as the initiating event leading to inflammatory response. The mechanism underlying barrier dysfunction in SAMP mice is unknown. Given that the epithelial barrier function is largely regulated by the apical tight junction, alterations in junctional protein expression as observed in Crohn’s disease patients (Am J Pathol 2001;159:2001–2009) have been shown to affect permeability. For example, decrease in occludin or increase in claudin-2 is associated with increased epithelial permeability in vitro (Cell Microbiol 2000;2:305–315, J Cell Biol 2001;153:263–272). Currently, it is thought that claudin-2 determines the transmembrane resistance across cell monolayers (J Cell Biol 2001;143:391–401, J Clin Invest 2001;107:1319–1327) and alters the cation selectivity of the tight junction thereby decreasing its “tightness” (J Cell Sci 115:4969–4076) and that occludin is essential for the formation of the actual tight junction seal (Burns 2005;31:838–844). However, alterations in claudin or occludin levels as the cause of barrier dysfunction needs further study; data in the literature regarding junctional protein levels are controversial regarding the role of these proteins in regulating permeability. For instance, occludin knockout mice do not exhibit any defect in permeability at baseline (Biochim Biophys Acta 2005;1669:34–42). It is clear that much work needs to be done to address the role of altered junctional protein expression as the cause of barrier dysfunction. Although the excitement and challenge now is to elucidate the mechanism that underlies barrier dysfunction, the study from Pizarro et al constitutes a landmark observation that underscores the importance of the epithelial barrier as an initiating factor in IBD. Further studies to determine the genetic, environmental, and immunologic contribution leading to barrier dysfunction in this experimental model and others could help to better understand the etiology of IBD." @default.
• W2072100897 created "2016-06-24" @default.
• W2072100897 creator A5012188262 @default.
• W2072100897 creator A5058959601 @default.
• W2072100897 date "2006-10-01" @default.
• W2072100897 modified "2023-09-26" @default.
• W2072100897 title "When the levee breaks: The etiologic role of epithelial barrier function defects in ileitis" @default.
• W2072100897 doi "https://doi.org/10.1053/j.gastro.2006.08.073" @default.
• W2072100897 hasPublicationYear "2006" @default.
• W2072100897 type Work @default.
• W2072100897 sameAs 2072100897 @default.
• W2072100897 citedByCount "0" @default.
• W2072100897 crossrefType "journal-article" @default.
• W2072100897 hasAuthorship W2072100897A5012188262 @default.
• W2072100897 hasAuthorship W2072100897A5058959601 @default.
• W2072100897 hasBestOaLocation W20721008971 @default.
• W2072100897 hasConcept C14036430 @default.
• W2072100897 hasConcept C142724271 @default.
• W2072100897 hasConcept C2779134260 @default.
• W2072100897 hasConcept C2779280984 @default.
• W2072100897 hasConcept C2780941987 @default.
• W2072100897 hasConcept C51911345 @default.
• W2072100897 hasConcept C71924100 @default.
• W2072100897 hasConcept C86803240 @default.
• W2072100897 hasConcept C95444343 @default.
• W2072100897 hasConceptScore W2072100897C14036430 @default.
• W2072100897 hasConceptScore W2072100897C142724271 @default.
• W2072100897 hasConceptScore W2072100897C2779134260 @default.
• W2072100897 hasConceptScore W2072100897C2779280984 @default.
• W2072100897 hasConceptScore W2072100897C2780941987 @default.
• W2072100897 hasConceptScore W2072100897C51911345 @default.
• W2072100897 hasConceptScore W2072100897C71924100 @default.
• W2072100897 hasConceptScore W2072100897C86803240 @default.
• W2072100897 hasConceptScore W2072100897C95444343 @default.
• W2072100897 hasIssue "4" @default.
• W2072100897 hasLocation W20721008971 @default.
• W2072100897 hasOpenAccess W2072100897 @default.
• W2072100897 hasPrimaryLocation W20721008971 @default.
• W2072100897 hasRelatedWork W1165770904 @default.
• W2072100897 hasRelatedWork W2026971815 @default.
• W2072100897 hasRelatedWork W2411806427 @default.
• W2072100897 hasRelatedWork W2417195432 @default.
• W2072100897 hasRelatedWork W2560433437 @default.
• W2072100897 hasRelatedWork W3026599649 @default.
• W2072100897 hasRelatedWork W3184832484 @default.
• W2072100897 hasRelatedWork W4253544342 @default.
• W2072100897 hasRelatedWork W4287065532 @default.
• W2072100897 hasRelatedWork W4318825633 @default.
• W2072100897 hasVolume "131" @default.
• W2072100897 isParatext "false" @default.
• W2072100897 isRetracted "false" @default.
• W2072100897 magId "2072100897" @default.
• W2072100897 workType "article" @default.