Wound Healing Responses at the Gastrointestinal Epithelium: a Close Look at Novel Regulatory Factors and Investigative Approaches

Zusammenfassung

Eine einschichtige Lage von Epithelzellen kleidet den Gastrointestinaltrakt höherer Lebewesen aus und trennt verschiedenste Antigene im Lumen des Darmes von den Immunzellen des Wirtsorganismus in der Lamina propria. Störungen dieser epithelialen Barriere, wie sie beispielsweise im Rahmen von chronisch entzündlichen Darmerkrankungen, von Darmischämien oder infolge bakterieller Infektionen beobachtet werden, induzieren eine ausgeprägte Entzündungsreaktion, die – primär protektiv – überschießen und den Wirtsorganismus dann gefährden kann. Deshalb führen epitheliale Verletzungen zur raschen Induktion einer lokalen Wundheilungsantwort, deren Ziel es ist, die Kontinuität der Epitheldecke und damit die Barrierefunktion wiederherzustellen. Teil dieser Schutzmechanismen ist neben der Epithelzell-Proliferation auch die koordinierte Migration von Epithelzellen in das Wundgebiet bis zum Wundschluss. Zahlreiche Faktoren modulieren diese Prozesse. Sie werden von den Epithelzellen selbst, von Zellen der Lamina propria wie auch von Mikroorganismen im Darmlumen synthetisiert. Dieser Übersichtsartikel fasst die im Rahmen neu entwickelter Ansätze jüngst erweiterten Erkenntnisse zur zellulären Signaltransduktion und der auf sie einwirkenden Faktoren im Rahmen der gastrointestinalen epithelialen Wundheilung und Homeostase kurz zusammen.

Abstract

The gastrointestinal epithelium functions as an important physical barrier that separates the rich, diverse, and potentially immunogenic luminal content from the underlying mucosal immune system. In pathological situations such as inflammatory bowel disease, ischemic/hypoxic episodes and bacterial infection, insults to the intestinal epithelium threaten the integrity of the mucosal barrier and represent a huge challenge for the host. During episodes of epithelial injury and barrier breakdown, the host initiates a rapid wound healing response aimed at resealing the gap region and reestablishing homeostasis. This response named ”restitution” involves migration of epithelial cells toward the injured regions, as well as epithelial cell proliferation until the gap is closed and the barrier function is reestablished. These biological processes are influenced by a variety of factors derived from the gastrointestinal microenvironment, including host epithelial and lamina propria cells, as well as the microbiota, and the dietary and non-dietary components present in the gastrointestinal lumen. In this manuscript, we will review both host signaling events and luminal factors that influence the wound healing response and have an impact on host homeostasis.

Schlüsselwörter

gastrointestinale Epithelzellen - Wundheilung - Schutzmechanismen - Signaltransduktion

Key words

gastrointestinal epithelium - wound healing - microbial host interaction - cell signaling

References

• 1 Packey C D, Sartor R B. Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases.  Curr Opin Infect Dis. 2009;  22 292-301
• 2 Packey C D, Sartor R B. Interplay of commensal and pathogenic bacteria, genetic mutations, and immunoregulatory defects in the pathogenesis of inflammatory bowel diseases.  J Intern Med. 2008;  263 597-606
• 3 Sartor R B. Microbial influences in inflammatory bowel diseases.  Gastroenterology. 2008;  134 577-594
• 4 Sartor R B. Mechanisms of Disease: pathogenesis of Crohn’s disease and ulcerative colitis.  Nat Clin Pract Gastroenterol Hepatol. 2006;  3 390-407
• 5 Hermiston M L, Gordon J I. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin.  Science. 1995;  270 1203-1207
• 6 Dieleman L A, Palmen M J, Akol H. et al . Chronic experimental colitis induced by dextran sulphate sodium (DSS) is characterized by Th1 and Th2 cytokines.  Clin Exp Immunol. 1998;  114 385-391
• 7 Neurath M F, Fuss I, Kelsall B L. et al . Antibodies to interleukin 12 abrogate established experimental colitis in mice.  J Exp Med. 1995;  182 1281-1290
• 8 Seno H, Miyoshi H, Brown S L. et al . Efficient colonic mucosal wound repair requires Trem2 signaling.  Proc Natl Acad Sci U S A. 2009;  106 256-261
• 9 Dignass A U. Mechanisms and modulation of intestinal epithelial repair.  Inflamm Bowel Dis. 2001;  7 68-77
• 10 Rieder F, Brenmoehl J, Leeb S. et al . Wound healing and fibrosis in intestinal disease.  Gut. 2007;  56 130-139
• 11 Ciacci C, Lind S E, Podolsky D K. Transforming growth factor beta regulation of migration in wounded rat intestinal epithelial monolayers.  Gastroenterology. 1993;  105 93-101
• 12 Dignass A U, Podolsky D K. Cytokine modulation of intestinal epithelial cell restitution: central role of transforming growth factor beta.  Gastroenterology. 1993;  105 1323-1332
• 13 Dignass A U, Tsunekawa S, Podolsky D K. Fibroblast growth factors modulate intestinal epithelial cell growth and migration.  Gastroenterology. 1994;  106 1254-1262
• 14 Wilson A J, Gibson P R. Epithelial migration in the colon: filling in the gaps.  Clin Sci. 1997;  93 97-108
• 15 Kato K, Chen M C, Nguyen M. et al . Effects of growth factors and trefoil peptides on migration and replication in primary oxyntic cultures.  Am J Physiol. 1999;  276 G1105-G1116
• 16 Taupin D, Podolsky D K. Trefoil factors: initiators of mucosal healing.  Nat Rev Mol Cell Biol. 2003;  4 721-732
• 17 Egan L J, Lecea de A, Lehrman E D. et al . Nuclear factor-kappa B activation promotes restitution of wounded intestinal epithelial monolayers.  Am J Physiol Cell Physiol. 2003;  285 C1028-C1035
• 18 Karrasch T, Steinbrecher K A, Allard B. et al . Wound-induced p38 MAPK-dependent histone H 3 phosphorylation correlates with increased COX-2 expression in enterocytes.  J Cell Physiol. 2006;  207 809-815
• 19 Jobin C, Sartor R B. The I kappa B/NF-kappa B system: a key determinant of mucosal inflammation and protection.  Am J Physiol Cell Physiol. 2000;  278 C451-C462
• 20 Karrasch T, Jobin C. NF-kappaB and the intestine: friend or foe?.  Inflamm Bowel Dis. 2008;  14 114-124
• 21 Dobrovolskaia M A, Kozlov S V. Inflammation and cancer: when NF-kappaB amalgamates the perilous partnership.  Curr Cancer Drug Targets. 2005;  5 325-344
• 22 Strauch E D, Bass B L, Rao J N. et al . NF-kappaB regulates intestinal epithelial cell and bile salt-induced migration after injury.  Ann Surg. 2003;  237 494-501
• 23 Shindo K, Iizuka M, Sasaki K. et al . Sucralfate prevents the delay of wound repair in intestinal epithelial cells by hydrogen peroxide through NF-kappaB pathway.  J Gastroenterol. 2006;  41 450-461
• 24 Morteau O, Morham S G, Sellon R. et al . Impaired mucosal defense to acute colonic injury in mice lacking cyclooxygenase-1 or cyclooxygenase-2.  J Clin Invest. 2000;  105 469-478
• 25 Kabashima K, Saji T, Murata T. et al . The prostaglandin receptor EP 4 suppresses colitis, mucosal damage and CD 4 cell activation in the gut.  J Clin Invest. 2002;  109 883-893
• 26 Nitta M, Hirata I, Toshina K. et al . Expression of the EP 4 prostaglandin E 2 receptor subtype with rat dextran sodium sulphate colitis: colitis suppression by a selective agonist, ONO-AE1 – 329.  Scand J Immunol. 2002;  56 66-75
• 27 Dieckgraefe B K, Weems D M, Santoro S A. et al . ERK and p38 MAP kinase pathways are mediators of intestinal epithelial wound-induced signal transduction.  Biochem Biophys Res Commun. 1997;  233 389-394
• 28 Goke M, Kanai M, Lynch-Devaney K. et al . Rapid mitogen-activated protein kinase activation by transforming growth factor alpha in wounded rat intestinal epithelial cells.  Gastroenterology. 1998;  114 697-705
• 29 Frey M R, Golovin A, Polk D B. Epidermal growth factor-stimulated intestinal epithelial cell migration requires Src family kinase-dependent p38 MAPK signaling.  J Biol Chem. 2004;  279 44 513-44 521
• 30 Frey M R, Dise R S, Edelblum K L. et al . p38 kinase regulates epidermal growth factor receptor downregulation and cellular migration.  EMBO J. 2006;  25 5683-5692
• 31 Fu X B, Yang Y H, Sun T Z. et al . Rapid mitogen-activated protein kinase by basic fibroblast growth factor in rat intestine after ischemia/reperfusion injury.  World J Gastroenterol. 2003;  9 1312-1317
• 32 Fu X B, Xing F, Yang Y H. et al . Activation of phosphorylating-p38 mitogen-activated protein kinase and its relationship with localization of intestinal stem cells in rats after ischemia-reperfusion injury.  World J Gastroenterol. 2003;  9 2036-2039
• 33 Nishimura T, Andoh A, Nishida A. et al . FR167653, a p38 mitogen-activated protein kinase inhibitor, aggravates experimental colitis in mice.  World J Gastroenterol. 2008;  14 5851-5856
• 34 ten Hove T, Blink van den B, Pronk I. et al . Dichotomal role of inhibition of p38 MAPK with SB 203 580 in experimental colitis.  Gut. 2002;  50 507-512
• 35 Bakin A V, Rinehart C, Tomlinson A K. et al . p38 mitogen-activated protein kinase is required for TGFbeta-mediated fibroblastic transdifferentiation and cell migration.  J Cell Sci. 2002;  115 3193-3206
• 36 Bates R C, Mercurio A M. Tumor necrosis factor-alpha stimulates the epithelial-to-mesenchymal transition of human colonic organoids.  Mol Biol Cell. 2003;  14 1790-1800
• 37 Karrasch T, Allard B, Jobin C. PI3K-dependent GSK3 beta phosphorylation is implicated in the intestinal epithelial cell wound-healing response.  Gastroenterology. 2006;  130 A490-A491
• 38 Novak A, Dedhar S. Signaling through beta-catenin and Lef/Tcf.  Cell Mol Life Sci. 1999;  56 523-537
• 39 Kolligs F T, Bommer G, Goke B. Wnt/beta-catenin/tcf signaling: a critical pathway in gastrointestinal tumorigenesis.  Digestion. 2002;  66 131-144
• 40 Bianchi M, De Lucchini S, Marin O. et al . Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP 1 during cell spreading and migration.  Biochem J. 2005;  391 359-370
• 41 Xu K P, Ding Y, Ling J. et al . Wound-induced HB-EGF ectodomain shedding and EGFR activation in corneal epithelial cells.  Invest Ophthalmol Vis Sci. 2004;  45 813-820
• 42 Tokumaru S, Higashiyama S, Endo T. et al . Ectodomain shedding of epidermal growth factor receptor ligands is required for keratinocyte migration in cutaneous wound healing.  J Cell Biol. 2000;  151 209-220
• 43 Beck P L, Rosenberg I M, Xavier R J. et al . Transforming growth factor-beta mediates intestinal healing and susceptibility to injury in vitro and in vivo through epithelial cells.  Am J Pathol. 2003;  162 597-608
• 44 Wachs F P, Krieg R C, Rodrigues C M. et al . Bile salt-induced apoptosis in human colon cancer cell lines involves the mitochondrial transmembrane potential but not the CD 95 (Fas/Apo-1) receptor.  Int J Colorectal Dis. 2005;  20 103-113
• 45 Owen C R, Yuan L, Basson M D. Smad3 knockout mice exhibit impaired intestinal mucosal healing.  Lab Invest. 2008;  88 1101-1109
• 46 Delaney J R, Mlodzik M. TGF-beta activated kinase-1: new insights into the diverse roles of TAK1 in development and immunity.  Cell Cycle. 2006;  5 2852-2855
• 47 Banerjee A, Gerondakis S. Coordinating TLR-activated signaling pathways in cells of the immune system.  Immunol Cell Biol. 2007;  85 420-424
• 48 Adhikari A, Xu M, Chen Z J. Ubiquitin-mediated activation of TAK1 and IKK.  Oncogene. 2007;  26 3214-3226
• 49 Kajino-Sakamoto R, Inagaki M, Lippert E. et al . Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis.  J Immunol. 2008;  181 1143-1152
• 50 Kim J Y, Kajino-Sakamoto R, Omori E. et al . Intestinal epithelial-derived TAK1 signaling is essential for cytoprotection against chemical-induced colitis.  PLoS ONE. 2009;  4 e4561
• 51 Burgess A W. EGFR family: structure physiology signalling and therapeutic targets.  Growth Factors. 2008;  26 263-274
• 52 Fiske W H, Threadgill D, Coffey R J. ERBBs in the gastrointestinal tract: recent progress and new perspectives.  Exp Cell Res. 2009;  315 583-601
• 53 Frey M R, Edelblum K L, Mullane M T. et al . The ErbB4 growth factor receptor is required for colon epithelial cell survival in the presence of TNF.  Gastroenterology. 2009;  136 217-226
• 54 El-Assal O N, Besner G E. HB-EGF enhances restitution after intestinal ischemia/reperfusion via PI 3K/Akt and MEK/ERK1 / 2 activation.  Gastroenterology. 2005;  129 609-625
• 55 Dise R S, Frey M R, Whitehead R H. et al . Epidermal growth factor stimulates Rac activation through Src and phosphatidylinositol 3-kinase to promote colonic epithelial cell migration.  Am J Physiol Gastrointest Liver Physiol. 2008;  294 G276-G285
• 56 Gayer C P, Chaturvedi L S, Wang S. et al . Delineating the signals by which repetitive deformation stimulates intestinal epithelial migration across fibronectin.  Am J Physiol Gastrointest Liver Physiol. 2009;  296 G876-G885
• 57 Durer U, Hartig R, Bang S. et al . TFF3 and EGF induce different migration patterns of intestinal epithelial cells in vitro and trigger increased internalization of E-cadherin.  Cell Physiol Biochem. 2007;  20 329-346
• 58 Hoffmann W. Trefoil factor family (TFF) peptides: regulators of mucosal regeneration and repair, and more.  Peptides. 2004;  25 727-730
• 59 Dignass A, Lynch-Devaney K, Kindon H. et al . Trefoil peptides promote epithelial migration through a transforming growth factor beta-independent pathway.  J Clin Invest. 1994;  94 376-383
• 60 Qureshi F G, Leaphart C, Cetin S. et al . Increased expression and function of integrins in enterocytes by endotoxin impairs epithelial restitution.  Gastroenterology. 2005;  128 1012-1022
• 61 Strauch E D, Wang J Y, Bass B L. Bile salt stimulates intestinal epithelial cell migration through TGFbeta after wounding.  J Surg Res. 2001;  97 49-53
• 62 Strauch E D, Yamaguchi J, Bass B L. et al . Bile salts regulate intestinal epithelial cell migration by nuclear factor-kappa B-induced expression of transforming growth factor-beta.  J Am Coll Surg. 2003;  197 974-984
• 63 Muhlbauer M, Allard B, Bosserhoff A K. et al . Differential effects of deoxycholic acid and taurodeoxycholic acid on NF{kappa}B signal transduction and IL-8 gene expression in colonic epithelial cells.  Am J Physiol Gastrointest Liver Physiol. 2004;  286 G1000-G1008
• 64 Yamaguchi N, Argueta J G, Masuhiro Y. et al . Adiponectin inhibits Toll-like receptor family-induced signaling.  FEBS Lett. 2005;  579 6821-6826
• 65 Toledo A, Yamaguchi J, Wang J Y. et al . Taurodeoxycholate stimulates intestinal cell proliferation and protects against apoptotic cell death through activation of NF-kappaB.  Dig Dis Sci. 2004;  49 1664-1671
• 66 Yamaguchi J, Toledo A, Bass B L. et al . Taurodeoxycholate increases intestinal epithelial cell proliferation through c-myc expression.  Surgery. 2004;  135 215-221
• 67 Roediger W E. Role of anaerobic bacteria in the metabolic welfare of the colonic mucosa in man.  Gut. 1980;  21 793-798
• 68 Huang N, Katz J P, Martin D R. et al . Inhibition of IL-8 gene expression in Caco-2 cells by compounds which induce histone hyperacetylation.  Cytokine. 1997;  9 27-36
• 69 Kamitani H, Ikawa H, Hsi L C. et al . Regulation of 12-lipoxygenase in rat intestinal epithelial cells during differentiation and apoptosis induced by sodium butyrate.  Arch Biochem Biophys. 1999;  368 45-55
• 70 Fusunyan R D, Quinn J J, Fujimoto M. et al . Butyrate switches the pattern of chemokine secretion by intestinal epithelial cells through histone acetylation.  Mol Med. 1999;  5 631-640
• 71 Wilson A J, Gibson P R. Short-chain fatty acids promote the migration of colonic epithelial cells in vitro.  Gastroenterology. 1997;  113 487-496
• 72 Wong J M, Souza de R, Kendall C W. et al . Colonic health: fermentation and short chain fatty acids.  J Clin Gastroenterol. 2006;  40 235-243
• 73 Wright N A, Hoffmann W, Otto W R. et al . Rolling in the clover: trefoil factor family (TFF)-domain peptides, cell migration and cancer.  FEBS Lett. 1997;  408 121-123
• 74 Playford R J, Marchbank T, Chinery R. et al . Human spasmolytic polypeptide is a cytoprotective agent that stimulates cell migration.  Gastroenterology. 1995;  108 108-116
• 75 Babyatsky M W, deBeaumont M, Thim L. et al . Oral trefoil peptides protect against ethanol- and indomethacin-induced gastric injury in rats.  Gastroenterology. 1996;  110 489-497
• 76 Mashimo H, Wu D C, Podolsky D K. et al . Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor.  Science. 1996;  274 262-265
• 77 Playford R J, Marchbank T, Goodlad R A. et al . Transgenic mice that overexpress the human trefoil peptide pS2 have an increased resistance to intestinal damage.  Proc Natl Acad Sci U S A. 1996;  93 2137-2142
• 78 Vandenbroucke K, Hans W, Van Huysse J. et al . Active delivery of trefoil factors by genetically modified Lactococcus lactis prevents and heals acute colitis in mice.  Gastroenterology. 2004;  127 502-513
• 79 Kjellev S, Thim L, Pyke C. et al . Cellular localization, binding sites, and pharmacologic effects of TFF3 in experimental colitis in mice.  Dig Dis Sci. 2007;  52 1050-1059
• 80 Podolsky D K, Gerken G, Eyking A. et al . Colitis-associated variant of TLR2 causes impaired mucosal repair because of TFF3 deficiency.  Gastroenterology. 2009;  137 209-220
• 81 Steidler L, Hans W, Schotte L. et al . Treatment of murine colitis by Lactococcus lactis secreting interleukin-10.  Science. 2000;  289 1352-1355
• 82 Steidler L, Neirynck S, Huyghebaert N. et al . Biological containment of genetically modified Lactococcus lactis for intestinal delivery of human interleukin 10.  Nat Biotechnol. 2003;  21 785-789
• 83 Nagy T A, Frey M R, Yan F. et al . Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling.  J Infect Dis. 2009;  199 641-651
• 84 Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F. et al . Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.  Cell. 2004;  118 229-241
• 85 Pull S L, Doherty J M, Mills J C. et al . Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury.  Proc Natl Acad Sci U S A. 2005;  102 99-104
• 86 Brown S L, Riehl T E, Walker M R. et al . Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury.  J Clin Invest. 2007;  117 258-269
• 87 Tarnawski A, Hollander D, Stachura J. et al . Vascular and microvascular changes – key factors in the development of acetic acid-induced gastric ulcers in rats.  J Clin Gastroenterol. 1990;  12 (Suppl 1) S148-S157
• 88 Tarnawski A, Hollander D, Krause W J. et al . ”Healed” experimental gastric ulcers remain histologically and ultrastructurally abnormal.  J Clin Gastroenterol. 1990;  12 (Suppl 1) S139-S147
• 89 Russo J M, Florian P, Shen L. et al . Distinct temporal-spatial roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure.  Gastroenterology. 2005;  128 987-1001
• 90 Williams R M, Zipfel W R, Webb W W. Multiphoton microscopy in biological research.  Curr Opin Chem Biol. 2001;  5 603-608
• 91 Xu C, Zipfel W, Shear J B. et al . Multiphoton fluorescence excitation: new spectral windows for biological nonlinear microscopy.  Proc Natl Acad Sci U S A. 1996;  93 10763-10768
• 92 Zipfel W R, Williams R M, Christie R. et al . Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation.  Proc Natl Acad Sci U S A. 2003;  100 7075-7080
• 93 Tirlapur U K, Konig K, Peuckert C. et al . Femtosecond near-infrared laser pulses elicit generation of reactive oxygen species in mammalian cells leading to apoptosis-like death.  Exp Cell Res. 2001;  263 88-97
• 94 Starodub O T, Demitrack E S, Baumgartner H K. et al . Disruption of the Cox-1 gene slows repair of microscopic lesions in the mouse gastric epithelium.  Am J Physiol Cell Physiol. 2008;  294 C223-C232
• 95 Watson A J, Chu S, Sieck L. et al . Epithelial barrier function in vivo is sustained despite gaps in epithelial layers.  Gastroenterology. 2005;  129 902-912
• 96 Bullen T F, Forrest S, Campbell F. et al . Characterization of epithelial cell shedding from human small intestine.  Lab Invest. 2006;  86 1052-1063
• 97 Moyer R A, Wendt M K, Johanesen P A. et al . Rho activation regulates CXCL12 chemokine stimulated actin rearrangement and restitution in model intestinal epithelia.  Lab Invest. 2007;  87 807-817
• 98 Amali A A, Rekha R D, Lin C J. et al . Thioacetamide induced liver damage in zebrafish embryo as a disease model for steatohepatitis.  J Biomed Sci. 2006;  13 225-232
• 99 Bates J M, Mittge E, Kuhlman J. et al . Distinct signals from the microbiota promote different aspects of zebrafish gut differentiation.  Dev Biol. 2006;  297 374-386
• 100 Cvejic A, Hall C, Bak-Maier M. et al . Analysis of WASp function during the wound inflammatory response – live-imaging studies in zebrafish larvae.  J Cell Sci. 2008;  121 3196-3206
• 101 Feitsma H, Cuppen E. Zebrafish as a cancer model.  Mol Cancer Res. 2008;  6 685-694
• 102 Flores M V, Hall C J, Davidson A J. et al . Intestinal differentiation in zebrafish requires Cdx1b, a functional equivalent of mammalian Cdx2.  Gastroenterology. 2008;  135 1665-1675
• 103 Grabher C, Look A T. Fishing for cancer models.  Nat Biotechnol. 2006;  24 45-46
• 104 Park S W, Davison J M, Rhee J. et al . Oncogenic KRAS induces progenitor cell expansion and malignant transformation in zebrafish exocrine pancreas.  Gastroenterology. 2008;  134 2080-2090
• 105 Trede N S, Langenau D M, Traver D. et al . The use of zebrafish to understand immunity.  Immunity. 2004;  20 367-379
• 106 Sar A M, Appelmelk B J, Vandenbroucke-Grauls C M. et al . A star with stripes: zebrafish as an infection model.  Trends Microbiol. 2004;  12 451-457
• 107 Wallace K N, Akhter van der S, Smith E M. et al . Intestinal growth and differentiation in zebrafish.  Mech Dev. 2005;  122 157-173
• 108 Yang J, Chan C Y, Jiang B. et al . hnRNP I Inhibits notch signaling and regulates intestinal epithelial homeostasis in the zebrafish.  PLoS Genet. 2009;  5 e1000363
• 109 Zhang Y, Bai X T, Zhu K Y. et al . In vivo interstitial migration of primitive macrophages mediated by JNK-matrix metalloproteinase 13 signaling in response to acute injury.  J Immunol. 2008;  181 2155-2164
• 110 Keller P J, Schmidt A D, Wittbrodt J. et al . Reconstruction of zebrafish early embryonic development by scanned light sheet microscopy.  Science. 2008;  322 1065-1069
• 111 Stoletov K, Montel V, Lester R D. et al . High-resolution imaging of the dynamic tumor cell vascular interface in transparent zebrafish.  Proc Natl Acad Sci U S A. 2007;  104 17406-17411
• 112 Helmchen F, Denk W. Deep tissue two-photon microscopy.  Nat Methods. 2005;  2 932-940
• 113 Brustein E, Marandi N, Kovalchuk Y. et al . ”In vivo” monitoring of neuronal network activity in zebrafish by two-photon Ca(2 + ) imaging.  Pflugers Arch. 2003;  446 766-773
• 114 Kirby B B, Takada N, Latimer A J. et al . In vivo time-lapse imaging shows dynamic oligodendrocyte progenitor behavior during zebrafish development.  Nat Neurosci. 2006;  9 1506-1511
• 115 Pack M, Solnica-Krezel L, Malicki J. et al . Mutations affecting development of zebrafish digestive organs.  Development. 1996;  123 321-328
• 116 Abreu M T, Fukata M, Arditi M. TLR signaling in the gut in health and disease.  J Immunol. 2005;  174 4453-4460
• 117 Neurath M F, Pettersson S, Meyer zum Buschenfelde K H. et al . Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice.  Nat Med. 1996;  2 998-1004
• 118 Chen L W, Egan L, Li Z W. et al . The two faces of IKK and NF-kappaB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion.  Nat Med. 2003;  9 575-581
• 119 Karrasch T, Kim J S, Jang B I. et al . The Flavonoid luteolin worsens chemical-induced colitis in NF-kappaB transgenic mice through blockade of NF-kappaB-dependent protective molecules.  PLoS ONE. 2007;  2 e596
• 120 Joo Y E, Karrasch T, Muhlbauer M. et al . Tomato lycopene extract prevents lipopolysaccharide-induced NF-kappaB signaling but worsens dextran sulfate sodium-induced colitis in NF-kappaBEGFP mice.  PLoS ONE. 2009;  4 e4562
• 121 Merritt A J, Potten C S, Kemp C J. et al . The role of p53 in spontaneous and radiation-induced apoptosis in the gastrointestinal tract of normal and p53-deficient mice.  Cancer Res. 1994;  54 614-617
• 122 Potten C S. Interleukin-11 protects the clonogenic stem cells in murine small-intestinal crypts from impairment of their reproductive capacity by radiation.  Int J Cancer. 1995;  62 356-361
• 123 Stallion A, Kou T D, Miller K A. et al . IL-10 is not protective in intestinal ischemia reperfusion injury.  J Surg Res. 2002;  105 145-152
• 124 Zhao H, Montalto M C, Pfeiffer K J. et al . Murine model of gastrointestinal ischemia associated with complement-dependent injury.  J Appl Physiol. 2002;  93 338-345
• 125 Morris G P, Wallace J L. The roles of ethanol and of acid in the production of gastric mucosal erosions in rats.  Virchows Arch B Cell Pathol Incl Mol Pathol. 1981;  38 23-38
• 126 Hingson D J, Ito S. Effect of aspirin and related compounds on the fine structure of mouse gastric mucosa.  Gastroenterology. 1971;  61 156-177
• 127 Sigthorsson G, Simpson R J, Walley M. et al . COX-1 and 2, intestinal integrity, and pathogenesis of nonsteroidal anti-inflammatory drug enteropathy in mice.  Gastroenterology. 2002;  122 1913-1923
• 128 Berg D J, Zhang J, Weinstock J V. et al . Rapid development of colitis in NSAID-treated IL-10-deficient mice.  Gastroenterology. 2002;  123 1527-1542
• 129 Watanabe T, Higuchi K, Kobata A. et al . Non-steroidal anti-inflammatory drug-induced small intestinal damage is Toll-like receptor 4 dependent.  Gut. 2008;  57 181-187