title: Early endothelial damage and increased colonic vascular permeability in the development of experimental ulcerative colitis in rats and mice.
abstract: The role of endothelial damage and increased vascular permeability (VP) in the pathogenesis of ulcerative colitis (UC) has not been investigated. We examined using functional, morphologic, and molecular biologic studies whether and to what extent the endothelial barrier dysfunction precedes enhanced epithelial permeability (EP) and the development of mucosal lesions during the early stages of experimental UC. We showed that in rats with iodoacetamide (IA)-induced UC increased colonic VP occurs early (ie, 2.6-fold increase at 15 min, P<0.01) preceding changes in epithelial barrier permeability. EP was unchanged at 15 and 30 min after IA administration and was increased 1.9-fold at 1 h and 6.7-fold at 2 h (both P<0.001) after IA. In the dextran sodium sulfate-induced slowly developing UC, colonic VP was significantly increased in 2 days (P<0.05) and EP only in 4 days (P<0.05). Mucosal endothelial injury led to hypoxia (P<0.05) of colonic surface epithelial cells 30 min after IA administration that was associated with increased expressions of transcription factors hypoxia-inducible factor-1α and early growth response-1. Electron and light microscopy demonstrated areas of colonic mucosa with perivascular edema covered by intact layer of surface epithelial cells in both rat and mouse models of UC. This is the first demonstration in four models of UC that endothelial damage, increased colonic VP, perivascular edema, and epithelial hypoxia precede epithelial barrier dysfunction that is followed by erosions, ulceration, and inflammation in UC.
authors: Diagnostic and Molecular Medicine, VA Long Beach Healthcare System, Long Beach, CA 90822, USA.
authors: Ganna
authors: G
authors: Tolstanova
authors: Xiaoming
authors: X
authors: Deng
authors: Samuel W
authors: SW
authors: French
authors: William
authors: W
authors: Lungo
authors: Brankica
authors: B
authors: Paunovic
authors: Tetyana
authors: T
authors: Khomenko
authors: Amrita
authors: A
authors: Ahluwalia
authors: Tessa
authors: T
authors: Kaplan
authors: Maria
authors: M
authors: Dacosta-Iyer
authors: Andrzej
authors: A
authors: Tarnawski
authors: Sandor
authors: S
authors: Szabo
authors: Zsuzsanna
authors: Z
authors: Sandor
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D015687:Cell Hypoxia; D003093:Colitis, Ulcerative / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000098:blood supply* / Q000473:pathology; D016264:Dextran Sulfate; D051766:Early Growth Response Protein 1 / Q000235:genetics; D004730:Endothelium, Vascular / Q000473:pathology* / Q000648:ultrastructure; D004848:Epithelium / Q000648:ultrastructure; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000037:antagonists & inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D016753:Interleukin-10 / Q000502:physiology; D007460:Iodoacetamide; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D044385:GTP-Binding Protein alpha Subunits; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D016264:Dextran Sulfate; D007460:Iodoacetamide