Absence of functional peroxisome proliferator-activated receptor-alpha enhanced ileum permeability during experimental colitis.
The aim of the present study was to examine the role of endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligand on the permeability and structure of small intestine tight junctions (TJs) in an animal model of experimental colitis, induced by dinitrobenzene sulfuric acid (DNBS). Four days after colitis induction with DNBS, the ileal TJs were studied by means of transmission electron microscopy using lanthanum nitrate and immunohistochemistry of occludin, zonula occludens 1, and claudin 2. Administration of DNBS to wild-type mice induced colon injury associated with a significant increase of plasma and colon tumor necrosis factor-alpha levels and with a significant increase of ileal permeability. Distal colitis in mice induced an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. Small intestinal permeability was associated with the presence of apoptosis (evaluated by FAS ligand expression and terminal deoxynucleotidyltransferase-mediated UTP nick end labeling coloration), which was associated with a significantly increased expression of proapoptotic Bax and decreased ileum content of antiapoptotic Bcl-2. Absence of a functional PPAR-alpha gene in PPAR-alpha knockout mice resulted in a significant augmentation of all the above-described parameters. Taken together, our results clearly demonstrate that endogenous PPAR-alpha ligands reduced small intestinal permeability in experimental colitis through the regulation of apoptosis and TJ protein.
Mazzon
Emanuela
E
Department of Clinical and Experimental Medicine and Pharmacology, University of Messina Torre Biologica, Policlinico Universitario, 98123 Messina, Italy.
Cuzzocrea
Salvatore
S
D000818:Animals; D002463:Cell Membrane Permeability / Q000235:genetics; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D007082:Ileum / Q000378:metabolism* / Q000473:pathology; D007408:Intestinal Absorption / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics* / Q000502:physiology
D047493:PPAR alpha