The tyrosine kinase inhibitor tyrphostin AG 126 reduces the development ofcolitis in the rat

Inflammatory bower disease is characterized by oxidative and nitrosative st ress, leukocyte infiltration, up-regulation of the expression of intercellu lar adhesion molecule-1 (ICAM-1), and up-regulation of P-selectin in the co lon. Here we investigate the effects of the tyrosine kinase inhibitor, Tyrp hostin AG 126, in rats subjected to experimental colitis. Colitis was induc ed in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DN BS). Rats experienced hemorrhagic diarrhea and weight loss. Four days after administration of DNBS, the mucosa of the colon exhibited large areas of n ecrosis. Neutrophil infiltration (determined by histology as well as an inc rease in myeloperoxidase activity in the mucosa) was associated with up-reg ulation of ICAM-1 and P-selectin, as well as high tissue levels of malondia ldehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polyme rase showed an intense staining in the inflamed colon. Staining with an ant i-COX-P antibody of sections of colon obtained from DNBS-treated rats showe d a diffuse staining of the inflamed tissue. Furthermore, expression of ind ucible nitric oxide synthase was found mainly in macrophages located within the inflamed colon of DNBS-treated rats. Tyrphostin AG 126 (5 mg/kg daily ip) significantly reduced the degree of hemorrhagic diarrhea and weight los s caused by administration of DNBS. Tyrphostin AG 126 also caused a substan tial reduction of (1) the phosphorylation of tyrosine residues of proteins (immunoblots of inflamed colon), (2) the degree of colonic injury, (3) the rise in myeloperoxidase activity (mucosa), (4) the increase in the tissue l evels of malondialdehyde, (5) the increase in staining (immunohistochemistr y) for nitrotyrosine and poly(ADP-ribose) polymerase, as well as (6) the up -regulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that the tyrosine kinase inhibitor Tyrphostin AG 126 reduces the degree of colitis caused by DNBS.