Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, up-regulation of the expression of
intercellular adhesion molecule-1 (ICAM-1), and up-regulation of
P-selectin in the colon. Here we investigate the effects of the
tyrosine kinase inhibitor,
Tyrphostin AG 126, in rats subjected to experimental
colitis.
Colitis was induced in rats by intracolonic instillation of
dinitrobenzene sulfonic acid (
DNBS). Rats experienced hemorrhagic
diarrhea and
weight loss. Four days after administration of
DNBS, the mucosa of the colon exhibited large areas of
necrosis. Neutrophil infiltration (determined by histology as well as an increase in
myeloperoxidase activity in the mucosa) was associated with up-regulation of
ICAM-1 and
P-selectin, as well as high tissue levels of
malondialdehyde. Immunohistochemistry for
nitrotyrosine and
poly(ADP-ribose) polymerase showed an intense staining in the inflamed colon. Staining with an anti-COX-2 antibody of sections of colon obtained from
DNBS-treated rats showed a diffuse staining of the inflamed tissue. Furthermore, expression of
inducible 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 loss caused by administration of
DNBS.
Tyrphostin AG 126 also caused a substantial 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 levels of
malondialdehyde, (5) the increase in staining (immunohistochemistry) 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 AG126 reduces the degree of
colitis caused by
DNBS.