A variety of hepatobiliary abnormalities occur in
inflammatory bowel diseases (IBDs). The role of tight junction (TJ) in hepatobiliary complications have been well described. The purpose of this study was to investigate the role of inducible
nitric oxide (NOS) in alteration of hepatocyte TJ paracellular barrier and in the rapid transcytotic vesicular pathway modification associated with intestinal
inflammation. To address this question, we used an experimental model of
colitis, induced by
dinitrobenzene sulfonic acid (
DNBS). When compared to
DNBS-treated iNOS wild-type (WT) mice,
DNBS-treated iNOS knock out mice (iNOSKO) mice experienced a significant less rate of the extent and severity of the histological signs of colon injury. Colon levels of the pro-inflammatory
cytokines tumour
necrosis factor,
interleukin-1beta and
interleukin-6 were also significantly reduced in iNOS-KO mice in comparison to wild-type mice. Liver histology from iNOSKO and wild-type mice iNOSWT did not show any parenchymal and portal tract
inflammation at 4 days after
DNBS administration. Serum total
bilirubin and
alanine aminotransferase, were significantly reduced in
DNBS-iNOSKO mice vs
DNBS-iNOSKO mice. Therefore, we found an increase of tight junctional permeability to
lanthanum nitrate (molecular weight, 433) in the livers from
DNBS-treated IL-10WT mice,
lanthanum accumulated throughout the junctional area up to the most apical region bordering the lumen. Absence of a functional iNOS gene in iNOSKO mice resulted in a significant reduction of apical diffusion of
lanthanum after
DNBS-induced
colitis. Immunofluorescent labeling of frozen liver sections from
DNBS-iNOSWT mice showed a significant alteration of the immunolocalization for
claudin-1 and zonula occludens (ZO)-1. In contrast, a significant reduced alteration in the localization of the immunosignals for
claudin-1 and ZO-1 was observed in the liver from iNOSKO mice after
DNBS administration. In conclusion, we suggest that the iNOS may represent an important pathophysiological mechanism of hepatobiliary
injuries and
cholestasis observed in patients with IBD.