Small intestine permeability is frequently altered in
inflammatory bowel disease and may be caused by the translocation of intestinal toxins through leaky small intestine tight junctions (TJs) and adherence. Recently, it has been shown that
5-lipoxygenase (5-LO) plays an important role in the development of various inflammatory conditions like
inflammatory bowel disease. In the present study, by comparing the responses in wild-type mice (5-LOWT) with those of mice lacking the
5-lipoxygenase (5-LOKO), we investigated the role played by this
enzyme in the permeability and structure of small intestine TJs in an animal model of experimental
colitis. To address this question, we used an experimental model of
colitis, induced by
dinitrobenzene sulfonic acid (
DNBS). Four days after
colitis induction by
DNBS, the ileal TJs were studied by means of transmission electron microscopy using
lanthanum nitrate and immunohistochemistry of
occludin and ZO-1. When compared with
DNBS-treated 5-LOWT mice,
DNBS-treated 5-LOKO mice experienced a reduced rate of the extent and severity of the histological signs of colon injury. After administration of
DNBS, 5-LOWT mice showed a significant increase of ileal permeability (88.3% +/- 1.2%) compared with
sham (5.6% +/- 0.5%). In
colitis, the percentage of "leaky" junctions in terminal ilea correlated positively with the macroscopic colon damage score. Distal
colitis in 5-LOWT mice induces an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. On the contrary, a significant reduction of (1) the degree of colon injury, (2) the alteration of ZO-1 and
occludin localization (immunohistochemistry), and (3) ileal permeability (8.1% +/- 0.7%) caused by
DNBS in the colon was observed in 5-LOKO mice. Similarly, the treatment of 5-LOWT with
zileuton (50 mg/kg per oral gavage twice a day), a 5-LO inhibitor, resulted in a significant reduction of all the previously described parameters. Taken together, our results clearly demonstrate that 5-LO modulates small intestinal permeability in experimental
colitis through the regulation of TJ
protein.