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Abstract
Angiotensin (Ang) II plays a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). Both ACEI and Ang II type 1 receptor blockers (ARBs) possess anticolitic efficacy; however, irbesartan (Irb) potential anti-ulcerative properties has not been reported previously. Colitis was induced in male Wistar rats by the rectal installation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Animals were divided into control, TNBS, sulfasalazine (Sulfz; 300 mg/kg), Irb (30 and 100 mg/kg), and combination (Sulfz/Irb30) groups. Irb at both dose levels attenuated the severity of colitis, as evidenced by decrease of ulcerative area, colon/spleen mass index, weight loss, and histopathological findings. It reduced the inflammatory response, via attenuation of nuclear factor (NF)-mB p65, tumor necrosis factor-{uF061}, interleukin-6, intracellular adhesion molecule-1, as well as myeloperoxidase activity. The drug was also able to restore junctional adhesion molecule (JAM)-A and trefoil factor (TFF)-3 to decrease epithelial barrier dysfunction. In association, the ARB was able to halt oxidative stress evidenced by the suppression of lipid peroxidation and capase-3, a marker of apoptosis. Besides, it increased nuclear factor nuclear factor (erythroidderived 2)-like-2 and hemeoxygenase-1. These effects were more prominent with the 100 mg/kg dose that was comparable to Sulfz. Meanwhile, the combination with Irb surpassed the anti-inflammatory, antioxidant and antiapoptotic effects and improved barrier strengthening mediated by Sulfz alone; however it did not modulate the reduction in the ulcer severity produced by Sulfz alone. In conclusion, Irb hampers IBD through the modulation of colonic inflammation, oxidative stress, and apoptosis, as well as enhancement of TFF-3 to preserve the tight junction JAM-A improving gut barrier function.