ORIGINAL PAPER 5-Aminosalicylic Acid Improves Indomethacin-Induced Enteropathy by Inhibiting iNOS Transcription in Rats Jyotirmoy Nandi Æ Bipin Saud Æ J. Michael Zinkievich Æ David T. Palma Æ Robert A. Levine Received: 17 November 2006 / Accepted: 21 March 2007 / Published online: 15 May 2007 Ó Springer Science+Business Media, LLC 2007 Abstract Nitric oxide has been implicated in the patho- genic mechanism of inflammatory bowel disease states. We evaluated indomethacin-induced enteropathy in rats, in relation to the expression of the inducible isoform of NO synthase (iNOS) using aminosalicylic acid (5-ASA), its isomer 4-ASA (10 or 50 mg/kg/day, po), and dexametha- sone, an iNOS transcription inhibitor (3 mg/kg/day, sc). Enteropathy was induced by indomethacin (7.5 mg/kg/day, sc) for two days and the small intestine was examined for lesions over the next 14 days. Indomethacin-induced small-intestinal ulcer size, mucosal myeloperoxidase activity, iNOS expression and serum nitrite/nitrate levels were maximally increased by day 4 and gradually de- creased by day 14. Treatment with 5-ASA, but not 4-ASA, decreased indomethacin-induced ulcer length, myeloper- oxidase activity, serum nitrite/nitrate levels and iNOS expression at day 4. Dexamethasone had a greater effect than 5-ASA in reducing myeloperoxidase activity and ulcer length by 26 and 32%, respectively. Dexamethasone also reduced serum nitrate/nitrite and iNOS expression to their basal levels. In conclusion, inhibition of iNOS expression by 5-ASA appears to be associated with diminished intestinal ulceration in indomethacin-induced enteropathy. Keywords Intestinal ulceration Á Dexamethasone Á Inducible nitric oxide synthase Á Prostaglandin Á TNF-a Introduction Nitric oxide (NO) is a ubiquitous mediator of numerous physiological processes in the gastrointestinal tract, including gastric mucosal protection [1, 2], regulation of blood flow [3, 4], stimulation of mucus secretion [5], and regulation of motility [6]. The physiological functions of NO are generally ascribed to NO derived from the con- stitutive isoforms of NO synthase (cNOS). On the other hand, relatively large concentrations of NO produced by the inducible isoform of NOS (iNOS) are potentially in- volved in the development of and/or exacerbation of inflammation [7–9]. This action of NO occurs through activation and expression of iNOS, which is triggered by inflammatory cytokines such as interleukin-1b and tumor- necrosis factor alpha (TNF-a). Activity of iNOS is in- creased in animal models of intestinal inflammation [10, 11] and in patients with Crohn’s disease or ulcerative colitis [12, 13]. Indomethacin (INDO)-induced enteritis shares clinical, histological, and pathophysiological characteristics with Crohn’s disease. In animal models, INDO-induced gas- trointestinal injury is associated with acute changes in morphology, i.e., villus smooth-muscle contraction, microvascular injury and changes in permeability [14]. The initial insult leading to these changes has been found to be a consequence of cyclooxygenase (COX) inhibition and subsequent mucosal prostaglandin (PG) deficiency, since INDO-induced lesions are prevented by the administration of PGs [15]. It has been shown that small amounts of NO stimulate the production of PGs and prevent reduction of the heme iron by interacting with scavenging oxygen rad- icals [16]. This would maintain the COX-associated heme iron in the ferric (Fe 3+ ) form, resulting in the formation of potentially protective anti-inflammatory PGs. However, the J. Nandi (&) Á B. Saud Á J. M. Zinkievich Á D. T. Palma Á R. A. Levine Division of Gastroenterology, Department of Medicine, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA e-mail: nandij@upstate.edu 123 Dig Dis Sci (2008) 53:123–132 DOI 10.1007/s10620-007-9832-2