Anti-Fibrotic Potential of All Trans Retinoic Acid in Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) embraces Crohn’s disease (CD), ulcerative colitis (UC) and the less common indeterminate colitis, all chronic inflammatory processes of the gastrointestinal (GI) tract. Together, they cause significant morbidity for a million and a half Americans [1]. Symptoms include diarrhea, nausea, abdominal pain, weight loss, which can occasionally prove fatal (i.e., toxic megacolon, perforated bowel) [2]. Patients are also at increased risk for colorectal cancer [3]. First line treatments, including various anti-inflammatory agents and antibiotics, are variably effective against active disease [4]. Remissions can be short-lived and uncontrolled activity is associated with significant side-effects [3]. Gut fibrosis will require most patients (80% and 45% of CD and UC patients, respectively) to undergo surgery [4]. Over the last decade, the so-called biological response modifiers or ‘biologics’, macromolecules that target inflammatory lymphocytes or the cytokines they produce, have emerged as effective therapeutic agents [5]. For example, infliximab, a chimeric anti-human tumor necrosis factor (TNF)-α antibody earned FDA approval almost 20 years ago, based on a high response rate, significant mucosal and fistula healing and long-term remissions in both CD and UC. Additional targets of biologics, either marketed or in various stages of development, include anti-p40, anti-p19, anti-interleukin (IL)-12/23, and antialpha 4/beta 7 integrin antibodies [5, 6]. However, an estimated 30% of patients will not respond to such treatments, and of those who initially respond, 50% will relapse within a year risking significant, often serious side effects including infections and increased risk of cancer. So far, biologics have had only a modest impact on surgery rates [7]. The need for novel therapies remains acute. Literature reports indicate that All trans retinoic acid (ATRA) provides benefit in various rodent models of IBD, including potential anti-fibrotic activity [8, 9]. Retinoic acid can exist in the body as any of five different chemical isomers (all-trans- RA, 9-cisRA, 13-cisRA, 11-cisRA and 9, 13-dicisRA). ATRA is the biologically active isomer and the primary enzymatic product of retinaldehyde oxidation. The retinoic acid family regulates a wide range of biological processes, including embryonic development, reproduction, vision, cell growth and differentiation, as well as, apoptosis and inflammation [10]. Topical ATRA is known as tretinoin, and is currently marketed under several trade names such as Retin-A？, Retin-A Micro？, Atralin？,