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 anti-alpha 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®, Renova®, and Avita® as FDA approved topical treatment for acne and skin wrinkles. Oral formulations, called isotretinoin (Accutane®, Claravis®, Sotret® and Amnesteem® and Vesanoid®) can cure severe acne and treat acute promyelocytic leukemia (APL), but oral dosing induces more severe side effects. Isotretinoin has not been tested in IBD clinical trials, perhaps due to the serious side effects associated with oral administration, including teratogenicity, suicidality, headache, dizziness, fever, weakness, tiredness, dry mouth, dry skin, other skin changes, thinning hair, nausea, vomiting, itching, bone pain, mouth sores, increased sweating, earaches, and perhaps even colitis. Black-box warnings for oral formulations have been issued by the FDA because of these serious side effects, including retinoic acid syndrome in APL patients. Retinoic acid syndrome may manifest as life threatening upper respiratory tract disturbances (dyspnea, respiratory insufficiency, pleural effusion, expiratory wheezing and increased susceptibility to pneumonia). Its frequency, mechanism and treatment have recently been reviewed [11]. Efforts to circumvent toxicities by tissue targeted administration have included encapsulation in liposomes and aerosolization, although none of these have progressed further in development or resulted in marketed products [12,13]. This review begins with an analysis of published studies bearing on the efficacy of ATRA as an anti-inflammatory treatment for IBD, including in vitro and in vivo work in rodents, as well as ex vivo studies using human tissues. Clinical reports about ATRA attenuation or induction of IBD will also be reviewed. Efforts to deliver ATRA directly to gut tissue to improve activity and reduce side effects will then be discussed. Finally, the potential of ATRA to treat fibrosis will be considered. If successful, oral delivery of ATRA directly to the immune structures of the gut could represent a novel IBD therapy with a potential to reduce fibrosis and the subsequent need for surgery.