Restoration of colonic barrier function by tofacitinib in experimental colitis: anti-inflammatory effects and decreased expression of claudins-2 and claudin-15.
Humberto Barbosa da Costa Filho, Gerardo Autran Cavalcante Araújo, Thiago Meneses Araújo Leite Sales, Suliana Mesquita Paula, Marco Antonio de Freitas Clementino, Alexandre Havt, Pedro Marcos Gomes Soares, Marcellus Henrique Loiola Ponte Souza
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引用次数: 0
Abstract
Background/aims: Inflammatory bowel disease can be triggered by disturbances in intestinal mucosal integrity, leading to bacterial transmigration. The treatment of inflammatory bowel diseases must not only aim to reduce inflammation, but also to reverse the damage to mucosal barrier function. Janus kinase (JAK) inhibitors have been used to treat inflammatory diseases, including ulcerative colitis. However, little is known about the ability of this class of drugs to reverse the loss of mucosal integrity. This study evaluated the effects of tofacitinib, a JAK pathway inhibitor, on inflammation and colonic mucosal integrity in a rat model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis.
Methods: Colitis was induced in Wistar rats via rectal administration of TNBS (20 mg+50% ethanol). The control group received only saline. The animals were pretreated with tofacitinib (15 mg/kg) or saline 30 minutes before induction and twice daily thereafter. Seven days after induction, the animals were euthanized, the colon was removed, and myeloperoxidase activity, baseline transepithelial electrical resistance (TER), TER after 1 hour, and fluorescein permeability were assessed. Tight junction proteins in the colon (claudin-2, claudin-15, and tricellulin) were detected using Western blotting.
Results: Tofacitinib treatment significantly reduced (P< 0.05) the inflammatory parameters and preserved the integrity of the intestinal epithelial barrier compared with the colitis group (P< 0.05), increased baseline TER, reduced the drop in TER after 1 hour, and decreased paracellular permeability to fluorescein by reducing claudin-2 and claudin-15 expression.
Conclusions: JAK inhibition by tofacitinib restored colonic barrier function through antiinflammatory effects and decreased claudin-2 and claudin-15 expressions.
期刊介绍：
Intestinal Research (Intest Res) is the joint official publication of the Asian Organization for Crohn''s and Colitis (AOCC), Chinese Society of IBD (CSIBD), Japanese Society for IBD (JSIBD), Korean Association for the Study of Intestinal Diseases (KASID), Taiwan Society of IBD (TSIBD) and Colitis Crohn''s Foundation (India) (CCF, india). The aim of the Journal is to provide broad and in-depth analysis of intestinal diseases, especially inflammatory bowel disease, which shows increasing tendency and significance. As a Journal specialized in clinical and translational research in gastroenterology, it encompasses multiple aspects of diseases originated from the small and large intestines. The Journal also seeks to propagate and exchange useful innovations, both in ideas and in practice, within the research community. As a mode of scholarly communication, it encourages scientific investigation through the rigorous peer-review system and constitutes a qualified and continual platform for sharing studies of researchers and practitioners. Specifically, the Journal presents up-to-date coverage of medical researches on the physiology, epidemiology, pathophysiology, clinical presentations, and therapeutic interventions of the intestinal diseases. General topics of interest include inflammatory bowel disease, colon and small intestine cancer or polyp, endoscopy, irritable bowel syndrome and other motility disorders, infectious enterocolitis, intestinal tuberculosis, and so forth. The Journal publishes diverse types of academic materials such as editorials, clinical and basic reviews, original articles, case reports, letters to the editor, brief communications, perspective, statement or commentary, and images that are useful to clinicians and researchers.
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