Abstract
Disruption of mucosal structure and barrier function contribute to the pathogenesis of inflammatory bowel disease (IBD). Efficacy of therapy in IBD is based on endoscopic mucosal healing, which occurs by a dynamic interplay of epithelial cell regeneration, migration and differentiation. Both mesalamine (5-ASA) and azathioprine (AZTP) promote this process through mechanisms not clearly understood. We examined molecular pathways implicated in epithelial barrier function that were altered by 5-ASA and AZTP. Paracellular permeability induced by inflammatory mediators was mitigated by both compounds through restoration of cellular anchoring complexes. 5-ASA and AZTP induced rearrangement and membranous localization of junctional proteins and modulated genes involved in tight junctions. Intestinal organoids from wildtype-mice treated with TNF-α and IL-10- deficient-mice displayed impaired epithelial barrier with loss of membranous E-cadherin and reduced Desmoglein-2 expression. These effects were counteracted by 5-ASA and AZTP. Unlike AZTP that exhibited antiproliferative effects, 5-ASA promoted wound healing in colon epithelial cells. Both affected cellular senescence, cell cycle distribution and restricted cells in G1 or S phase without inducing apoptosis. This study provides mechanistic evidence that molecular actions of 5-ASA and AZTP on intestinal epithelia are fundamental in the resolution of barrier dysfunction.
Highlights
Disruption of intestinal architecture associated with alterations in intestinal barrier function is a hallmark of inflammatory bowel diseases (IBD) like ulcerative colitis (UC) and Crohn’s disease (CD)[1]
tran-sepithelial electrical resistance (TER) was reduced by TNF-α and this effect was prevented by 5-ASA and AZTP (Supplementary Fig. 1C)
In IBD, mucosal healing is a key parameter to assess the efficacy of treatment, and a predictive factor for sustained clinical remission
Summary
Disruption of intestinal architecture associated with alterations in intestinal barrier function is a hallmark of inflammatory bowel diseases (IBD) like ulcerative colitis (UC) and Crohn’s disease (CD)[1]. Www.nature.com/scientificreports patients and in the animal model of spontaneous colitis is associated with increased DNA damage, contributing to intestinal carcinogenesis[13] These data suggest that chronic inflammation in IBD alters mucosal homeostasis by affecting multiple cellular pathways in intestinal epithelium. The primary goal is mucosal healing, by suppression of inflammation and maintenance of clinical remission These drugs are effective alone: 5-ASA in mild to moderate UC; or thiopurines in moderate to severe IBD. It is critical to identify their molecular interactions with the intestinal epithelium to elucidate the mechanistic aspects of mucosal healing Whether these drugs act through similar pathways or exhibit differential molecular effects has not been investigated in IEC. Utilizing functional assays of paracellular permeability and wound healing, we examined the underlying molecular pathways influenced by 5-ASA and AZTP towards the maintenance of epithelial barrier integrity
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