Protease-Activated Receptors – Key Regulators of Inflammatory Bowel Diseases Progression

Abstract

The pathogenesis and course of inflammatory bowel diseases are related to both immune system disorders and dysfunction of colon permeability. Moreover, co-existing diseases in patients with Crohn’s disease and ulcerative colitis are identified. Currently, there are some therapeutic strategies that affect the function of cytokine/s causing inflammation in the intestinal wall. However, additional approaches which target other components of inflammatory bowel diseases pathogenesis are still needed. Accumulating evidence suggests that proteases and protease-activated receptors seem to be responsible for colitis progression. Experimental and observational studies showed alteration of protease-activated receptors expression in the colon of patients with Crohn’s disease and ulcerative colitis. Furthermore, it was suggested that the expression of protease-activated receptors correlated with inflammatory bowel diseases activity. Moreover, regulation of protease-activated receptors seems to be responsible for the modulation of colitis and clinical manifestation of inflammatory bowel diseases. In this review, we present the current state of knowledge about the contribution of protease-activated receptors to Crohn’s disease and ulcerative colitis and its implications for diagnosis and treatment.

Therapeutic Effect of Proteinase-Activated Receptor-1 Antagonist on Colitis-Associated Carcinogenesis

“… 18 The expression of PAR 1 is up-regulated in IBD patients. 19 , 29 , 30 Therefore, the therapeutic effects of E5555 observed in the AOM/DSS model in the present study could be extrapolated to the therapeutic application of PAR 1 antagonism to the treatment of IBD patients. In fact, the ameliorating effects of PAR 1 antagonists on the damaged intestinal mucosa and increased level of thrombin at the site of inflammation were observed in clinical studies.…”

Current understanding of the interplay between extracellular matrix remodelling and gut permeability in health and disease

“…In vitro studies conducted on HT-29 and Caco-2 cell lines highlighted the role of ELA2A in increasing epithelial permeability, which was found to be prevented by elafin administration [ 6 ]. Among the serine proteases, trypsin and cathepsin G have been linked to increased activation of protease-activated receptors (PARs) [ 108 , 109 ]. An inverse ratio was observed between increased PAR-1 and PAR-2 and decreased ZO-1, suggesting that active degrading properties and increased paracellular permeability are mediated by these enzymes [ 110 , 111 ].…”

90K/Mac-2 BP Is a New Predictive Biomarker of Response to Infliximab Therapy in IBD Patients

“…The pathogenesis of IBD is not entirely clear, but we know that, in genetically predisposed individuals, it can be triggered by one or more factors acting in a vicious circle, self-fueling the chronic inflammation. Among these: various inappropriate and deregulated activations of the immune system [ 4 , 5 , 6 , 7 , 8 ]; several environmental factors; diet and intestinal dysbiosis, a condition characterized by an imbalance in the gut microbial community, thus favoring the prevalence of pathogens versus healthy microbial species [ 9 , 10 , 11 ]. Currently, the main target of IBD therapies is tumor necrosis factor (TNF), a pro-inflammatory cytokine.…”