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Epithelial production of elastase is increased in inflammatory bowel disease and causes mucosal inflammation.

ABSTRACT: Imbalance between proteases and their inhibitors plays a crucial role in the development of Inflammatory Bowel Diseases (IBD). Increased elastolytic activity is observed in the colon of patients suffering from IBD. Here, we aimed at identifying the players involved in elastolytic hyperactivity associated with IBD and their contribution to the disease. We revealed that epithelial cells are a major source of elastolytic activity in healthy human colonic tissues and this activity is greatly increased in IBD patients, both in diseased and distant sites of inflammation. This study identified a previously unrevealed production of elastase 2A (ELA2A) by colonic epithelial cells, which was enhanced in IBD patients. We demonstrated that ELA2A hyperactivity is sufficient to lead to a leaky epithelial barrier. Epithelial ELA2A hyperactivity also modified the cytokine gene expression profile with an increase of pro-inflammatory cytokine transcripts, while reducing the expression of pro-resolving and repair factor genes. ELA2A thus appears as a novel actor produced by intestinal epithelial cells, which can drive inflammation and loss of barrier function, two essentials pathophysiological hallmarks of IBD. Targeting ELA2A hyperactivity should thus be considered as a potential target for IBD treatment.

SUBMITTER: Motta JP

PROVIDER: S-EPMC8075934 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:We assessed practice patterns for monitoring mucosal inflammation after biologic initiation and the association between monitoring approaches and development of disease-related complications for Crohn's disease (CD) and ulcerative colitis (UC). METHODS:This study used a Truven Health MarketScan (2007-2016) query for CD and UC patients initiating biologic therapy. Cumulative 24-month disease-related complications (corticosteroids, change of biologic, hospitalization, surgery) in patients undergoing proactive disease monitoring with lower endoscopy, fecal calprotectin, or cross-sectional radiographic enterography (computed tomography enterography or magnetic resonance enterography) within 6 months of biologic initiation vs no early monitoring after biologic initiation were compared. Cox proportional hazard ratios (HRs with 95% confidence intervals [CIs]) adjusted for propensity score were used. RESULTS:Within the first 24 months after biologic initiation, monitoring (proactive or reactive) was performed in 56.4% of CD patients and 67.8% of UC patients, with considerable geographic variability. Early (within 6 months) proactive monitoring was endoscopy-based (87.9%), performed in 11% of CD (n = 2195/19,899) and 12.8% of UC (n = 925/7247) patients. Compared with no early monitoring, early proactive monitoring was associated with a reduction in disease-related complications for CD (adjusted HR [aHR], 0.90; 95% CI, 0.84-0.96) and UC (aHR, 0.87; 95% CI, 0.78-0.97) and predominately driven by a reduction in corticosteroid use (CD: aHR, 0.83; 95% CI, 0.77-0.90; UC: aHR, 0.77; 95% CI, 0.69-0.87). Results were consistent across multiple sensitivity analyses. CONCLUSIONS:Early proactive monitoring of mucosal inflammation in CD and UC within 6 months of biologic initiation was associated with reduction in disease-related complications over 24 months, primarily related to reduced steroid utilization. Wide variation exists in practice patterns for monitoring of mucosal inflammation after biologic initiation.

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Epithelial production of elastase is increased in inflammatory bowel disease and causes mucosal inflammation.

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