Distribution of epithelial endoplasmic reticulum stress-related proteins in adult and pediatric Crohn's disease: Association with inflammation and fibrosis.

Objective: Intestinal strictures in Crohn's disease (CD), driven by fibrosis remain challenging to treat. Current treatments focus on inflammation, but are less effective against fibrosis. Endoplasmic Reticulum Stress-Related Proteins, including Protein disulfide isomerases (PDIs), may contribute to fibrosis; their roles in CD remain unclear. This study investigated the distribution of AGR2, BiP, PDIA6, ERP44 in intestinal epithelium and their association with fibrosis and inflammation in pediatric and adult CD.

Methods: We retrospectively analyzed 224 patients (2009-2023). CD patients with and without strictures, non IBD controls, and ulcerative colitis patients were compared. Immunohistochemistry assessed Endoplasmic Reticulum Stress-Related protein distribution in epithelium. H&E and Masson's trichrome staining evaluated inflammation and fibrosis. Correlations between protein distribution, inflammation and fibrosis were examined.

Results: AGR2 and BiP were increased in fibro-inflammatory and fibrotic intestinal epithelial tissues, especially in pediatric-onset CD. ERP44 was associated with fibrosis exclusively in pediatric CD. PDIA6 was upregulated in CD compared to non IBD, without fibrosis association. Distinct protein distribution patterns were observed between pediatric and adult CD, and between ileum and colon.

Conclusions: Distinct patterns of AGR2, BiP, PDIA6, and ERP44 in fibrotic and inflammatory intestinal tissues suggest potential roles in CD-associated fibrosis, warranting exploration as biomarkers or therapeutic targets.