Submission ID 92998

Poster Code HR-P-94
Title of Abstract Effect of pancrestatin inhibition on colonic epithelial cells in an experimental model of ulcerative colitis
Abstract Submission Ulcerative colitis (UC), an inflammatory disorder of the colon, is characterized by impaired mucosal repair. Pancreastatin (PST), an intestinal epithelial cells-derived peptide highly expressed in colonic tissues of UC patients, binds to the glucose-regulated protein (GRP)78, which regulates ER signaling and survival pathways. Moreover, PST correlates with colitis severity a mucosal barrier dysfunction. However, the effect of PST on the colon mucosal healing process remains unknown. We investigated the impact of PST inhibition with pancreastatin inhibitor 8 (PSTI8) on colonic epithelial regeneration in an experimental model of UC induced by dextran sulfate sodium (DSS). C57BL/6 mice treated intrarectally with PSTi8 (2.5mg/mL/kg) or PBS for six-days received 5% DSS or water (control) for five-days. The disease activity index was assessed daily. Colonic tissues were tested for inflammatory and regenerative cytokines interleukin (IL)-6, IL-18, and IL-22. Genetic markers associated with microbial infiltration (resistin-like molecule, RELMβ), stem cells (fast-cycling Lgr5, and fetal-like Ly6a cells) and GRP78-mediated ER activation (ATF6), apoptosis (CHOP), cell survival and proliferation (Gsk3b and mTOR) were evaluated using qRT-PCR. In acute colitis, PST inhibition reduced disease activity with higher stool consistency (p<0.01), delayed bleeding onset (2-4 days,) lower macroscopic score (3.75-3, p=0.05), and lower RELMβ expression (1.7-0.38, p<0.16). DSS-mediated colitis was associated with elevated IL-6 and reduced IL-22 in PSTi8 and PBS-treated mice. No changes were noted between both group. Contrastingly, PSTi8 treatment in basal conditions resulted in markedly elevated IL-22 concentration. Inflammation down-regulated Lgr5 expression and increased Ly6a in PBS-treated mice (p<0.0001). However, Ly6a expression was reduced in PSTi8-treated mice in colitis. Moreover, PST inhibition led to elevated ATF6, CHOP, Gsk3b, and mTOR expression in colitic PSTi8-treated compared to PSTi8-control mice. Yet no changes were noted between PBS-treated colitic mice and control mice. PST inhibition reduced disease severity and lowered inflammation while increasing ER stress, cell survival, and proliferation.
Please indicate who nominated you Dr. Hope Anderson
What Canadian Institutes of Health Research (CIHR) institute is your research most closely aligned? Infection and Immunity
What Canadian Institutes of Health Research (CIHR) pillar of health research does your research fall under? Biomedical
PDF of abstract CSHFR-Abstract.pdf
2023-02-01 at 01:26:59
Presenter and Author(s) Diane Tshikudi
Diane Tshikudi

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