Human pancreatic secretory trypsin inhibitor stabilizes intestinal mucosa against noxious agents
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Marchbank, T and Mahmood, A and Fitzgerald, AJ and Domin, J and Butler, M and Goodlad, RA and Elia, G and Cox, HM and van Heel, DA and Ghosh, S and Playford, RJ, Human pancreatic secretory trypsin inhibitor stabilizes intestinal mucosa against noxious agents, American Journal of Pathology, 171, (5) pp. 1462-1473. ISSN 0002-9440 (2007) [Refereed Article]
Pancreatic secretory trypsin inhibitor (PSTI) is a serine protease inhibitor, expressed in gut mucosa, whose function is unclear. We, therefore, examined the effects of PSTI on gut stability and repair. Transgenic mice overexpressing human PSTI within the jejunum (FABPi-1178 to +28 hPSTI construct) showed no change in baseline morphology or morphometry but reduced indomethacin-induced injury in overexpressing hPSTI region by 42% (P < 0.01). Systemic recombinant hPSTI did not affect baseline morphology or morphometry but truncated injurious effects in prevention and recovery rat models of dextran-sodium-sulfate-induced colitis. In vitro studies showed PSTI stimulated cell migration but not proliferation of human colonic carcinoma HT29 or immortalized mouse colonic YAMC cells. PSTI also induced changes in vectorial ion transport (short-circuit current) when added to basolateral but not apical surfaces of polarized monolayers of Colony-29 cells. Restitution and vectorial ion transport effects of PSTI were dependent on the presence of a functioning epidermal growth factor (EGF) receptor because cells with a disrupted (EGFR -/- immortalized cells) or neutralized (EGFR blocking antibodies or tyrosine kinase inhibitor) receptor prevented these effects. PSTI also reduced the cytokine release of lipopolysaccharide-stimulated dendritic cells. We conclude that administration of PSTI may provide a novel method of stabilizing intestinal mucosa against noxious agents and stimulating repair after injury. Copyright © American Society for Investigative Pathology.
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