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(American Journal of Pathology. 2007;171:1462-1473.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.070192

Human Pancreatic Secretory Trypsin Inhibitor Stabilizes Intestinal Mucosa against Noxious Agents

Tania Marchbank*, Asif Mahmood{dagger}, Anthony J. Fitzgerald{dagger}, Jan Domin{ddagger}, Matt Butler{dagger}, Robert A. Goodlad§, George Elia§, Helen M. Cox, David A. van Heel*, Subrata Ghosh{dagger} and Raymond J. Playford*

From the Centre for Gastroenterology,* Institute of Cell and Molecular Science, Barts and The London School of Medicine, Queen Mary University of London, London; the Gastroenterology{dagger} and Renal Medicine Sections,{ddagger} Hammersmith Hospital, Imperial College, London; the Histopathology Unit,§ Cancer Research United Kingdom–London Research Institute, Lincoln’s Inn Fields; and the Wolfson Centre for Age-Related Diseases, King’s College London, London, United Kingdom

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.




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Copyright © 2007 by the American Society for Investigative Pathology.