title: Human pancreatic secretory trypsin inhibitor stabilizes intestinal mucosa against noxious agents.
abstract: 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.
authors.affiliation: Centre for Gastroenterology, Institute of Cell and Molecular Science, Barts and The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: Tania
authors.initials: T
authors.lastname: Marchbank
authors.forename: Asif
authors.initials: A
authors.lastname: Mahmood
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Fitzgerald
authors.forename: Jan
authors.initials: J
authors.lastname: Domin
authors.forename: Matt
authors.initials: M
authors.lastname: Butler
authors.forename: Robert A
authors.initials: RA
authors.lastname: Goodlad
authors.forename: George
authors.initials: G
authors.lastname: Elia
authors.forename: Helen M
authors.initials: HM
authors.lastname: Cox
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: Subrata
authors.initials: S
authors.lastname: Ghosh
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Playford
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D003713:Dendritic Cells / Q000502:physiology; D016264:Dextran Sulfate; D066246:ErbB Receptors / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D006801:Humans; D007213:Indomethacin; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000502:physiology; D017136:Ion Transport; D007579:Jejunal Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D014359:Trypsin Inhibitor, Kazal Pancreatic
chemical_list: D002352:Carrier Proteins; C493321:Fabp1 protein, rat; D050556:Fatty Acid-Binding Proteins; D011994:Recombinant Proteins; C486642:SPINK1 protein, human; D014359:Trypsin Inhibitor, Kazal Pancreatic; D016264:Dextran Sulfate; D066246:ErbB Receptors; D007213:Indomethacin