title: Membrane-bound serine protease inhibitor HAI-1 is required for maintenance of intestinal epithelial integrity.
abstract: Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-bound serine protease inhibitor expressed in epithelial tissues. Mutant mouse models revealed that HAI-1/SPINT1 is essential for placental labyrinth formation and is critically involved in regulating epidermal keratinization through interaction with its cognate cell surface protease, matriptase. HAI-1/SPINT1 is abundantly expressed in both human and mouse intestinal epithelium; therefore, we analyzed its role in intestinal function using mice with intestinal epithelial cell-specific deletion of Spint1 generated by interbreeding mice carrying Spint1(LoxP) homozygous alleles with transgenic mice carrying the Cre recombinase gene controlled by the intestine-specific Villin promoter. Although the resulting mice had normal development and appearance, crypts in the proximal aspect of the colon, including the cecum, exhibited histologic abnormalities and increased apoptosis and epithelial cell turnover accompanied by increased intestinal permeability. Distended endoplasmic reticula were observed ultrastructurally in some crypt epithelial cells, indicative of endoplasmic reticular stress. To study the role of HAI-1/SPINT1 in mucosal injury, we induced colitis by adding dextran sodium sulfate to the drinking water. After dextran sodium sulfate treatment, intestine-specific HAI-1/SPINT1-deficient mice had more severe symptoms and a significantly lower survival rate relative to control mice. These results suggest that HAI-1/SPINT1 plays an important role in maintaining colonic epithelium integrity.
authors.affiliation: Section of Oncopathology and Regenerative Biology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Kawaguchi
authors.forename: Naoki
authors.initials: N
authors.lastname: Takeda
authors.forename: Shinri
authors.initials: S
authors.lastname: Hoshiko
authors.forename: Kenji
authors.initials: K
authors.lastname: Yorita
authors.forename: Takashi
authors.initials: T
authors.lastname: Baba
authors.forename: Akira
authors.initials: A
authors.lastname: Sawaguchi
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Nezu
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukushima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kataoka
mesh_terms: D000818:Animals; D017209:Apoptosis; D002462:Cell Membrane / Q000378:metabolism*; D003092:Colitis / Q000473:pathology; D016264:Dextran Sulfate; D004198:Disease Susceptibility; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004848:Epithelium / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D017353:Gene Deletion; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000473:pathology* / Q000648:ultrastructure; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D010539:Permeability; D011485:Protein Binding; D053491:Proteinase Inhibitory Proteins, Secretory
chemical_list: D008562:Membrane Glycoproteins; D053491:Proteinase Inhibitory Proteins, Secretory; C504591:Spint1 protein, mouse; D016264:Dextran Sulfate