Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity
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 form...
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| Veröffentlicht in: | The American journal of pathology 2011-10, Vol.179 (4), p.1815-1826 |
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| creator | Kawaguchi, Makiko Takeda, Naoki Hoshiko, Shinri Yorita, Kenji Baba, Takashi Sawaguchi, Akira Nezu, Yuriko Yoshikawa, Tsutomu Fukushima, Tsuyoshi Kataoka, Hiroaki |
| description | 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 Spint1LoxP 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. |
| doi_str_mv | 10.1016/j.ajpath.2011.06.038 |
| format | Article |
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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 Spint1LoxP 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.</description><identifier>ISSN: 0002-9440</identifier><identifier>EISSN: 1525-2191</identifier><identifier>DOI: 10.1016/j.ajpath.2011.06.038</identifier><identifier>PMID: 21840293</identifier><identifier>CODEN: AJPAA4</identifier><language>eng</language><publisher>Bethesda, MD: Elsevier Inc</publisher><subject>Animals ; Apoptosis ; Biological and medical sciences ; Cell Membrane - metabolism ; Colitis - pathology ; Dextran Sulfate ; Disease Susceptibility ; Epithelial Cells - metabolism ; Epithelial Cells - pathology ; Epithelial Cells - ultrastructure ; Epithelium - metabolism ; Epithelium - pathology ; Epithelium - ultrastructure ; Gene Deletion ; Humans ; Intestines - metabolism ; Intestines - pathology ; Intestines - ultrastructure ; Investigative techniques, diagnostic techniques (general aspects) ; Medical sciences ; Membrane Glycoproteins - deficiency ; Membrane Glycoproteins - metabolism ; Mice ; Mice, Knockout ; Organ Specificity ; Pathology ; Pathology. 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All rights reserved. 2011 American Society for Investigative Pathology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c613t-c0301ef1c2b2d70d48218def325f75f3ce76046d3f3ee7da436a0ef010937bf13</citedby><cites>FETCH-LOGICAL-c613t-c0301ef1c2b2d70d48218def325f75f3ce76046d3f3ee7da436a0ef010937bf13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181355/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ajpath.2011.06.038$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>230,315,728,781,785,886,3551,27929,27930,46000,53796,53798</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24591398$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21840293$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kawaguchi, Makiko</creatorcontrib><creatorcontrib>Takeda, Naoki</creatorcontrib><creatorcontrib>Hoshiko, Shinri</creatorcontrib><creatorcontrib>Yorita, Kenji</creatorcontrib><creatorcontrib>Baba, Takashi</creatorcontrib><creatorcontrib>Sawaguchi, Akira</creatorcontrib><creatorcontrib>Nezu, Yuriko</creatorcontrib><creatorcontrib>Yoshikawa, Tsutomu</creatorcontrib><creatorcontrib>Fukushima, Tsuyoshi</creatorcontrib><creatorcontrib>Kataoka, Hiroaki</creatorcontrib><title>Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity</title><title>The American journal of pathology</title><addtitle>Am J Pathol</addtitle><description>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 Spint1LoxP 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.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Cell Membrane - metabolism</subject><subject>Colitis - pathology</subject><subject>Dextran Sulfate</subject><subject>Disease Susceptibility</subject><subject>Epithelial Cells - metabolism</subject><subject>Epithelial Cells - pathology</subject><subject>Epithelial Cells - ultrastructure</subject><subject>Epithelium - metabolism</subject><subject>Epithelium - pathology</subject><subject>Epithelium - ultrastructure</subject><subject>Gene Deletion</subject><subject>Humans</subject><subject>Intestines - metabolism</subject><subject>Intestines - pathology</subject><subject>Intestines - ultrastructure</subject><subject>Investigative techniques, diagnostic techniques (general aspects)</subject><subject>Medical sciences</subject><subject>Membrane Glycoproteins - deficiency</subject><subject>Membrane Glycoproteins - metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Organ Specificity</subject><subject>Pathology</subject><subject>Pathology. 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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.</abstract><cop>Bethesda, MD</cop><pub>Elsevier Inc</pub><pmid>21840293</pmid><doi>10.1016/j.ajpath.2011.06.038</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Apoptosis Biological and medical sciences Cell Membrane - metabolism Colitis - pathology Dextran Sulfate Disease Susceptibility Epithelial Cells - metabolism Epithelial Cells - pathology Epithelial Cells - ultrastructure Epithelium - metabolism Epithelium - pathology Epithelium - ultrastructure Gene Deletion Humans Intestines - metabolism Intestines - pathology Intestines - ultrastructure Investigative techniques, diagnostic techniques (general aspects) Medical sciences Membrane Glycoproteins - deficiency Membrane Glycoproteins - metabolism Mice Mice, Knockout Organ Specificity Pathology Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques Permeability Protein Binding Regular |
| title | Membrane-Bound Serine Protease Inhibitor HAI-1 Is Required for Maintenance of Intestinal Epithelial Integrity |
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