The plasminogen‐activating system in hepatic stellate cells

Urokinase plasminogen activator (uPA) generates plasmin, a process inhibited by plasminogen‐activator inhibitor (PAI)‐1 and localized to the cell surface by binding of uPA to a specific receptor. Plasmin degrades extracellular matrix (ECM) both directly and by activation of matrix metalloproteinases...

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Veröffentlicht in:Hepatology (Baltimore, Md.) Md.), 1996-11, Vol.24 (5), p.1172-1178
Hauptverfasser: Leyland, H, Gentry, J, Arthur, M J, Benyon, R C
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Gentry, J
Arthur, M J
Benyon, R C
description Urokinase plasminogen activator (uPA) generates plasmin, a process inhibited by plasminogen‐activator inhibitor (PAI)‐1 and localized to the cell surface by binding of uPA to a specific receptor. Plasmin degrades extracellular matrix (ECM) both directly and by activation of matrix metalloproteinases (MMPs). Because stellate cells play a central role in the pathogenesis of liver fibrosis both via production of ECM proteins and through secretion of MMPs, their contribution to plasmin generation was assessed. Stellate cells were prepared from rat liver and cultured on plastic. Northern analysis showed cellular expression of messenger RNA (mRNA) for PAI‐1, uPA, and uPA receptor. Zymography/reverse zymography identified cell‐surface‐associated uPA activity and uPA and PAI‐1 in culture media. Net uPA activity in culture media was maximal after 7 days in culture and then declined, whereas PAI‐1 antigen levels remained consistently elevated between 7 and 21 days in culture. Stellate cell‐mediated plasmin generation was also seen in in vitro cultures supplemented with plasminogen. Because hepatic stellate cells (HSCs) contain retinoids and release them on activation, the effect of retinoic acid on the plasminogen‐activating system was also assessed. Treatment of cultured HSCs with retinoic acid (1 μmol/L) increased uPA secretion 2.6‐fold but did not alter PAI‐1. We conclude that stellate cells synthesize key components of the plasminogen‐activating system and generate plasmin and therefore have the ability to regulate MMP activation. Upregulation of uPA synthesis by retinoic acid may have implications in matrix remodeling in sites of stellate cell activation in which high concentrations of retinoids may be achieved.
doi_str_mv 10.1002/hep.510240532
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Plasmin degrades extracellular matrix (ECM) both directly and by activation of matrix metalloproteinases (MMPs). Because stellate cells play a central role in the pathogenesis of liver fibrosis both via production of ECM proteins and through secretion of MMPs, their contribution to plasmin generation was assessed. Stellate cells were prepared from rat liver and cultured on plastic. Northern analysis showed cellular expression of messenger RNA (mRNA) for PAI‐1, uPA, and uPA receptor. Zymography/reverse zymography identified cell‐surface‐associated uPA activity and uPA and PAI‐1 in culture media. Net uPA activity in culture media was maximal after 7 days in culture and then declined, whereas PAI‐1 antigen levels remained consistently elevated between 7 and 21 days in culture. Stellate cell‐mediated plasmin generation was also seen in in vitro cultures supplemented with plasminogen. Because hepatic stellate cells (HSCs) contain retinoids and release them on activation, the effect of retinoic acid on the plasminogen‐activating system was also assessed. Treatment of cultured HSCs with retinoic acid (1 μmol/L) increased uPA secretion 2.6‐fold but did not alter PAI‐1. We conclude that stellate cells synthesize key components of the plasminogen‐activating system and generate plasmin and therefore have the ability to regulate MMP activation. 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Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Other diseases. Semiology</subject><subject>Plasminogen - metabolism</subject><subject>Plasminogen Activator Inhibitor 1 - analysis</subject><subject>Plasminogen Activator Inhibitor 1 - biosynthesis</subject><subject>Plasminogen Activator Inhibitor 1 - genetics</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Cell Surface - analysis</subject><subject>Receptors, Cell Surface - biosynthesis</subject><subject>Receptors, Cell Surface - genetics</subject><subject>Receptors, Urokinase Plasminogen Activator</subject><subject>RNA, Messenger - analysis</subject><subject>Tretinoin - pharmacology</subject><subject>Urokinase-Type Plasminogen Activator - analysis</subject><subject>Urokinase-Type Plasminogen Activator - biosynthesis</subject><subject>Urokinase-Type Plasminogen Activator - genetics</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kL9OwzAQxi0EKqUwMiJlQGwpZzux44EBVYUiVYKhzJbjOK1R_hGnoGw8As_Ik-CqUdmYTnf3u_vuPoQuMUwxALndmGYaYyARxJQcoTGOCQ8pjeEYjYFwCAWm4hSdOfcGACIiyQiNEgGUimiM7lYbEzSFcqWt6rWpfr6-le7sh-pstQ5c7zpTBrYKvIov6cDnRaE6E2gf3Tk6yVXhzMUQJ-j1Yb6aLcLl8-PT7H4ZasooCWnCMogJMEF4inPNI5PSNIOURTlPc5ZyrYmiOMdYKGDU-AFFPJ-BoIYwOkE3-71NW79vjetkad3uAlWZeuskT2IQ2L80QeEe1G3tXGty2bS2VG0vMcidXdI_Ig92ef5qWLxNS5Md6MEf378e-sppVeStqrR1B4xEnHPGPcb32KctTP-_plzMX_4O-AWb8oKT</recordid><startdate>199611</startdate><enddate>199611</enddate><creator>Leyland, H</creator><creator>Gentry, J</creator><creator>Arthur, M J</creator><creator>Benyon, R C</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>199611</creationdate><title>The plasminogen‐activating system in hepatic stellate cells</title><author>Leyland, H ; Gentry, J ; Arthur, M J ; Benyon, R C</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3632-386d05206927b1fc74eb3bd0b64f7bf6b7cc2a31f119a063e386a2206d093e263</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Adipocytes - metabolism</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Culture Media, Conditioned</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Liver - metabolism</topic><topic>Liver Cirrhosis - etiology</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Other diseases. Semiology</topic><topic>Plasminogen - metabolism</topic><topic>Plasminogen Activator Inhibitor 1 - analysis</topic><topic>Plasminogen Activator Inhibitor 1 - biosynthesis</topic><topic>Plasminogen Activator Inhibitor 1 - genetics</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Cell Surface - analysis</topic><topic>Receptors, Cell Surface - biosynthesis</topic><topic>Receptors, Cell Surface - genetics</topic><topic>Receptors, Urokinase Plasminogen Activator</topic><topic>RNA, Messenger - analysis</topic><topic>Tretinoin - pharmacology</topic><topic>Urokinase-Type Plasminogen Activator - analysis</topic><topic>Urokinase-Type Plasminogen Activator - biosynthesis</topic><topic>Urokinase-Type Plasminogen Activator - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Leyland, H</creatorcontrib><creatorcontrib>Gentry, J</creatorcontrib><creatorcontrib>Arthur, M J</creatorcontrib><creatorcontrib>Benyon, R C</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Leyland, H</au><au>Gentry, J</au><au>Arthur, M J</au><au>Benyon, R C</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The plasminogen‐activating system in hepatic stellate cells</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>1996-11</date><risdate>1996</risdate><volume>24</volume><issue>5</issue><spage>1172</spage><epage>1178</epage><pages>1172-1178</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><abstract>Urokinase plasminogen activator (uPA) generates plasmin, a process inhibited by plasminogen‐activator inhibitor (PAI)‐1 and localized to the cell surface by binding of uPA to a specific receptor. Plasmin degrades extracellular matrix (ECM) both directly and by activation of matrix metalloproteinases (MMPs). Because stellate cells play a central role in the pathogenesis of liver fibrosis both via production of ECM proteins and through secretion of MMPs, their contribution to plasmin generation was assessed. Stellate cells were prepared from rat liver and cultured on plastic. Northern analysis showed cellular expression of messenger RNA (mRNA) for PAI‐1, uPA, and uPA receptor. Zymography/reverse zymography identified cell‐surface‐associated uPA activity and uPA and PAI‐1 in culture media. Net uPA activity in culture media was maximal after 7 days in culture and then declined, whereas PAI‐1 antigen levels remained consistently elevated between 7 and 21 days in culture. Stellate cell‐mediated plasmin generation was also seen in in vitro cultures supplemented with plasminogen. Because hepatic stellate cells (HSCs) contain retinoids and release them on activation, the effect of retinoic acid on the plasminogen‐activating system was also assessed. Treatment of cultured HSCs with retinoic acid (1 μmol/L) increased uPA secretion 2.6‐fold but did not alter PAI‐1. We conclude that stellate cells synthesize key components of the plasminogen‐activating system and generate plasmin and therefore have the ability to regulate MMP activation. Upregulation of uPA synthesis by retinoic acid may have implications in matrix remodeling in sites of stellate cell activation in which high concentrations of retinoids may be achieved.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>8903394</pmid><doi>10.1002/hep.510240532</doi><tpages>7</tpages></addata></record>
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subjects Adipocytes - metabolism
Animals
Biological and medical sciences
Culture Media, Conditioned
Gastroenterology. Liver. Pancreas. Abdomen
Liver - metabolism
Liver Cirrhosis - etiology
Liver. Biliary tract. Portal circulation. Exocrine pancreas
Male
Medical sciences
Other diseases. Semiology
Plasminogen - metabolism
Plasminogen Activator Inhibitor 1 - analysis
Plasminogen Activator Inhibitor 1 - biosynthesis
Plasminogen Activator Inhibitor 1 - genetics
Rats
Rats, Sprague-Dawley
Receptors, Cell Surface - analysis
Receptors, Cell Surface - biosynthesis
Receptors, Cell Surface - genetics
Receptors, Urokinase Plasminogen Activator
RNA, Messenger - analysis
Tretinoin - pharmacology
Urokinase-Type Plasminogen Activator - analysis
Urokinase-Type Plasminogen Activator - biosynthesis
Urokinase-Type Plasminogen Activator - genetics
title The plasminogen‐activating system in hepatic stellate cells
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