A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation
Abstract Background Neutrophil elastase (NE) rapidly degrades gel-forming airway mucins in cystic fibrosis (CF) sputum. We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro. Methods Sputa were collected from CF patients ( n = 5) chronically or inte...
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| Veröffentlicht in: | Journal of cystic fibrosis 2016-05, Vol.15 (3), p.325-331 |
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| creator | Chillappagari, Shashi Müller, Christian Mahavadi, Poornima Guenther, Andreas Nährlich, Lutz Rosenblum, Jonathan Rubin, Bruce K Henke, Markus O |
| description | Abstract Background Neutrophil elastase (NE) rapidly degrades gel-forming airway mucins in cystic fibrosis (CF) sputum. We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro. Methods Sputa were collected from CF patients ( n = 5) chronically or intermittently infected with Pseudomonas aeruginosa (P.a.). Mucin degradation was analyzed using western blot. Protease inhibitor studies were performed using alpha1-proteinase inhibitor (A1-PI Prolastin®) and KRP-109. Elastase activity assays were performed using spectrophotometry. Results There were significant differences in the amount of active NE in different CF sputum samples. KRP-109 decreased the NE driven mucin degradation in vitro. Pseudomonas elastases appeared to blunt elastase inhibition by A1-PI or KRP-109. Conclusion Inhibitors of neutrophil and Pseudomonas -derived elastases might rescue mucus clearance and reverse airway obstruction in CF. |
| doi_str_mv | 10.1016/j.jcf.2015.10.008 |
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We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro. Methods Sputa were collected from CF patients ( n = 5) chronically or intermittently infected with Pseudomonas aeruginosa (P.a.). Mucin degradation was analyzed using western blot. Protease inhibitor studies were performed using alpha1-proteinase inhibitor (A1-PI Prolastin®) and KRP-109. Elastase activity assays were performed using spectrophotometry. Results There were significant differences in the amount of active NE in different CF sputum samples. KRP-109 decreased the NE driven mucin degradation in vitro. Pseudomonas elastases appeared to blunt elastase inhibition by A1-PI or KRP-109. Conclusion Inhibitors of neutrophil and Pseudomonas -derived elastases might rescue mucus clearance and reverse airway obstruction in CF.</description><identifier>ISSN: 1569-1993</identifier><identifier>EISSN: 1873-5010</identifier><identifier>DOI: 10.1016/j.jcf.2015.10.008</identifier><identifier>PMID: 26526358</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Airway Obstruction - metabolism ; Airway Obstruction - physiopathology ; Benzoxazines - metabolism ; Cystic fibrosis ; Cystic Fibrosis - complications ; Cystic Fibrosis - metabolism ; Humans ; Leukocyte Elastase - antagonists & inhibitors ; Leukocyte Elastase - metabolism ; Mucin ; Mucins - analysis ; Mucins - metabolism ; Mucociliary Clearance ; Protease and anti-protease balance ; Pseudomonas aeruginosa - isolation & purification ; Pseudomonas aeruginosa - physiology ; Pseudomonas Infections - diagnosis ; Pseudomonas Infections - etiology ; Pulmonary/Respiratory ; Pyrrolidines - metabolism ; Respiratory Tract Infections - diagnosis ; Respiratory Tract Infections - etiology ; Small molecule inhibitors ; Spectrophotometry - methods ; Sputum - metabolism ; Sputum - microbiology</subject><ispartof>Journal of cystic fibrosis, 2016-05, Vol.15 (3), p.325-331</ispartof><rights>European Cystic Fibrosis Society.</rights><rights>2015 European Cystic Fibrosis Society.</rights><rights>Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c451t-400ccea8e4031e85c52804cff586556fdd979bfafb94d36f61ed3f42ba01871c3</citedby><cites>FETCH-LOGICAL-c451t-400ccea8e4031e85c52804cff586556fdd979bfafb94d36f61ed3f42ba01871c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1569199315002507$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26526358$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chillappagari, Shashi</creatorcontrib><creatorcontrib>Müller, Christian</creatorcontrib><creatorcontrib>Mahavadi, Poornima</creatorcontrib><creatorcontrib>Guenther, Andreas</creatorcontrib><creatorcontrib>Nährlich, Lutz</creatorcontrib><creatorcontrib>Rosenblum, Jonathan</creatorcontrib><creatorcontrib>Rubin, Bruce K</creatorcontrib><creatorcontrib>Henke, Markus O</creatorcontrib><title>A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation</title><title>Journal of cystic fibrosis</title><addtitle>J Cyst Fibros</addtitle><description>Abstract Background Neutrophil elastase (NE) rapidly degrades gel-forming airway mucins in cystic fibrosis (CF) sputum. We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro. Methods Sputa were collected from CF patients ( n = 5) chronically or intermittently infected with Pseudomonas aeruginosa (P.a.). Mucin degradation was analyzed using western blot. Protease inhibitor studies were performed using alpha1-proteinase inhibitor (A1-PI Prolastin®) and KRP-109. Elastase activity assays were performed using spectrophotometry. Results There were significant differences in the amount of active NE in different CF sputum samples. KRP-109 decreased the NE driven mucin degradation in vitro. Pseudomonas elastases appeared to blunt elastase inhibition by A1-PI or KRP-109. Conclusion Inhibitors of neutrophil and Pseudomonas -derived elastases might rescue mucus clearance and reverse airway obstruction in CF.</description><subject>Airway Obstruction - metabolism</subject><subject>Airway Obstruction - physiopathology</subject><subject>Benzoxazines - metabolism</subject><subject>Cystic fibrosis</subject><subject>Cystic Fibrosis - complications</subject><subject>Cystic Fibrosis - metabolism</subject><subject>Humans</subject><subject>Leukocyte Elastase - antagonists & inhibitors</subject><subject>Leukocyte Elastase - metabolism</subject><subject>Mucin</subject><subject>Mucins - analysis</subject><subject>Mucins - metabolism</subject><subject>Mucociliary Clearance</subject><subject>Protease and anti-protease balance</subject><subject>Pseudomonas aeruginosa - isolation & purification</subject><subject>Pseudomonas aeruginosa - physiology</subject><subject>Pseudomonas Infections - diagnosis</subject><subject>Pseudomonas Infections - etiology</subject><subject>Pulmonary/Respiratory</subject><subject>Pyrrolidines - metabolism</subject><subject>Respiratory Tract Infections - diagnosis</subject><subject>Respiratory Tract Infections - etiology</subject><subject>Small molecule inhibitors</subject><subject>Spectrophotometry - methods</subject><subject>Sputum - metabolism</subject><subject>Sputum - microbiology</subject><issn>1569-1993</issn><issn>1873-5010</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kUtv1TAQhS0EouXCD2CDvGTRXGbiOA8hIVUVL1EJxGNtOc6YOjjxrZ0g3X-Po9uyYMHGj9E5RzPfMPYcYY-A9atxPxq7LwFl_u8B2gfsHNtGFBIQHua3rLsCu06csScpjQDYQNM-ZmdlLctayPacmUueJu09n4Ins3riM61LDIcb5zl5nRadiLv5xvVuCfGCf_r6pUDoLu5riZtjWpzh1vUxJJf4tBo384F-Rj3oxYX5KXtktU_07O7esR_v3n6_-lBcf37_8eryujCVxKWoAIwh3VIFAqmVRpYtVMZa2dZS1nYYuqbrrbZ9Vw2itjXSIGxV9hry0GjEjr085R5iuF0pLWpyyZD3eqawJoVNh0IA5HPH8CQ1uecUyapDdJOOR4WgNrZqVJmt2thupcw2e17cxa_9RMNfxz3MLHh9ElAe8rejqJJxNBsaXCSzqCG4_8a_-cdtvJud0f4XHSmNYY1zpqdQpVKB-rYtd9stSoBSQiP-AMQTnt8</recordid><startdate>20160501</startdate><enddate>20160501</enddate><creator>Chillappagari, Shashi</creator><creator>Müller, Christian</creator><creator>Mahavadi, Poornima</creator><creator>Guenther, Andreas</creator><creator>Nährlich, Lutz</creator><creator>Rosenblum, Jonathan</creator><creator>Rubin, Bruce K</creator><creator>Henke, Markus O</creator><general>Elsevier B.V</general><scope>6I.</scope><scope>AAFTH</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>20160501</creationdate><title>A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation</title><author>Chillappagari, Shashi ; Müller, Christian ; Mahavadi, Poornima ; Guenther, Andreas ; Nährlich, Lutz ; Rosenblum, Jonathan ; Rubin, Bruce K ; Henke, Markus O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c451t-400ccea8e4031e85c52804cff586556fdd979bfafb94d36f61ed3f42ba01871c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Airway Obstruction - metabolism</topic><topic>Airway Obstruction - physiopathology</topic><topic>Benzoxazines - metabolism</topic><topic>Cystic fibrosis</topic><topic>Cystic Fibrosis - complications</topic><topic>Cystic Fibrosis - metabolism</topic><topic>Humans</topic><topic>Leukocyte Elastase - antagonists & inhibitors</topic><topic>Leukocyte Elastase - metabolism</topic><topic>Mucin</topic><topic>Mucins - analysis</topic><topic>Mucins - metabolism</topic><topic>Mucociliary Clearance</topic><topic>Protease and anti-protease balance</topic><topic>Pseudomonas aeruginosa - isolation & purification</topic><topic>Pseudomonas aeruginosa - physiology</topic><topic>Pseudomonas Infections - diagnosis</topic><topic>Pseudomonas Infections - etiology</topic><topic>Pulmonary/Respiratory</topic><topic>Pyrrolidines - metabolism</topic><topic>Respiratory Tract Infections - diagnosis</topic><topic>Respiratory Tract Infections - etiology</topic><topic>Small molecule inhibitors</topic><topic>Spectrophotometry - methods</topic><topic>Sputum - metabolism</topic><topic>Sputum - microbiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chillappagari, Shashi</creatorcontrib><creatorcontrib>Müller, Christian</creatorcontrib><creatorcontrib>Mahavadi, Poornima</creatorcontrib><creatorcontrib>Guenther, Andreas</creatorcontrib><creatorcontrib>Nährlich, Lutz</creatorcontrib><creatorcontrib>Rosenblum, Jonathan</creatorcontrib><creatorcontrib>Rubin, Bruce K</creatorcontrib><creatorcontrib>Henke, Markus O</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</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>Journal of cystic fibrosis</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chillappagari, Shashi</au><au>Müller, Christian</au><au>Mahavadi, Poornima</au><au>Guenther, Andreas</au><au>Nährlich, Lutz</au><au>Rosenblum, Jonathan</au><au>Rubin, Bruce K</au><au>Henke, Markus O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation</atitle><jtitle>Journal of cystic fibrosis</jtitle><addtitle>J Cyst Fibros</addtitle><date>2016-05-01</date><risdate>2016</risdate><volume>15</volume><issue>3</issue><spage>325</spage><epage>331</epage><pages>325-331</pages><issn>1569-1993</issn><eissn>1873-5010</eissn><abstract>Abstract Background Neutrophil elastase (NE) rapidly degrades gel-forming airway mucins in cystic fibrosis (CF) sputum. We hypothesized that KRP-109, a small molecule NE inhibitor, would inhibit CF mucin degradation in vitro. Methods Sputa were collected from CF patients ( n = 5) chronically or intermittently infected with Pseudomonas aeruginosa (P.a.). Mucin degradation was analyzed using western blot. Protease inhibitor studies were performed using alpha1-proteinase inhibitor (A1-PI Prolastin®) and KRP-109. Elastase activity assays were performed using spectrophotometry. Results There were significant differences in the amount of active NE in different CF sputum samples. KRP-109 decreased the NE driven mucin degradation in vitro. Pseudomonas elastases appeared to blunt elastase inhibition by A1-PI or KRP-109. Conclusion Inhibitors of neutrophil and Pseudomonas -derived elastases might rescue mucus clearance and reverse airway obstruction in CF.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>26526358</pmid><doi>10.1016/j.jcf.2015.10.008</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Airway Obstruction - metabolism Airway Obstruction - physiopathology Benzoxazines - metabolism Cystic fibrosis Cystic Fibrosis - complications Cystic Fibrosis - metabolism Humans Leukocyte Elastase - antagonists & inhibitors Leukocyte Elastase - metabolism Mucin Mucins - analysis Mucins - metabolism Mucociliary Clearance Protease and anti-protease balance Pseudomonas aeruginosa - isolation & purification Pseudomonas aeruginosa - physiology Pseudomonas Infections - diagnosis Pseudomonas Infections - etiology Pulmonary/Respiratory Pyrrolidines - metabolism Respiratory Tract Infections - diagnosis Respiratory Tract Infections - etiology Small molecule inhibitors Spectrophotometry - methods Sputum - metabolism Sputum - microbiology |
| title | A small molecule neutrophil elastase inhibitor, KRP-109, inhibits cystic fibrosis mucin degradation |
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