Protein Kinase Involved in Lung Injury Susceptibility: Evidence from Enzyme Isoform Genetic Knockout and in vivo Inhibitor Treatment
Acute lung injury (ALI) associated with sepsis and iatrogenic ventilator-induced lung injury resulting from mechanical ventilation are major medical problems with an unmet need for small molecule therapeutics. Prevailing hypotheses identify endothelial cell (EC) layer dysfunction as a cardinal event...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 100; no. 10; pp. 6233 - 6238 |
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Main Authors | , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
13.05.2003
National Acad Sciences The National Academy of Sciences |
Subjects | |
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Abstract | Acute lung injury (ALI) associated with sepsis and iatrogenic ventilator-induced lung injury resulting from mechanical ventilation are major medical problems with an unmet need for small molecule therapeutics. Prevailing hypotheses identify endothelial cell (EC) layer dysfunction as a cardinal event in the pathophysiology, with intracellular protein kinases as critical mediators of normal physiology and possible targets for drug discovery. The 210,000 molecular weight myosin light chain kinase (MLCK210, also called EC MLCK because of its abundance in EC) is hypothesized to be important for EC barrier function and might be a potential therapeutic target. To test these hypotheses directly, we made a selective MLCK210 knockout mouse that retains production of MLCK108 (also called smooth-muscle MLCK) from the same gene. The MLCK210 knockout mice are less susceptible to ALI induced by i.p. injection of the endotoxin lipopolysaccharide and show enhanced survival during subsequent mechanical ventilation. Using a complementary chemical biology approach, we developed a new class of small-molecule MLCK inhibitor based on the pharmacologically privileged aminopyridazine and found that a single i.p. injection of the inhibitor protected WT mice against ALI and death from mechanical ventilation complications. These convergent results from two independent approaches demonstrate a pivotal in vivo role for MLCK in susceptibility to lung injury and validate MLCK as a potential drug discovery target for lung injury. |
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AbstractList | Acute lung injury (ALI) associated with sepsis and iatrogenic ventilator-induced lung injury resulting from mechanical ventilation are major medical problems with an unmet need for small molecule therapeutics. Prevailing hypotheses identify endothelial cell (EC) layer dysfunction as a cardinal event in the pathophysiology, with intracellular protein kinases as critical mediators of normal physiology and possible targets for drug discovery. The 210,000molecular weight myosin light chain kinase (MLCK210, also called EC MLCK because of its abundance in EC) is hypothesized to be important for EC barrier function and might be a potential therapeutic target. To test these hypotheses directly, we made a selective MLCK210 knockout mouse that retains production of MLCK108 (also called smooth-muscle MLCK) from the same gene. The MLCK210 knockout mice are less susceptible to ALI induced by i.p. injection of the endotoxin lipopolysaccharide and show enhanced survival during subsequent mechanical ventilation. Using a complementary chemical biology approach, we developed a new class of small-molecule MLCK inhibitor based on the pharmacologically privileged aminopyridazine and found that a single i.p. injection of the inhibitor protected WT mice against ALI and death from mechanical ventilation complications. These convergent results from two independent approaches demonstrate a pivotal in vivo role for MLCK in susceptibility to lung injury and validate MLCK as a potential drug discovery target for lung injury. Acute lung injury (ALI) associated with sepsis and iatrogenic ventilator-induced lung injury resulting from mechanical ventilation are major medical problems with an unmet need for small molecule therapeutics. Prevailing hypotheses identify endothelial cell (EC) layer dysfunction as a cardinal event in the pathophysiology, with intracellular protein kinases as critical mediators of normal physiology and possible targets for drug discovery. The 210,000 molecular weight myosin light chain kinase (MLCK210, also called EC MLCK because of its abundance in EC) is hypothesized to be important for EC barrier function and might be a potential therapeutic target. To test these hypotheses directly, we made a selective MLCK210 knockout mouse that retains production of MLCK108 (also called smooth-muscle MLCK) from the same gene. The MLCK210 knockout mice are less susceptible to ALI induced by i.p. injection of the endotoxin lipopolysaccharide and show enhanced survival during subsequent mechanical ventilation. Using a complementary chemical biology approach, we developed a new class of small-molecule MLCK inhibitor based on the pharmacologically privileged aminopyridazine and found that a single i.p. injection of the inhibitor protected WT mice against ALI and death from mechanical ventilation complications. These convergent results from two independent approaches demonstrate a pivotal in vivo role for MLCK in susceptibility to lung injury and validate MLCK as a potential drug discovery target for lung injury. Acute lung injury (ALI) associated with sepsis and iatrogenic ventilator-induced lung injury resulting from mechanical ventilation are major medical problems with an unmet need for small molecule therapeutics. Prevailing hypotheses identify endothelial cell (EC) layer dysfunction as a cardinal event in the pathophysiology, with intracellular protein kinases as critical mediators of normal physiology and possible targets for drug discovery. The 210,000 molecular weight myosin light chain kinase (MLCK210, also called EC MLCK because of its abundance in EC) is hypothesized to be important for EC barrier function and might be a potential therapeutic target. To test these hypotheses directly, we made a selective MLCK210 knockout mouse that retains production of MLCK108 (also called smooth-muscle MLCK) from the same gene. The MLCK210 knockout mice are less susceptible to ALI induced by i.p. injection of the endotoxin lipopolysaccharide and show enhanced survival during subsequent mechanical ventilation. Using a complementary chemical biology approach, we developed a new class of small-molecule MLCK inhibitor based on the pharmacologically privileged aminopyridazine and found that a single i.p. injection of the inhibitor protected WT mice against ALI and death from mechanical ventilation complications. These convergent results from two independent approaches demonstrate a pivotal in vivo role for MLCK in susceptibility to lung injury and validate MLCK as a potential drug discovery target for lung injury. Acute lung injury (ALI) associated with sepsis and iatrogenic ventilator-induced lung injury resulting from mechanical ventilation are major medical problems with an unmet need for small molecule therapeutics. Prevailing hypotheses identify endothelial cell (EC) layer dysfunction as a cardinal event in the pathophysiology, with intracellular protein kinases as critical mediators of normal physiology and possible targets for drug discovery. The 210,000 molecular weight myosin light chain kinase (MLCK210, also called EC MLCK because of its abundance in EC) is hypothesized to be important for EC barrier function and might be a potential therapeutic target. To test these hypotheses directly, we made a selective MLCK210 knockout mouse that retains production of MLCK108 (also called smooth-muscle MLCK) from the same gene. The MLCK210 knockout mice are less susceptible to ALI induced by i.p. injection of the endotoxin lipopolysaccharide and show enhanced survival during subsequent mechanical ventilation. Using a complementary chemical biology approach, we developed a new class of small-molecule MLCK inhibitor based on the pharmacologically privileged aminopyridazine and found that a single i.p. injection of the inhibitor protected WT mice against ALI and death from mechanical ventilation complications. These convergent results from two independent approaches demonstrate a pivotal in vivo role for MLCK in susceptibility to lung injury and validate MLCK as a potential drug discovery target for lung injury. [PERIODICAL ABSTRACT] |
Author | Wainwright, Mark S. Jia, Yuzhi Watterson, D. Martin Zasadzki, Magdalena Rossi, Janet Shirinsky, Vladimir Van Eldik, Linda J. Velentza, Anastasia V. Steinhorn, David Schavocky, James Haiech, Jacques Crawford, Susan |
AuthorAffiliation | Departments of Pediatrics, † Molecular Pharmacology and Biological Chemistry, § Pathology, and Cell and Molecular Biology, and the ‡ Drug Discovery Program, Northwestern University, Chicago, IL 60611; ¶ Laboratory of Cell Motility, Russian Cardiology Research Center, Moscow 121552, Russia; and ‖ Institut G. Laustriat, Université Louis Pasteur and Centre National de la Recherche Scientifique Unité Mixte de Recherche 7034, F-67401 Illkirch, France |
AuthorAffiliation_xml | – name: Departments of Pediatrics, † Molecular Pharmacology and Biological Chemistry, § Pathology, and Cell and Molecular Biology, and the ‡ Drug Discovery Program, Northwestern University, Chicago, IL 60611; ¶ Laboratory of Cell Motility, Russian Cardiology Research Center, Moscow 121552, Russia; and ‖ Institut G. Laustriat, Université Louis Pasteur and Centre National de la Recherche Scientifique Unité Mixte de Recherche 7034, F-67401 Illkirch, France |
Author_xml | – sequence: 1 givenname: Mark S. surname: Wainwright fullname: Wainwright, Mark S. – sequence: 2 givenname: Janet surname: Rossi fullname: Rossi, Janet – sequence: 3 givenname: James surname: Schavocky fullname: Schavocky, James – sequence: 4 givenname: Susan surname: Crawford fullname: Crawford, Susan – sequence: 5 givenname: David surname: Steinhorn fullname: Steinhorn, David – sequence: 6 givenname: Anastasia V. surname: Velentza fullname: Velentza, Anastasia V. – sequence: 7 givenname: Magdalena surname: Zasadzki fullname: Zasadzki, Magdalena – sequence: 8 givenname: Vladimir surname: Shirinsky fullname: Shirinsky, Vladimir – sequence: 9 givenname: Yuzhi surname: Jia fullname: Jia, Yuzhi – sequence: 10 givenname: Jacques surname: Haiech fullname: Haiech, Jacques – sequence: 11 givenname: Linda J. surname: Van Eldik fullname: Van Eldik, Linda J. – sequence: 12 givenname: D. Martin surname: Watterson fullname: Watterson, D. Martin |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/12730364$$D View this record in MEDLINE/PubMed |
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Notes | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 To whom correspondence should be addressed. E-mail: m-watterson@northwestern.edu. Communicated by David L. Garbers, University of Texas Southwestern Medical Center, Dallas, TX |
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SubjectTerms | Adult respiratory distress syndrome Alleles Amino Acid Sequence Animals Biological Sciences Drug discovery Enzyme Inhibitors - pharmacology Enzymes Genetic Predisposition to Disease - genetics Genetics Histology Injuries Isoenzymes - chemistry Isoenzymes - deficiency Isoenzymes - genetics Lipopolysaccharides - toxicity Lung - pathology Lung Diseases - genetics Lung Diseases - prevention & control Lung Injury Lungs Mice Mice, Knockout Molecular Sequence Data Myosin-Light-Chain Kinase - chemistry Myosin-Light-Chain Kinase - deficiency Myosin-Light-Chain Kinase - genetics Physical trauma Proteins Reproductive technologies Sepsis Ventilation systems |
Title | Protein Kinase Involved in Lung Injury Susceptibility: Evidence from Enzyme Isoform Genetic Knockout and in vivo Inhibitor Treatment |
URI | https://www.jstor.org/stable/3147571 http://www.pnas.org/content/100/10/6233.abstract https://www.ncbi.nlm.nih.gov/pubmed/12730364 https://www.proquest.com/docview/201320420/abstract/ https://search.proquest.com/docview/18752351 https://pubmed.ncbi.nlm.nih.gov/PMC156355 |
Volume | 100 |
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