title: Critical role of non-muscle myosin light chain kinase in thrombin-induced endothelial cell inflammation and lung PMN infiltration.
abstract: The pathogenesis of acute lung injury (ALI) involves bidirectional cooperation and close interaction between inflammatory and coagulation pathways. A key molecule linking coagulation and inflammation is the procoagulant thrombin, a serine protease whose concentration is elevated in plasma and lavage fluids of patients with ALI and acute respiratory distress syndrome (ARDS). However, little is known about the mechanism by which thrombin contributes to lung inflammatory response. In this study, we developed a new mouse model that permits investigation of lung inflammation associated with intravascular coagulation. Using this mouse model and in vitro approaches, we addressed the role of non-muscle myosin light chain kinase (nmMLCK) in thrombin-induced endothelial cell (EC) inflammation and lung neutrophil (PMN) infiltration. Our in vitro experiments revealed a key role of nmMLCK in ICAM-1 expression by its ability to control nuclear translocation and transcriptional capacity of RelA/p65 in EC. When subjected to intraperitoneal thrombin challenge, wild type mice showed a marked increase in lung PMN infiltration via expression of ICAM-1. However, these responses were markedly attenuated in mice deficient in nmMLCK. These results provide mechanistic insight into lung inflammatory response associated with intravascular coagulation and identify nmMLCK as a critical target for modulation of lung inflammation.
authors.affiliation: Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America. Fabeha_Fazal@URMC.Rochester.edu
authors.forename: Fabeha
authors.initials: F
authors.lastname: Fazal
authors.forename: Kaiser M
authors.initials: KM
authors.lastname: Bijli
authors.forename: Matthew
authors.initials: M
authors.lastname: Murrill
authors.forename: Antony
authors.initials: A
authors.lastname: Leonard
authors.forename: Mohammad
authors.initials: M
authors.lastname: Minhajuddin
authors.forename: Khandaker N
authors.initials: KN
authors.lastname: Anwar
authors.forename: Jacob N
authors.initials: JN
authors.lastname: Finkelstein
authors.forename: D Martin
authors.initials: DM
authors.lastname: Watterson
authors.forename: Arshad
authors.initials: A
authors.lastname: Rahman
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D002467:Cell Nucleus / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology*; D008168:Lung / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009219:Myosin-Light-Chain Kinase / Q000502:physiology*; D009504:Neutrophils / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: C090509:Icam1 protein, mouse; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D009219:Myosin-Light-Chain Kinase; D013917:Thrombin
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