Critical role of non-muscle myosin light chain kinase in thrombin-induced endothelial cell inflammation and lung PMN infiltration

• Published in: PloS one Vol. 8; no. 3; p. e59965
• Main Authors: Fazal, Fabeha, Bijli, Kaiser M, Murrill, Matthew, Leonard, Antony, Minhajuddin, Mohammad, Anwar, Khandaker N, Finkelstein, Jacob N, Watterson, D Martin, Rahman, Arshad
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21-03-2013; Public Library of Science (PLoS)
• Subjects: Animals; Biology; Blood Coagulation; Cell Nucleus - metabolism; Chains; Coagulation; Computational fluid dynamics; Cooperation; Dentistry; Edema; Endothelial cells; Endothelial Cells - cytology; Endothelial Cells - metabolism; Endothelium; Female; Gene Expression Regulation; Human Umbilical Vein Endothelial Cells; Humans; Immunoglobulins; Infiltration; Inflammation; Inflammatory response; Intercellular adhesion molecule 1; Intercellular Adhesion Molecule-1 - metabolism; Kinases; Leukocytes, Mononuclear - cytology; Lung - metabolism; Lung diseases; Lungs; Male; Medicine; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle proteins; Muscles; Myosin; Myosin-light-chain kinase; Myosin-Light-Chain Kinase - physiology; Neutrophils; Neutrophils - metabolism; Nuclear transport; Pathogenesis; Pediatrics; Permeability; Peroxidase - metabolism; Phosphorylation; Proteins; Respiratory distress syndrome; Rodents; Sepsis; Serine; Serine proteinase; Stability; Thrombin; Thrombin - metabolism; Transcription; Transcription Factor RelA - metabolism; Transcription factors; Translocation; New York; Chicago Illinois; United States > US; Illinois
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0059965

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.