Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury.
Acute lung injury (ALI) and mechanical ventilator-induced lung injury (VILI), major causes of acute respiratory failure with elevated morbidity and mortality, are characterized by significant pulmonary inflammation and alveolar/vascular barrier dysfunction. Previous studies highlighted the role of the non-muscle myosin light chain kinase isoform (nmMLCK) as an essential element of the inflammatory response, with variants in the MYLK gene that contribute to ALI susceptibility. To define nmMLCK involvement further in acute inflammatory syndromes, we used two murine models of inflammatory lung injury, induced by either an intratracheal administration of lipopolysaccharide (LPS model) or mechanical ventilation with increased tidal volumes (the VILI model). Intravenous delivery of the membrane-permeant MLC kinase peptide inhibitor, PIK, produced a dose-dependent attenuation of both LPS-induced lung inflammation and VILI (~50% reductions in alveolar/vascular permeability and leukocyte influx). Intravenous injections of nmMLCK silencing RNA, either directly or as cargo within angiotensin-converting enzyme (ACE) antibody-conjugated liposomes (to target the pulmonary vasculature selectively), decreased nmMLCK lung expression (∼70% reduction) and significantly attenuated LPS-induced and VILI-induced lung inflammation (∼40% reduction in bronchoalveolar lavage protein). Compared with wild-type mice, nmMLCK knockout mice were significantly protected from VILI, with significant reductions in VILI-induced gene expression in biological pathways such as nrf2-mediated oxidative stress, coagulation, p53-signaling, leukocyte extravasation, and IL-6-signaling. These studies validate nmMLCK as an attractive target for ameliorating the adverse effects of dysregulated lung inflammation.
Institute for Personalized and Respiratory Medicine, Department of Medicine, University of Illinois at Chicago, 1705 Polk # 305, Chicago, IL 60612, USA.
Tamara
T
Mirzapoiazova
Jaideep
J
Moitra
Liliana
L
Moreno-Vinasco
Saad
S
Sammani
Jerry R
JR
Turner
Eddie T
ET
Chiang
Carrie
C
Evenoski
Ting
T
Wang
Patrick A
PA
Singleton
Yong
Y
Huang
Yves A
YA
Lussier
D Martin
DM
Watterson
Steven M
SM
Dudek
Joe G N
JG
Garcia
D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D000818:Animals; D000906:Antibodies; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007275:Injections, Intravenous; D008070:Lipopolysaccharides; D008081:Liposomes; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018994:Myosin Light Chains / Q000378:metabolism; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000276:immunology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D055397:Ventilator-Induced Lung Injury / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*
D000906:Antibodies; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008081:Liposomes; D018994:Myosin Light Chains; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D009219:Myosin-Light-Chain Kinase; D007703:Peptidyl-Dipeptidase A