MLCK210 gene knockout or kinase inhibition preserves lung function following endotoxin-induced lung injury in mice.
Barrier dysfunction, involving the endothelium or epithelium, is implicated in the pathophysiology of many disease states, including acute and ventilator-associated lung injury. Evidence from cell culture, in vivo and clinical studies, has identified myosin light chain kinase as a drug discovery target for such diseases. Here, we measured disease-relevant end points to test the hypothesis that inhibition of myosin light chain kinase is a potential therapeutic target for treatment of barrier dysfunction resulting from acute lung injury. We used a combined gene knockout and chemical biology approach with an in vivo intact lung injury model. We showed that inhibition of myosin light chain kinase protects lung function, preserves oxygenation, prevents acidosis, and enhances survival after endotoxin exposure with subsequent mechanical ventilation. This protective effect provided by the small molecule inhibitor of myosin light chain kinase is present when the inhibitor is administered during a clinically relevant injury paradigm after endotoxin exposure. Treatment with inhibitor confers additional protection against acute lung injury to that provided by a standard protective mode of ventilation. These results support the hypothesis that myosin light chain kinase is a potential therapeutic target for acute lung injury and provide clinical end points of arterial blood gases and pulmonary compliance that facilitate the direct extrapolation of these studies to measures used in critical care medicine.
Rossi
Janet L
JL
Center for Drug Discovery and Chemical Biology, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Northwestern Univ., 303 E. Chicago Ave., Ward 8-196, Chicago, IL 60611, USA. j-rossi@northwestern.edu
Velentza
Anastasia V
AV
Steinhorn
David M
DM
Watterson
D Martin
DM
Wainwright
Mark S
MS
D000136:Acid-Base Equilibrium / Q000187:drug effects / Q000502:physiology; D000818:Animals; D019446:Endotoxemia / Q000150:complications*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity; D008170:Lung Compliance / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D010100:Oxygen / Q000097:blood; D011175:Positive-Pressure Respiration; D011654:Pulmonary Edema / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D011659:Pulmonary Gas Exchange / Q000187:drug effects / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D011724:Pyridazines; D009219:Myosin-Light-Chain Kinase; D010100:Oxygen