Submitted on September 26, 2006
Accepted on February 13, 2007
MLCK210 gene knockout or kinase inhibition preserves lung function following endotoxin-induced lung injury in mice
Janet Lyn Rossi1*, Anastasia V. Velentza2, David M. Steinhorn3, D. Martin Watterson4, and Mark S. Wainwright5
1 Center for Drug Discovery and Chemical Biology , Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
2 Center for Drug Discovery and Chemical Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; Genomics Institute of the Novartis Research Foundation, San Diego, California, United States
3 Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
4 Center for Drug Discovery and Chemical Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
5 Center for Drug Discovery and Chemical Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States; Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
* To whom correspondence should be addressed. E-mail: j-rossi{at}northwestern.edu.
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 endpoints 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 provides clinical endpoints of arterial blood gases and pulmonary compliance that facilitate the direct extrapolation of these studies to measures used in critical care medicine.
