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.