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Inhibition of the Src and Jak Kinases Protects against Lipopolysaccharide-induced Acute Lung Injury

Pulmonary and Critical Care Division, and Departments of Physiology and Surgery, Tufts–New England Medical Center, Boston, Massachusetts; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; and Department of Pathology, Brown University School of Medicine, Providence, Rhode Island

Correspondence and requests for reprints should be addressed to Amy R. Simon, M.D., Pulmonary and Critical Care Division, Tufts–New England Medical Center, Box 369, 750 Washington Street, Boston, MA 02111. E-mail: amy.simon{at}tufts.edu

The cascade of cellular and molecular pathways mediating acute lung injury is complex and incompletely defined. Although the Src and Jak family of kinases is upregulated in LPS-induced murine lung injury, their role in the development of lung injury is unknown. Here we report that systemic inhibition of these kinases using specific small molecule inhibitors (PP2, SU6656, tyrphostin A1) significantly attenuated LPS-induced lung injury, as determined by histologic and capillary permeability assays. These inhibitors blocked LPS-dependent cytokine and chemokine production in the lung and in the serum. In contrast, lung-targeted inhibition of these kinases in the airway epithelium via adenoviral-mediated gene transfer of dominant negative Src or of suppressor of cytokine signaling (SOCS-1) disrupted lung cytokine production but had no effect on systemic cytokine production or lung vascular permeability. Mice were significantly protected from lethal LPS challenge by the small molecule inhibitors of Jak and Src kinase. Importantly, this protection was still evident even when the inhibitors were administered 6 hours after LPS challenge. Taken together, these observations suggest that Jak and Src kinases participate in acute lung injury and verify the potential of this class of selective tyrosine kinase inhibitors to serve as novel therapeutic agents for this disease.

Key Words: acute lung injury • Jak kinase • lipopolysaccharide • signal transducers and activators of transcription • Src kinase

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