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Published ahead of print on January 21, 2005, doi:10.1164/rccm.200407-981OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 8, April 2005, 858-867

A more recent version of this article appeared on April 15, 2005
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Submitted on August 1, 2004
Accepted on January 15, 2005

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

Mariano Severgnini1, Satoe Takahashi1, Powen Tu1, George Perides2, Robert J Homer3, Jhung W Jhung4, Deepa Bhavsar5, Brent H Cochran5, and Amy R Simon1*

1 Pulmonary and Critical Care Division, Tufts-New England Medical Center, Boston, MA, USA; Department of Physiology, Tufts University School of Medicine, Boston, MA, USA, 2 Department of Surgery, Tufts-New England Medical Center, Boston, MA, USA, 3 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA, 4 Department of Pathology, Brown University School of Medicine, Providence, RI, USA, 5 Department of Physiology, Tufts University School of Medicine, Boston, MA, USA

* To whom correspondence should be addressed. E-mail: amy.simon{at}tufts.edu.

The cascade of cellular and molecular pathways mediating acute lung injury are complex and incompletely defined. Although the Src and Jak family of kinases are upregulated in lipopolysaccharide-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,TyrphostinA1) significantly attenuated lipopolysaccharide-induced lung injury, as determined by histologic and capillary permeability assays. These inhibitors blocked lipopolysaccharide-dependent cytokine and chemokine production in the lung and systemically. 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 lipopolysaccharide 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 post-lipopolysaccharide 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, Src Kinase, Jak Kinase, Signal Transducers and Activators of Transcription, Lipopolysaccharide




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