Inhibition of the Src and Jak kinases protects against lipopolysaccharide-induced acute lung injury.

Abstract

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.

• Authors: Mariano Severgnini, Satoe Takahashi, Powen Tu, George Perides, Robert J Homer, Jhung W Jhung, Deepa Bhavsar, Brent H Cochran, Amy R Simon
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 171 Issue 8 Pg. 858-67 (Apr 15 2005) ISSN: 1073-449X [Print] United States
• PMID: 15665321 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Indoles
• Lipopolysaccharides
• Proto-Oncogene Proteins
• SU 6656
• Sulfonamides
• Tyrphostins
• Protein-Tyrosine Kinases
• Jak2 protein, mouse
• Janus Kinase 2
• src-Family Kinases
• tyrphostin A23

Topics

• Adenoviridae (genetics)
• Animals
• Capillary Leak Syndrome (genetics, immunology)
• Enzyme Activation (drug effects, genetics, immunology)
• Enzyme Inhibitors (pharmacology)
• Escherichia coli
• Gene Expression Regulation (drug effects)
• Gene Transfer Techniques
• Indoles (pharmacology)
• Janus Kinase 2
• Lipopolysaccharides (immunology)
• Lung (drug effects, immunology, pathology)
• Mice
• Mice, Inbred BALB C
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics)
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics)
• Respiratory Distress Syndrome (immunology, pathology)
• Signal Transduction (drug effects, genetics)
• Sulfonamides (pharmacology)
• Transcriptional Activation (immunology)
• Tyrphostins (pharmacology)
• src-Family Kinases (antagonists & inhibitors, genetics)