Document Detail


Inhibition of the Src and Jak kinases protects against lipopolysaccharide-induced acute lung injury.
MedLine Citation:
PMID:  15665321     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2005-01-21
Journal Detail:
Title:  American journal of respiratory and critical care medicine     Volume:  171     ISSN:  1073-449X     ISO Abbreviation:  Am. J. Respir. Crit. Care Med.     Publication Date:  2005 Apr 
Date Detail:
Created Date:  2005-04-08     Completed Date:  2006-06-19     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  9421642     Medline TA:  Am J Respir Crit Care Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  858-67     Citation Subset:  AIM; IM    
Affiliation:
Pulmonary and Critical Care Division, Tufts-New England Medical Center, Box 369, 750 Washington Street, Boston, MA 02111, USA.
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MeSH Terms
Descriptor/Qualifier:
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, Adult / immunology*,  pathology
Signal Transduction / drug effects,  genetics
Sulfonamides / pharmacology
Transcriptional Activation / immunology
Tyrphostins / pharmacology
src-Family Kinases / antagonists & inhibitors*,  genetics
Grant Support
ID/Acronym/Agency:
GM51551/GM/NIGMS NIH HHS; P30-DK-34928/DK/NIDDK NIH HHS; R01HL-68753-01A1/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Indoles; 0/Lipopolysaccharides; 0/Proto-Oncogene Proteins; 0/SU 6656; 0/Sulfonamides; 0/Tyrphostins; 118409-57-7/tyrphostin A23; EC 2.7.10.1/Janus Kinase 2; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.10.2/Jak2 protein, mouse; EC 2.7.10.2/src-Family Kinases

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