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Src Tyrosine Kinases Mediate Activations of NF-B and Integrin Signal during Lipopolysaccharide-Induced Acute Lung Injury¹

Hui S. Lee^*, Changsuk Moon^*, Hye W. Lee^*, Eun-Mi Park, Min-Sun Cho and Jihee L. Kang^2,*

^* Department of Physiology, Department of Pharmacology, and Department of Pathology, Division of Cell Biology, Ewha Medical Research Center, School of Medicine, Ewha Womans University, Seoul, South Korea

Src tyrosine kinases (TKs) are signaling proteins involved in cell signaling pathways toward cytoskeletal, membrane and nuclear targets. In the present study, using a selective Src TK inhibitor, PP1, we investigated the roles of Src TKs in the key pulmonary responses, NF-B activation, and integrin signaling during acute lung injury in BALB/C mice intratracheally treated with LPS. LPS resulted in c-Src phosphorylation in lung tissue and the phospho-c-Src was predominantly localized in recruited neutrophils and alveolar macrophages. PP1 inhibited LPS-induced increases in total protein content in bronchoalveolar lavage fluid, neutrophil recruitment, and increases in the production or activity of TNF- and matrix metalloproteinase-9. PP1 also blocked LPS-induced NF-B activation, and phosphorylation and degradation of IB-. The inhibition of NF-B activation by PP1 correlated with a depression of LPS-induced integrin signaling, which included increases in the phosphorylations of integrin β₃, and of the focal adhesion kinase (FAK) family members, FAK and Pyk2, in lung tissue, and reductions in the fibrinogen-binding activity of alveolar macrophages. Moreover, treatment with anti-_v, anti-β₃, or Arg-Gly-Asp-Ser (RGDS), inhibited LPS-induced NF-B activation. Taken together, our findings suggest that Src TKs play a critical role in LPS-induced activations of NF-B and integrin (_vβ₃) signaling during acute lung injury. Therefore, Src TK inhibition may provide a potential means of ameliorating inflammatory cascade-associated lung injury.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Korea Research Foundation Grant KRF-2005- 041-E00034.

² Address correspondence and reprint requests to Dr. Jihee Lee Kang, Department of Physiology, School of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-ku, Seoul, Korea. E-mail: jihee{at}ewha.ac.kr

³ Abbreviations used in this paper: TK, tyrosine kinase; FAK, focal adhesion kinase; RGDS, Arg-Gly-Asp-Ser; RGES, Arg-Gly-Glu-Ser; ECM, extracellular matrix; BAL, bronchoalveolar lavage; MMP-9, matrix metalloproteinase-9.