Src tyrosine kinases mediate activations of NF-κB and integrin signal during lipopolysaccharide-induced acute lung injury

Hui S. Lee, Changsuk Moon, Hye W. Lee, Eun Mi Park, Min Sun Cho, Jihee Lee Kang

Research output: Contribution to journalArticlepeer-review

78 Scopus citations

Abstract

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-κB 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-α and matrix metalloproteinase-9. PP1 also blocked LPS-induced NF-κB activation, and phosphorylation and degradation of IκB-α. The inhibition of NF-κB 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-αv, anti-β3, or Arg-Gly-Asp-Ser (RGDS), inhibited LPS-induced NF-κB activation. Taken together, our findings suggest that Src TKs play a critical role in LPS-induced activations of NF-κB and integrin (αvβ3) signaling during acute lung injury. Therefore, Src TK inhibition may provide a potential means of ameliorating inflammatory cascade-associated lung injury.

Original languageEnglish
Pages (from-to)7001-7011
Number of pages11
JournalJournal of Immunology
Volume179
Issue number10
DOIs
StatePublished - 15 Nov 2007

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