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

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-α_v, 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 (α_vβ₃) signaling during acute lung injury. Therefore, Src TK inhibition may provide a potential means of ameliorating inflammatory cascade-associated lung injury.