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

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.

A critical role for Lyn kinase in strengthening endothelial integrity and barrier function

“…Inhibition of c-Src and Yes protects against LPS-induced increases in vascular permeability. [26][27][28] As LPS can also activate Lyn, 29 we investigated the role of Lyn in the regulation of vascular permeability by determining mouse lung capillary filtration coefficient (K f,c ). 30,31 Injection of LPS (intraperitoneally) significantly increased the K f,c compared with basal conditions in wild-type mice ( Figure 1A).…”

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

“…SHP2 has been implicated in the regulation of FAK phosphorylation, and thus activation (9,30). Thrombin, LPS, and S1P have all been previously observed to differentially alter FAK phosphorylation status (31,32). Thus, we next assessed whether FAK plays a role in the mechanism through which SHP2 exerts protection of endothelial barrier function.…”

Lipopolysaccharide induces ICAM-1 expression via a c-Src/NADPH oxidase/ROS-dependent NF-κB pathway in human pulmonary alveolar epithelial cells

“…c-Src has been shown to regulate ICAM-1 expression in various cell types (9,16). In addition, LPS can mediate c-Src activation and then cause the inflammatory responses (7,10). Previous studies indicated that c-Src regulates platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) transactivation (13), which further promotes inflammatory responses.…”