Erlotinib Protects LPS-Induced Acute Lung Injury in Mice by Inhibiting EGFR/TLR4 Signaling Pathway.

Abstract

Epidermal growth factor receptor (EGFR) has been reported to initiate the inflammatory response, but its activation in lipopolysaccharide (LPS)-induced murine model of acute lung injury (ALI) remains unclear. In this study, we investigated the role of EGFR in the LPS-induced murine model of ALI and explored whether its inhibitor erlotinib could affect the progression of lung injury. We first detected the phosphorylated EGFR (p-EGFR)/EGFR ratio at different time points after LPS stimulation, and then different concentrations of erlotinib were used to treat mice at 1 h before LPS stimulation and collected samples at the time point of the highest p-EGFR/EGFR ratio. Lung injury indicators were detected and compared among groups. EGFR and toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signal transduction factors, including p-EGFR, p-AKT, p-ERK1/2, p-p65, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β), were measured with western blot. We found that the mice challenged with LPS suffered from the most serious lung injury at 24 h after LPS stimulation when the p-EGFR/EGFR ratio was relatively the highest. Erlotinib significantly diminished LPS-induced exudation of total cells, neutrophils, and proteins in BALF. Both the ELISA and western blot results showed that erlotinib attenuated the expression of TNF-α and IL-1β in LPS-induced ALI in mice. Inhibition of EGFR by erlotinib downregulated the expression of p-p65 protein level as well as blocked the activation of AKT and ERK1/2 signaling pathway. Taken together, erlotinib alleviated the LPS-induced ALI in a dose-dependent manner by suppressing EGFR activation and downregulating the NF-κB-mediated secretion of proinflammatory cytokines.