Inhibition of epidermal growth factor receptor attenuates LPS-induced inflammation and acute lung injury in rats.

Xiaoou Shan,Hongjin Chen,Lili Dong,Beibei Wu,Zhiguo Liu,Liqin Wu,Zhiguo Feng,Tingting Xu,Guang Liang,Jie Hu,Yali Zhang,Wei Wang

doi:10.18632/oncotarget.15790

Abstract

Acute lung injury (ALI) and its severe form acute respiratory distress syndrome remain the leading cause of morbidity and mortality in intensive care units. Inhibition of epidermal growth factor receptor (EGFR) has been found to be able to reduce inflammatory response. However, it is still unclear whether EGFR inhibition can prevent ALI. This study aimed to validate the EGFR's role in ALI and investigated the effects of EGFR inhibition on lipopolysaccharides (LPS)-induced ALI in rats. In vitro, both pharmacological inhibitors (AG1478 and 451) and si-RNA silencing of EGFR significantly inhibited LPS-induced EGFR signaling activation and inflammatory response in human lung epithelial cells or macrophages. Mechanistically, LPS induced EGFR activation via TLR4 and c-Src signaling. In vivo, rat model with ALI induced by intratracheal instillation of LPS was treated by oral administration of AG1478 and 451. It was observed that AG1478 and 451 blocked the activation of EGFR signaling in lung tissue and reduced the LPS-induced infiltration of inflammatory cells, inflammatory gene expression, and lung injuries. This study demonstrates that TLR4/c-Src-dependent EGFR signaling plays an important role in LPS-induced ALI, and that EGFR may be a potential target in treating ALI.

Highlights

Acute lung injury (ALI), known as acute respiratory distress syndrome (ARDS), is a severe, life-threatening medical condition characterized by acute and widespread inflammation in the lungs [1]
This study demonstrates that Toll-like receptor 4 (TLR4)/c-Src-dependent epidermal growth factor receptor (EGFR) signaling plays an important role in LPS-induced ALI, and that EGFR may be a potential target in treating ALI
Upon LPS stimulation, macrophages developed the activation of EGFR signaling pathway, such as EGFR phosphorylation (Figure 1C), extracellular regulated kinase (ERK) phosphorylation (Figure 1D), and protein kinase www.impactjournals.com/oncotarget (AKT) phosphorylation (Figure 1E)

Summary

Introduction

Acute lung injury (ALI), known as acute respiratory distress syndrome (ARDS), is a severe, life-threatening medical condition characterized by acute and widespread inflammation in the lungs [1]. While ALI may be triggered by trauma or infection, it is usually the result of sepsis. Inflammation, such as that caused by sepsis, produces endothelial dysfunction, fluid leakage from the capillaries and impaired drainage of fluid from the lungs [2]. None of the pharmacological treatments evaluated in Phase II and Phase III for ALI/ARDS has been proven to be effective [5].

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