Inhibition of epidermal growth factor receptor attenuates LPS-induced inflammation and acute lung injury in rats
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Xiaoou Shan1,2,*, Yali Zhang1,*, Hongjin Chen1,*, Lili Dong1,3, Beibei Wu2, Tingting Xu2, Jie Hu1, Zhiguo Liu1, Wei Wang1,4, Liqin Wu2, Zhiguo Feng1, Guang Liang1
1Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
2The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Zhejiang, China
3Children’s Hospital of Zhengzhou, Zhengzhou, Henan, China
4School of Pharmacy, Qingdao University, Qingdao, Shandong, China
*These authors contributed equally to this work
Guang Liang, email: firstname.lastname@example.org
Zhiguo Feng, email: email@example.com
Keywords: acute lung injury, epidermal growth factor receptor, inflammation, lipopolysaccharide, mouse peritoneal macrophages
Received: November 22, 2016 Accepted: February 15, 2017 Published: March 01, 2017
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.
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