PMID- 32187954 OWN - NLM STAT- MEDLINE DCOM- 20201218 LR - 20201218 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 125 DP - 2020 May TI - Amphiregulin inhibits TNF-alpha-induced alveolar epithelial cell death through EGFR signaling pathway. PG - 109995 LID - S0753-3322(20)30186-4 [pii] LID - 10.1016/j.biopha.2020.109995 [doi] AB - BACKGROUND: We previously observed that amphiregulin (Areg), a ligand of epithelial growth factor receptor (EGFR), was highly expressed in lipopolysaccharide (LPS)-induced acute lung injury (ALI) lung tissues mainly by the classically activated (M1) alveolar macrophages (AMs). Areg also plays a protective role in LPS-induced injury in lung tissues and alveolar epithelial cells (AECs). However, whether Areg is co-expressed with tumor necrosis factor (TNF)-alpha in ALI lung tissues, and can directly inhibit TNF-alpha-induced AEC injury remains unclear. METHODS: We first detected the kinetic expressions of Areg and TNF-alpha in LPS-stimulated lung tissues and M1 AMs and then identified the role of exogenous recombinant Areg (rmAreg) in the injured lung tissues. The effect of Areg on TNF-alpha-induced apoptosis in MLE-12 cells, a kind of AECs, was examined by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The activation of the EGFR-AKT pathway and caspase-3, -8, and -9 were detected by Western blotting. The EGFR knockdown by small interfering RNA was used to assess the role of EGFR in Areg functions. RESULTS: Areg production occurred in close parallel with TNF-alpha expression in M1 AMs and ALI lung tissues, and rmAreg attenuated LPS-induced ALI in mice. TNF-alpha stimulation induced significant apoptosis in MLE-12 cells, but this apoptosis was inhibited under rmAreg treatment. Moreover, rmAreg enhanced the activation of EGFR and AKT, and reduced the expressions of cleaved caspase-3, -8, and -9 in ALI lung tissues and TNF-alpha-challenged MLE-12 cells. However, the EGFR knockdown significantly inhibited the Areg-induced improvement in apoptosis, enhancement of EGFR and AKT activation, and reduction of cleaved caspase-3, -8, and -9 expressions. CONCLUSIONS: Areg and TNF-alpha were synchronously produced by ALI lung tissues and M1 AMs, and Areg directly inhibited the TNF-induced apoptosis and transduction of caspase death signals in AECs via the EGFR pathway. CI - Copyright (c) 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved. FAU - Meng, Chen AU - Meng C AD - Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China; Institute of Anesthesiology, Hubei University of Medicine, Shiyan, 442000, Hubei, China. Electronic address: 27739865@qq.com. FAU - Wang, Silu AU - Wang S AD - Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China; Institute of Anesthesiology, Hubei University of Medicine, Shiyan, 442000, Hubei, China. Electronic address: 514977213@qq.com. FAU - Wang, Xue AU - Wang X AD - Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China; Institute of Anesthesiology, Hubei University of Medicine, Shiyan, 442000, Hubei, China. Electronic address: 754337370@qq.com. FAU - Lv, Jing AU - Lv J AD - Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China; Institute of Anesthesiology, Hubei University of Medicine, Shiyan, 442000, Hubei, China. Electronic address: roylvjing@163.com. FAU - Zeng, Wenjing AU - Zeng W AD - Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China; Institute of Anesthesiology, Hubei University of Medicine, Shiyan, 442000, Hubei, China. Electronic address: 99220532@qq.com. FAU - Chang, Ruijie AU - Chang R AD - Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China. Electronic address: 1297432533@qq.com. FAU - Li, Qing AU - Li Q AD - Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China; Institute of Anesthesiology, Hubei University of Medicine, Shiyan, 442000, Hubei, China. Electronic address: Liqing8801@163.com. FAU - Wang, Xianyu AU - Wang X AD - Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, Hubei, China; Institute of Anesthesiology, Hubei University of Medicine, Shiyan, 442000, Hubei, China. Electronic address: wxytj@126.com. LA - eng PT - Journal Article DEP - 20200227 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 0 (Amphiregulin) RN - 0 (Areg protein, mouse) RN - 0 (Lipopolysaccharides) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 3.4.22.- (Caspases) SB - IM MH - Acute Lung Injury/genetics/*physiopathology MH - Alveolar Epithelial Cells MH - Amphiregulin/*metabolism MH - Animals MH - Apoptosis/physiology MH - Caspases/metabolism MH - Cell Line MH - ErbB Receptors/*genetics MH - Gene Knockdown Techniques MH - Lipopolysaccharides MH - Macrophages, Alveolar/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Signal Transduction/physiology MH - Tumor Necrosis Factor-alpha/*metabolism OTO - NOTNLM OT - Acute lung injury OT - Alveolar epithelial cells OT - Amphiregulin OT - Apoptosis OT - ErbB receptors OT - Tumor necrosis factor-alpha COIS- Declaration of Competing Interest The authors declare no conflicts of interest related to the current study. EDAT- 2020/03/20 06:00 MHDA- 2020/12/19 06:00 CRDT- 2020/03/20 06:00 PHST- 2019/11/06 00:00 [received] PHST- 2020/01/26 00:00 [revised] PHST- 2020/01/31 00:00 [accepted] PHST- 2020/03/20 06:00 [entrez] PHST- 2020/03/20 06:00 [pubmed] PHST- 2020/12/19 06:00 [medline] AID - S0753-3322(20)30186-4 [pii] AID - 10.1016/j.biopha.2020.109995 [doi] PST - ppublish SO - Biomed Pharmacother. 2020 May;125:109995. doi: 10.1016/j.biopha.2020.109995. Epub 2020 Feb 27.