Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 125, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2020.109995
Keywords
Acute lung injury; Amphiregulin; Tumor necrosis factor-alpha; ErbB receptors; Apoptosis; Alveolar epithelial cells
Funding
- National Natural Science Foundation of China [81700082]
- Natural science Foundation of Hubei Province of China [2017CFB387]
- Scientific and Technological Project of Shiyan City of Hubei Province [19Y28]
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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.
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