NMDA receptor activation induces damage of alveolar type II cells and lung fibrogenesis through ferroptosis.

Autor: Cheng HP; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China., Feng DD; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Li XH; Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China., Gao LH; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Qiu YJ; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Liang XY; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Zhou Y; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Huang P; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Shao M; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Zhang YN; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Chang YF; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Fu JF; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Huang YH; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China., Liu W; Xiangya Nursing School, Central South University, Changsha, Hunan, China., Tang SY; Xiangya Nursing School, Central South University, Changsha, Hunan, China., Li C; Department of Physiology, Changzhi Medical College, Changzhi, Shanxi, China. Electronic address: c.li@czmc.edu.cn., Luo ZQ; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China. Electronic address: luoziqiang@csu.edu.cn.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Molecular cell research [Biochim Biophys Acta Mol Cell Res] 2023 Oct; Vol. 1870 (7), pp. 119535. Date of Electronic Publication: 2023 Jul 13.
DOI: 10.1016/j.bbamcr.2023.119535
Abstrakt: Ferroptosis, a newly discovered type of regulated cell death, has been implicated in numerous human diseases. Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease with poor prognosis and limited treatment options. Emerging evidence has linked ferroptosis and glutamate-determined cell fate which is considered a new light on the etiology of pulmonary fibrosis. Here, we observed that N-methyl d-aspartate receptor (NMDAR) activation promoted cell damage and iron deposition in MLE-12 cells in a dose-, time-, and receptor-dependent manner. This mediated substantial Ca 2+ influx, upregulated the expression levels of nNOS and IRP1, and affected intracellular iron homeostasis by regulating the expression of iron transport-related proteins (i.e., TFR1, DMT1, and FPN). Excessive iron load promoted the continuous accumulation of total intracellular and mitochondrial reactive oxygen species, which ultimately led to ferroptosis. NMDAR inhibition reduced lung injury and pulmonary fibrosis in bleomycin-induced mice. Bleomycin stimulation upregulated the expression of NMDAR1, nNOS, and IRP1 in mouse lung tissues, which ultimately led to iron deposition via regulation of the expression of various iron metabolism-related genes. NMDAR activation initiated the pulmonary fibrosis process by inducing iron deposition in lung tissues and ferroptosis of alveolar type II cells. Our data suggest that NMDAR activation regulates the expression of iron metabolism-related genes by promoting calcium influx, increasing nNOS and IRP1 expression, and increasing iron deposition by affecting cellular iron homeostasis, ultimately leading to mitochondrial damage, mitochondrial dysfunction, and ferroptosis. NMDAR activation-induced ferroptosis of alveolar type II cells might be a key event to the initiation of pulmonary fibrosis.
Competing Interests: Declaration of competing interest The authors declare no competing interests.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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