Department of Toxicology, Shaanxi Provincial Key Lab of Free Radical Biology and Medicine, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
Department of Toxicology, Shaanxi Provincial Key Lab of Free Radical Biology and Medicine, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
Eur J Pharmacol. 2023 Oct 15;957:176017. doi: 10.1016/j.ejphar.2023.176017. Epub 2023 Sep 4.
Phosgene is widely used as an industrial chemical, and phosgene inhalation causes acute lung injury (ALI), which may further progress into pulmonary edema. Currently, an antidote for phosgene poisoning is not known. Alpha-1 antitrypsin (α1-AT) is a protease inhibitor used to treat patients with emphysema who are deficient in α1-AT. Recent studies have revealed that α1-AT has both anti-inflammatory and anti-SARS-CoV-2 effects. Herein, we aimed to investigate the role of α1-AT in phosgene-induced ALI. We observed a time-dependent increase in α1-AT expression and secretion in the lungs of rats exposed to phosgene. Notably, α1-AT was derived from neutrophils but not from macrophages or alveolar type II cells. Moreover, α1-AT knockdown aggravated phosgene- and lipopolysaccharide (LPS)-induced inflammation and cell death in human bronchial epithelial cells (BEAS-2B). Conversely, α1-AT administration suppressed the inflammatory response and prevented death in LPS- and phosgene-exposed BEAS-2B cells. Furthermore, α1-AT treatment increased the inhibitor of DNA binding 1 (ID1) gene expression, which suppressed NF-κB pathway activation, reduced inflammation, and inhibited cell death. These data demonstrate that neutrophil-derived α1-AT acts as a self-protective mechanism, which protects against phosgene-induced ALI by activating the ID1-dependent anti-inflammatory response. This study may provide novel strategies for the treatment of patients with phosgene-induced ALI.
光气被广泛用作工业化学品，吸入光气会导致急性肺损伤（ALI），进而可能发展为肺水肿。目前，尚无针对光气中毒的解毒剂。α1-抗胰蛋白酶（α1-AT）是一种用于治疗α1-AT 缺乏症肺气肿患者的蛋白酶抑制剂。最近的研究表明，α1-AT 具有抗炎和抗 SARS-CoV-2 的作用。在此，我们旨在研究α1-AT 在光气诱导的 ALI 中的作用。我们观察到，暴露于光气的大鼠肺部的α1-AT 表达和分泌呈时间依赖性增加。值得注意的是，α1-AT 来源于中性粒细胞，而不是巨噬细胞或肺泡 II 型细胞。此外，α1-AT 敲低加重了光气和脂多糖（LPS）诱导的人支气管上皮细胞（BEAS-2B）炎症和细胞死亡。相反，α1-AT 给药抑制了 LPS 和光气暴露的 BEAS-2B 细胞中的炎症反应并防止细胞死亡。此外，α1-AT 治疗增加了 DNA 结合抑制因子 1（ID1）基因的表达，抑制了 NF-κB 通路的激活，减轻了炎症并抑制了细胞死亡。这些数据表明，中性粒细胞衍生的α1-AT 作为一种自我保护机制，通过激活 ID1 依赖性抗炎反应来防止光气诱导的 ALI。这项研究可能为治疗光气诱导的 ALI 患者提供新的策略。
