Alpha-1 antitrypsin protects against phosgene-induced acute lung injury by activating the ID1-dependent anti-inflammatory response

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 (alpha 1-AT) is a protease inhibitor used to treat patients with emphysema who are deficient in alpha 1-AT. Recent studies have revealed that alpha 1-AT has both anti-inflammatory and anti-SARS-CoV-2 effects. Herein, we aimed to investigate the role of alpha 1-AT in phosgene-induced ALI. We observed a time-dependent increase in alpha 1-AT expression and secretion in the lungs of rats exposed to phosgene. Notably, alpha 1-AT was derived from neutrophils but not from macrophages or alveolar type II cells. Moreover, alpha 1-AT knockdown aggravated phosgene- and lipopolysaccharide (LPS)-induced inflammation and cell death in human bronchial epithelial cells (BEAS-2B). Conversely, alpha 1-AT administration suppressed the inflammatory response and prevented death in LPS- and phosgene-exposed BEAS-2B cells. Furthermore, alpha 1-AT treatment increased the inhibitor of DNA binding 1 (ID1) gene expression, which suppressed NF-kappa B pathway activation, reduced inflammation, and inhibited cell death. These data demonstrate that neutrophil-derived alpha 1-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.