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 (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. Phosgene inhalation leads to the recruitment of neutrophils into the lungs. The recruited neutrophils express and release α1-AT, which enters bronchial epithelial cells and increases ID1 expression, thereby inhibiting NF-κB activation. The inactivation of NF-κB reduces the release of inflammatory cytokines and death of bronchial epithelial cells. Endogenous and exogenous α1-AT alleviate phosgene-induced inflammation and acute lung injury. [Display omitted]