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

ABSTRACT

Phosgene, a highly dangerous chemical warfare agent, is widely used as an industrial chemical. Phosgene inhalation causes acute lung injury (ALI), which may further progress into pulmonary edema. Currently, there is no known antidote for phosgene poisoning. Alpha-1 antitrypsin (α1-AT) is a protease inhibitor that has been used to treat emphysema patients, who are deficient in α1-AT, for decades. Recent studies have shown that α1-AT has both anti-inflammatory and anti-SARS-CoV-2 effects. In this study, 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. Interestingly, α1-AT was derived from neutrophils, but not from macrophages or alveolar type II cells, and 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 expression of the inhibitor of DNA binding (ID1) gene, which suppressed NF-κB pathway activation, reduced inflammation, and inhibited cell death. These data demonstrate that neutrophil-derived α1-AT 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.