SerpinB1 is Required for Rev-erbα-mediated Protection in Lipopolysaccharide-induced Acute Lung Injury

Background and Purpose Acute lung injury (ALI) is a serious, life-threatening inflammation of the lungs with a lack of effective treatment. We previously showed that serine protease inhibitor B1 (SerpinB1) protects against ALI induced by orthotopic autologous liver transplantation. However, the role of SerpinB1 in lipopolysaccharide (LPS) -induced ALI and its regulatory mechanisms are unknown. Experimental Approach Wild-type (WT) and SerpinB1 knockout (KO) mice were subjected to intratracheal LPS stimulation to induce ALI. Some of the WT and KO mice were injected intraperitoneally with melatonin, a rhythm-related protein Rev-erbα agonist. Circadian rhythm disruption was induced in WT mice by exposing mice to 24 hours of continuous darkness or light conditions after intratracheal LPS administration. Neutrophils were isolated from alveolar lavage fluid of WT and KO mice as well as from human peripheral blood. Neutrophils were treated with LPS and melatonin. Key Results We found that circadian rhythm disruption by either 24 hours dark or light conditions exacerbated LPS-induced ALI and reduced Rev-erbα and SerpinB1 protein expressions in the lung, whereas melatonin treatment increased SerpinB1 expression and attenuated LPS-induced ALI in WT mice, but not in KO mice. In neutrophils, Rev-erbα was co-localized with SerpinB1 and bound to its promoter to trigger SerpinB1 transcription. Furthermore, LPS stimulation increased neutrophil extracellular trap (NET) formation, which was reduced by melatonin treatment in neutrophils from WT mice, but not from KO mice. Conclusions and Implications SerpinB1 is rhythmically regulated by Rev-erbα, and its downregulation exacerbates LPS-induced ALI by inducing NET formation.

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