Jatrorrhizine alleviates cytokine storm secondary lung injury via regulating CD39-dominant purinergic braking and downstream NLRP3 inflammasome.

Abstract

Cytokine storm secondary lung injury (CSSLI) is a form of acute lung injury (ALI) comparable to that caused by sepsis for which there are no effective therapeutic strategies. Coptis chinensis Franch. and Scutellaria baicalensis Georgi. are two botanical medicines that exhibit anti-inflammatory properties. This study aimed to investigate the underlying therapeutic mechanism of the combination (CCSB) treatment in mice with ALI. A high dosage of lipopolysaccharide (LPS) was administered intraperitoneally to C57BL/6 mice to establish an ALI model. The AMP-Glo™ assay was applied to screen for the component with the most potent CD39-promoting enzyme activity from CCSB constituents migrating to the bloodstream. The PMA-differentiated THP-1 and RAW264.7 macrophage cell lines were stimulated with LPS and adenosine triphosphate, followed by treatment with Jatrorrhizine (JH). The administration of CCSB demonstrated a notable improvement in lung injury through the modulation of the CD39-P2X7 purinergic pathway and subsequent regulation of the NLRP3 inflammasome. The restrained CD39 and A2b were reversed by JH, leading to the suppression of the P2X7-NLRP3 signaling pathway. In addition, the utilization of a CD39 inhibitor (POM-1) attenuated the inhibitory effect of JH on the NLRP3 signaling pathway. CCSB successfully rescued CSSLI, along with its small-molecule component JH, which demonstrated the ability to inhibit the NLRP3 signaling pathway and pyroptosis, at least partially through regulating the CD39 enzyme.