P2Y12R Blockade Attenuates LPS-Induced Acute Lung Injury Associated with Suppression of Inflammasome-Mediated Pyroptotic Signaling

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Purpose: Acute lung injury (ALI) is characterized by excessive inflammation and cell death, with no specific pharmacological treatment. P2Y12 receptor (P2Y12R) is implicated in regulating inflammation, but their role in ALI remains unclear. This study investigates the effects of P2Y12R antagonists including Clopidogrel, Prasugrel, and Ticagrelor on LPS-induced ALI in mice, focusing on inflammation and pyroptosis. Methods: Mice were pre-treated with P2Y12R antagonists before LPS administration. Lung injury was assessed via histology, wet/dry ratio, myeloperoxidase (MPO) activity, and inflammatory cytokine levels in bronchoalveolar lavage fluid (BALF). Gene and protein levels of IL-1β, IL-6, TNF-α, and inflammasome components (NLRP3, ASC, Caspase-1, GSDMD) were measured. Ultrastructural changes were analyzed by transmission electron microscopy (TEM). Results: P2Y12R antagonists reduced histological injury, pulmonary edema, and inflammatory cytokines in BALF, with Ticagrelor showing the most prominent effects. Gene and protein levels of IL-1β, IL-6, and TNF-α were decreased. P2Y12R antagonists also inhibited inflammasome activation and pyroptosis. TEM analysis showed reduced organelle damage in treated groups. Conclusion: P2Y12R antagonists, particularly Ticagrelor, attenuate lung injury and were associated with suppression of the NLRP3/caspase-1/GSDMD pyroptotic signaling axis.

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