Estrogen-Dependent Modulation of Purinergic Receptor Blockade in Sepsis-Induced Lung Injury

Sepsis is characterized by dysregulated host response to infection, causing tissue damage, organ failure, and potentially death. During sepsis, the lung is one of the first organs to be impacted, leading to acute lung injury (ALI). Platelets are integral in hemostasis and modulate immune responses during sepsis.Activation of the purinergic signaling pathways through ADP receptors P2Y 12 and P2Y 1 on platelets contributes to the pathophysiology of sepsis. Sex is a significant risk factor for sepsis, with males exhibiting higher susceptibility and poorer outcomes. Our group has previously shown that targeting purinergic signaling in a murine model of sepsis reduces platelet activation and modulates immune response in a sex-specific manner. This study explores the effect of blocking purinergic signaling in an estrogen-depleted environment in female septic mice. Female wild-type (fWT) and Ovariectomized (OVX) mice underwent either sham surgery or cecal ligation and puncture (CLP) to induce sepsis-induced ALI. Following the CLP procedure, both fWT and OVX mice were administered intraperitoneal injections of 30 mg/kg Ticagrelor (TIC - P2Y 12 antagonist) or 10 mg/kg MRS2279 (MRS - P2Y 1 antagonist). Twenty-four hours post-surgery, whole blood samples were obtained via cardiac puncture, and bronchoalveolar lavage fluid (BALf) and lung tissue were harvested. Septic fWT and OVX mice showed elevated plasma cytokine levels of p-selectin, IL-1a, MIP-1, a and Rantes. However, in septic mice treated with TIC or MRS, P-selectin, IL-1a, MIP-1a, and Rantes plasma levels were significantly reduced in OVX mice compared to fWT. IL-6, IL-16, MIG, and Pecam-1 in the BALf of fWT and OVX septic mice were elevated compared with sham. Following TIC or MRS treatment during CLP, IL-6, IL-16, MIG, and Pecam-1 levels were significantly reduced in OVX but not in fWT mice. P2Y 12 protein level was significantly increased in the lungs of septic OVX, but not fWT, compared with their respective sham groups. Following TIC or MRS treatment during sepsis, the P2Y 12 protein level was significantly decreased in OVX CLP mice. No significant change was noted in P2Y 1 protein expression in all groups for both OVX and fWT. P2Y12 and P2Y1 receptor blockade impact cytokine secretion and lung P2Y12 levels differently based on estrogen exposure, highlighting the need for sex-specific sepsis treatments. This work was supported by the Research grant AI156627-01 (EL) from the National Institute of Health. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.