PCSK9 Promotes Platelet Activation and NET Formation, Aggravating Pulmonary Microthrombosis in Sepsis-Induced Lung Injury.

Background: Sepsis-induced lung injury is a major clinical challenge, frequently complicated by pulmonary microthrombosis, which exacerbates disease severity and worsens prognosis. Recent studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in inflammatory and thrombotic processes. However, the contribution of PCSK9 to pulmonary microthrombosis in sepsis remains unclear. Methods: Adult male C57BL/6J mice were subjected to cecal ligation and puncture (CLP) to induce sepsis. Twelve hours post-CLP, mice received either recombinant PCSK9 (1 μg, i.p.) or the PCSK9 inhibitor evolocumab (10 mg/kg, i.p.). Platelet activation and pulmonary microthrombosis were assessed using hematoxylin-eosin staining, immunofluorescence, and thromboelastography. Results: Administration of PCSK9 significantly enhanced platelet activation and increased neutrophil extracellular trap (NET) formation, promoting pulmonary microthrombosis in septic mice. In contrast, administration of evolocumab effectively attenuated platelet activation, reduced NET formation, and alleviated pulmonary microthrombosis. Conclusions: PCSK9 exacerbates sepsis-induced pulmonary microthrombosis by promoting platelet activation and NET formation. Targeting PCSK9 may represent a novel therapeutic strategy for preventing thrombotic complications in sepsis-induced lung injury.