ABX-1431, a Selective Monoacylglycerol Lipase Inhibitor, Mitigates Ventilator-Associated Pneumonia in Mice

Study Objective: Elucidate the protective effects of Monoacylglycerol Lipase (MAGL) inhibition in a murine model of Ventilator-Associated Pneumonia. Given the anti-inflammatory effects of MAGL inhibition, we hypothesized that selective pharmacological inhibition of MAGL could reduce lung inflammation and injury in a Ventilator Associated Pneumonia (VAP) mouse model. Methods: VAP was modeled on C57BL/6 wild-type (WT) mice. Mice received intratracheal injections of Pseudomonas aeruginosa (PA) and after 24h mice were subjected to injurious mechanical ventilation (30 mL/kg body weight, 2h) using the FlexiVent mouse ventilator. To inhibit MAGL, ABX-1431 (5 mg/kg), a selective inhibitor, was administered intraperitoneally to the mice 30 minutes after PA injection and 1h before ventilation. Bronchoalveolar lavage fluid (BALF) and lung tissue were collected immediately after ventilation. The total cell number in the BALF was determined and the neutrophil population was determined by differential staining. The lung injury was assessed by histology and ELISA was used to measure the level of proinflammatory cytokines in the BALF. The inflammatory signaling in the lung was examined by immunoblot. Results: Pharmacological inhibition of MAGL attenuated immune cell infiltration into the alveoli, as evidenced by a significantly lower total BALF cell count in ABX-1431-treated mice compared to vehicle controls. Additionally, ABX-1431 treatment resulted in a reduced percentage of neutrophils in the lungs. Histological analysis using H&E staining demonstrated that MAGL inhibition alleviated lung injury. Furthermore, ABX-1431 administration decreased the BALF levels of TNF-α and IL-1β, which were elevated in response to VAP. Immunoblot analysis also revealed that MAGL inhibition suppressed VAP-induced activation of c-Jun N-terminal kinase (JNK). Conclusion: In the mouse model of VAP, this study highlights the potential therapeutic benefits of MAGL inhibition in mitigating lung inflammation. By reducing immune cell infiltration, suppressing JNK signaling, and decreasing inflammatory cytokine production, MAGL inhibition emerges as a promising strategy for attenuating the inflammatory response associated with VAP. Standard abbreviations for units of measure: Milliliter (ml), Gram (g), Milligram (mg), Kilogram (kg), Picogram (pg), and Hours (h). Institutional funding from the Macon & Joan Brock Virginia Health Sciences at Old Dominion University and Department of Medical Student Research. 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.