A77-12 Ventilation Induced Lung and Brain Injury in Alzheimer's Mice: Effects of NLRP3 Inhibition

Abstract Rationale Mechanical ventilation, while lifesaving, can cause primary injury to the lungs (ventilation-induced lung injury “VILI”) that could result in secondary injury to the brain through inflammatory signaling known as ventilation-induced brain injury (VIBI). The NLRP3 inflammasome is a key driver of cytokine release and cellular injury in both pulmonary and neuroinflammatory pathways. MCC950, a selective NLRP3 inhibitor, has shown promise in reducing inflammation in preclinical disease models of lung and brain injury. This study investigates whether pharmacologic inhibition of NLRP3 can mitigate MV-induced lung-brain inflammation in aged Alzheimer’s disease mice. Methods The experimental methods were conducted using 12 to 15 months old female mice randomly separated into three subject groups: 3xTg-AD C57-BL6 mice (Alzheimer’s Disease model, a triple-transgenic strain with mutations in the APP, MAPT, and PSEN1 genes), 3xTg-AD C57-BL6 NLRP3 inhibited mice (3xTg-AD strain with NLRP3 inflammasome formation inhibition using MCC950), and dosed control C57-BL6 mice (3xTg-AD strain with dosed with the drug vehicle only, Dimethyl sulfoxide (DSMO) and saline). Mice from each group were anesthetized, intubated intratracheally, and mechanically ventilated for 2 hours on high-pressure settings of 30 cmH2O to stimulate lung injury. Mechanical scans were performed every 30 minutes, and samples were collected immediately after the final time point. The control group did not receive mechanical ventilation, and samples were collected directly after sedation. Sample collections included retrieving blood from the vena cava, perfusion through the left ventricle of the heart and brain, bronchoalveolar lavage fluid (BALF), and lung collections, respectively. Plasma was extracted from the blood sample. Results Ventilated 3xTg-AD mice showed increased lung resistance and elastance, reduced compliance, compared to MCC950-treated mice, consistent with VILI. MCC950 treatment improved lung hysteresis and reduced energy loss and minute work of breathing, which potentially reduced inflammation and preserved alveolar architecture. Conclusions NLRP3 inhibition via MCC950 attenuates pulmonary inflammation in ventilated 3xTg-AD mice, supporting the role of the inflammasome in lung mechanics, driving systemic inflammation, and contributing to crosstalk. These findings suggest that targeting NLRP3 may be a viable therapeutic approach to reduce ventilator-associated injury, particularly in aging and neurodegenerative contexts. This abstract is funded by: None