B75-05 Sex-Related Differences in the Development of Pulmonary and Systemic Inflammation in Indirect and Direct Murine Models of Acute Lung Injury (ALI)

Background Sex is a critical biological variable influencing systemic and pulmonary inflammation in critical illness. Clinical data show that males experience higher inflammatory burden, septic shock, and ICU mortality than females. However, whether females are protected from or are equally vulnerable to ventilator-induced lung injury (VILI) remains uncertain. Thus, we tested the hypothesis that male and female mice display distinct inflammatory and physiological responses in two ALI models: (i) mechanical ventilation with high tidal volume (HTV) and (ii) cecal ligation-two puncture (CL2P). Methods C57Bl/6j male and female mice, 8-10 weeks of age, were anesthetized with Ketamine/Xylazine (90 mg/kg and 9 mg/kg, respectively, ip). For HTV studies, tracheostomized mice were ventilated using a Flexivent system (30 mL/kg, 70 breaths/min, I:E 2:1, FiO2 0.5) and compared to low tidal volume-ventilated controls (10 mL/kg). For experiments focused on sepsis, in anesthetized mice a small traverse incision was made in their lower left quadrant. The cecum was then exposed, ligated and punctured twice with a 19G needle. Animals were euthanized 72 h later, and lung tissues were harvested for molecular and functional analyses. Results Female mice in the HTV study displayed higher mortality and stronger inflammation compared to HTV-ventilated male mice. Bronchoalveolar lavage fluid (BALF) analysis showed that female mice were prone to higher infiltration of immune cells, while histological analysis of lungs and quantification of injury via the Lung Injury Score indicated similar level of lung inflammation, edema, and immune cell infiltration across sexes. Similarly, in the CL2P studies, female mice exhibited higher weight loss compared to their male counterparts. Analysis of pulmonary function showed that female mice were more sensitive to ALI than males: they presented a greater downward shift in pressure-volume relationships, higher respiratory resistance and greater loss in dynamic and static compliance than males. Conclusions Sex strongly influences pulmonary and systemic inflammation in ALI. Female mice exhibit more severe inflammation, higher mortality, and worsened respiratory mechanics across both models. Further studies are required to understand the molecular players responsible for sex-related differences in critically ill patients. This abstract is funded by: DoD