Effect Of Gender On The Treatment Responses To Rapamycin On The Progression Of Emphysema In Cigarette Smoke-Exposed Mice

SESSION TITLE: Obstructive Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Emphysema is characterized by the permanent enlargement of distal airspaces. Current therapies focus on symptom relief as little can halt disease progression. Given its role in cell aging/damage, the mTOR pathway has been studied with respect to emphysema. While inhibition of this pathway with rapamycin has been shown to delay progression of cigarette-smoke (CS) induced emphysema, effects of gender have not been examined. We aim to characterize the effects of rapamycin on the progression of CS induced lung injury in male and female mice. METHODS: A prospective study of 151 mice (C57B/6 strain) was conducted. The mice were separated into two cohorts: CS exposure vs. no CS exposure. The CS exposed group was stratified based on gender and treatment with rapamycin (CS-D) or a vehicle (CS-V) whereas the no CS exposure group was stratified by gender alone. Mice were sacrificed at 0, 3 and 5 months to obtain alveolar histologic data (chord length [Lm]) and pre-mortem physiologic data by Scireq Flexivent (total lung capacity [TLC], static compliance [Cst], dynamic compliance [Cdy], and Pressure-Volume [PV] loops). Statistical analysis was performed by Mann-Whitney t-test and Kruskall-Wallis test using PRISM GraphPad software with a p < 0.05 considered significant. RESULTS: Male CS-V mice had a higher lung compliance at 3 months compared to male CS-D mice as seen on the PV loops. Ventilator data showed male CS-V mice to have a higher average TLC (1.56mL vs 1.43mL; p= 0.002) and Cst (0.11 mL/cmH2O vs 0.09 mL/cmH2O; p = 0.002) at 3 months compared to male CS-D mice. This difference in ventilator parameters did not persist at 5 months and were not different between CS-V and CS-D mice (p > 0.05). On histology, CS-V mice had longer Lm than non-CS exposed mice over the 5 month study period with the largest difference at 5 months (75.12 um vs 66.28 um; p= 0.003). Male CS-V mice had longer Lm than CS-D mice at 3 months (69.59 um vs 65.47 um; p= 0.016), but not at 5 months. No significant differences in Lm were seen between CS-V and CS-D mice at 3 and 5 months in the female group. CONCLUSIONS: Protection against CS induced emphysema by treatment with rapamycin is highly gender dependent. Males benefit significantly with rapamycin treatment while females do not. This therapeutic effect is not durable over long/chronic CS exposure. CLINICAL IMPLICATIONS: Rapamycin may be a viable option for temporarily delaying the progression of CS-induced emphysema, though further investigation into the mechanisms by which gender influences the progression of CS-induced emphysema related to the biology of mTOR and aging are needed. DISCLOSURES: No relevant relationships by Marie Burdick, source=Web Response No relevant relationships by Kranthikiran Earasi, source=Web Response No relevant relationships by Mu He, source=Web Response No relevant relationships by Jamie MacLeod, source=Web Response No relevant relationships by Lukasz Myc, source=Web Response No relevant relationships by Zaid Obaida, source=Web Response No relevant relationships Added 05/30/2020 by Yun Shim, source=Web Response, value=Intellectual property rights Removed 06/01/2020 by Yun Shim, source=Web Response No relevant relationships Added 05/30/2020 by Yun Shim, source=Web Response, value=Salary Removed 06/01/2020 by Yun Shim, source=Web Response No relevant relationships by Chunzi Song, source=Web Response No relevant relationships by Zhimin Zhang, source=Web Response