Abstract 175: Delayed Effects of Ischemic Stroke on Lung Mechanics and Intrinsic Antioxidant Defenses

Abstract

Ischemia-reperfusion injury causes central and peripheral inflammatory changes for which there are no viable therapeutic options. Following ischemic stroke, danger signals are released into the periphery, which activate circulating immune and endothelial cells and therefore contribute to collateral tissue damage. Our lab and others have shown the lung is particularly susceptible to injury and inflammation following ischemic stroke. However, the mechanistic basis for this susceptibility is unknown. We hypothesized that focal ischemic stroke induces lung injury and inflammation by reducing endogenous antioxidants, such as superoxide dismutase 3 (SOD3), within the lung. To test this hypothesis, we performed middle cerebral artery occlusion (MCAO: 60-minutes) or sham surgery on C57BL/6 mice before initiating reperfusion for 3-days (n=8/group), after which brain and lung were collected for analysis. In a separate cohort of C57BL/6 mice (n=5/group), we used the FlexiVent system and Inficon’s Gas Chromatography to assess lung mechanics and gas exchange, respectively. In the lung of mice that received MCAO, we observed a significant reduction in SOD3 (Sham vs. MCAO, Mean±SD: 1.772±0.32AU vs 0.94±0.24AU; p=0.04) and VCAM-1 (1.00±0.17AU vs. 0.30±0.12AU; p=0.0028) levels. This was accompanied by an increase in 4-HNE protein adducts (0.45±0.06AU vs 1.94±0.5AU; p=0.019) in the lung following stroke, indicating greater oxidative injury. In our functional analyses, we found that stroke induced a significant decrease in lung compliance (0.04±0.02mL/cmH 2 O vs 0.03±0.001 mL/cmH 2 O, p=0.04) and an increase in elastance (25.28±1.26cmH 2 O/mL vs 29.2±0.90cmH 2 O/mL, p=0.03) while simultaneously changing resistance at the airways (0.31±0.08cmH 2 O.s/mL vs 0.19±0.01cmH 2 O.s/mL, p=0.008) and distal alveolar spaces (0.58±0.04 cmH 2 O.s/mL vs 0.75±0.04cmH 2 O.s/mL, p=0.01). However, ischemic stroke did not change lung gas exchange (0.77±0.12AU vs 0.74±0.06AU; n.s.); this finding was corroborated by the lack of any robust structural changes in the lung following injury (11.83±0.93um vs 13.54±2.79um). Taken together, these findings highlight ischemic stroke drives changes in lung mechanics by altering the inflammatory and redox environment within the lung.