Ventilator-induced Lung Injury Associated With Endothelial Cell Mitochondrial Fission

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Abstract RATIONALE: Mechanical ventilation (MV) represents a cornerstone of supportive care for sepsis-induced acute respiratory distress syndrome. Unfortunately, cyclic positive pressure from MV can exacerbate lung injury, a phenomenon known as ventilator-induced lung injury (VILI). Recent studies highlight the crucial role of mitochondrial dysfunction in VILI development. Here, we evaluated whether cyclic stretch modulates the activity of the major mitochondrial fission mediator, dynamin-related protein 1 (Drp1) in pulmonary endothelial cells, contributing to lung injury. Further, we evaluated if genetic variations of Drp1 are associated with MV-induced lung injury susceptibility. METHODS: Human lung microvascular endothelial cells (HLMVEC) were exposed to cyclic stretch for 4-12h, mimicking the degree of stretch by MV. Silencing Drp1: C57 mice were intravenously injected with 5mg/kg siDrp1 with jetPEI polymer. After 72h, mice were exposed to high tidal ventilation (HTV, tidal volume= 30mL/kg, BR=75bpm, 4h) or allowed to spontaneously breathe. Drp1 activity inhibition: mice were intraperitoneally pretreated with 1mg/kg of P110 for 1h then exposed to HTV or not. Human genetic association study (HGAS): We analyzed data for 604 patients enrolled in the Pittsburgh ALIR study who were intubated and MV for acute respiratory failure from different etiologies. Statistical analysis: For animal/in vitro studies, means ± SEM was calculated and compared by the t-test. ANOVA for repeated measures was used when multiple comparisons were made with Student-Newman-Keuls post hoc testing. For the HGAS, we used non-parametric tests to compare continuous and categorical variables between genotypes and an additive genetic model. p-values<0.05 considered significant. RESULTS: Exposing HLMVEC to cyclic stretch reduced basal respiration (30%, p=0.0008), max respiratory capacity (31%, p<0.0001), and mitochondrial aspect ratio (64%, p<0.0001), indicative of mitochondrial dysfunction and a fission phenotype. Silencing Drp1 prior to cyclic stretch prevented these changes (p<0.0001). siRNA-mediated Drp1 knockdown of Drp1 in mice was protective against VILI, demonstrated by reductions in lung inflammation, edema, and injury by 54%, 73%, and 32%, respectively (p<0.0001). Pretreatment with P110 was also protective, reducing pulmonary inflammation, edema, and injury by 53%, 32%, and 41%, respectively (p<0.0001). Lastly, in a cohort of 604 critically ill patients on MV, we found significant associations between two variants of DNM1L with plasma biomarkers of endothelial injury and inflammation (p<0.0015). CONCLUSIONS: DNML1 genetic variants are associated with systemic inflammation and endothelial injury biomarkers in MV patients. Our data demonstrate that DNML1 genetics modulate the severity of VILI and therapeutically targeting Drp1-mitochondrial fission is a promising strategy to improve MV outcomes.

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