Mitochondrial function in lungs of rats with different susceptibilities to hyperoxia-induced acute lung injury.

Abstract

Adult rats exposed to hyperoxia (>95% O₂) die from respiratory failure in 60-72 h. However, rats preconditioned with >95% O₂ for 48 h followed by 24 h in room air acquire tolerance of hyperoxia (H-T), whereas rats preconditioned with 60% O₂ for 7 days become more susceptible (H-S). Our objective was to evaluate lung tissue mitochondrial bioenergetics in H-T and H-S rats. Bioenergetics was assessed in mitochondria isolated from lung tissue of H-T, H-S, and control rats. Expressions of complexes involved in oxidative phosphorylation (OxPhos) were measured in lung tissue homogenate. Pulmonary endothelial filtration coefficient (K_f) and tissue mitochondrial membrane potential (Δψ_m) were evaluated in isolated perfused lungs (IPLs). Results show that ADP-induced state 3 OxPhos capacity (V_max) decreased in H-S mitochondria but increased in H-T. Δψ_m repolarization time following ADP-stimulated depolarization increased in H-S mitochondria. Complex I expression decreased in H-T (38%) and H-S (43%) lung homogenate, whereas complex V expression increased (70%) in H-T lung homogenate. Δψ_m is unchanged in H-S and H-T lungs, but complex II has a larger contribution to Δψ_m in H-S than H-T lungs. K_f increased in H-S, but not in H-T lungs. For H-T, increased complex V expression and V_max counter the effect of the decrease in complex I expression on Δψ_m. A larger complex II contribution to Δψ_m along with decreased V_max and increased K_f could make H-S rats more hyperoxia susceptible. Results are clinically relevant since ventilation with ≥60% O₂ is often required for extended periods in patients with acute respiratory distress syndrome (ARDS).NEW & NOTEWORTHY We assessed lung tissue mitochondrial bioenergetics in rats with tolerance (H-T) or susceptibility (H-S) to hyperoxia-induced ARDS. Results from studies in isolated mitochondria, tissue homogenate, and isolated perfused lungs show that mitochondrial bioenergetics are differentially altered in H-T and H-S lungs suggesting a potential role for mitochondrial bioenergetics in hyperoxia-induced ARDS. Results are clinically relevant since hyperoxia exposure is a primary therapy for patients with ARDS, and differential sensitivity to hyperoxia surely occurs in humans.