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Objective: Rat exposure to hyperoxia is a well-established model of human ARDS. Adult rats exposed to hyperoxia (100% O 2 ) die from respiratory failure within 60-72 hours. However, rats preconditioned by exposure to >95% O 2 for 48 hrs followed by a 24-hr “rest period” in room air (H-T) acquire tolerance of the otherwise lethal effects of exposure to 100% O 2 . In contrast, rats preconditioned by exposure to 60% O 2 for 7 days (H-S) become more susceptible to 100% O 2 . The objective was to evaluate lung tissue mitochondrial bioenergetics in H-T and H-S rats. Methods: Adult rats were exposed to room air (normoxia), >95% O 2 for 48 hrs followed by exposure to room air for 24 hrs (H-T), or 60% O 2 for 7 days (H-S). Mitochondria were isolated from lung tissue and used to assess mitochondrial bioenergetics. Expressions of electron transport chain complexes were measured in lung tissue homogenate using western blot. Isolated perfused lungs (IPL) were used to determine pulmonary vascular endothelial filtration coeffcient ( K f ) as a measure of pulmonary vascular permeability, and lung tissue mitochondrial membrane potential (ΔΨ m ). Results: Western blot shows decreased (38%) complex I expression, but increased (70%) complex V expression in H-T lung tissue homogenate compared to normoxia. Complex I expression decreased (43%) in H-S lung tissue homogenate. State 3 oxidative phosphorylation (OxPhos) capacity (V max ) and respiratory control ratio decreased in mitochondria isolated from H-S lungs. V max increased in mitochondria of H-T lungs. Time for ΔΨ m repolarization following ADP-stimulated depolarization increased in mitochondria isolated from H-S lungs. IPL studies revealed that tissue ΔΨ m is unchanged in H-S and H-T lungs compared to normoxics. Furthermore, complex I plays the dominant role in ΔΨ m in H-T and normoxia lungs with no contribution from complex II, whereas complex II has a larger contribution to ΔΨ m in H-S lungs than in H-T or normoxia. K f increased (+178%) in H-S, but not H-T lungs. Discussion: For H-T lungs, decreased complex I expression is countered by increased complex V expression, which could also account for increased V max . This along with high tissue glutathione content protects mitochondria from stress such as exposure to 100% O 2 . For H-S lungs, the effect of decreased complex I expression on lung tissue ΔΨ m is countered by a larger contribution from complex II. However, higher dependency of ΔΨ m on complex II could lead to higher mitochondrial oxidant production since complex II is the main source of oxidants in rat lungs. This along with decreased V max and increased K f make H-S rats more susceptible to stress such as exposure to 100% O 2 . These results are clinically relevant since exposure to hyperoxia is a primary therapy for patients with ARDS, and ventilation with 60% O 2 is often required for prolonged periods of time, particularly with COVID-19. This study was funded by NHLBI grant 2R15HL129209-03, Department of Veterans Affairs Merit Review Award BX001681, and NSF grant DMS 2153387. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Taheri et al. (Wed,) studied this question.