Hypoxic Preconditioning Improves Diaphragm Function via Reactive Oxygen Species Formation
Chien, Michael T.
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Chronic obstructive pulmonary disease (COPD) is characterized by several deleterious alterations of the respiratory muscles, particularly the diaphragm, leading to the excessive intracellular formation of reactive oxygen species (ROS). Hypoxic preconditioning (HPC) therapies, however, have proven effective in protecting skeletal diaphragm muscle from this oxidative damage. We used mice diaphragm to test the hypothesis that HPC will be effective in reducing harmful levels of hypoxia-induced ROS formation and consequently increase diaphragmatic force generation. Isolated diaphragm muscle was subjected to 3, 5, or 10 cycles of acute HPC treatment (2 min of 95% N2 and 5% C02 followed by 2 min of 95% 02 and 5% C02) while living mice were treated daily with chronic HPC (2 min of 5 Torr 02 balanced with N2 followed by 2 min of 21% 02) over a 2-week period. Both muscle treatments were then electrically stimulated in a COPD-like environment (95% N2 and 5% C02). Five cycles of acute HPC and chronic HPC treatments resulted in increased diaphragmatic force generation. Ultrasound techniques were then applied to measure diaphragm displacement and respiratory rate in the chronic HPC model. Similarly, antioxidants ebselen and tiron were also able to rescue muscle function. Additionally, we used several inhibitors to further elucidate upon a possible HPC protection pathway. These results demonstrate that, in hypoxic mice diaphragm, 1) acute and chronic HPC reduced intracellular ROS formation in contracting skeletal muscle, 2) HPC rescued diaphragmatic force generation, and 3) Antioxidant treatment with ebselen or tiron reduced ROS generation to baseline levels.