Hyperbaric oxygen therapy mitigates respiratoryneuromuscular pathology after spinal cord injury

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ABSTRACT Hyperbaric oxygen (HBO) therapy involves brief (≤1 hr) exposure to pressurized oxygen at ≤3 ATM and is used frequently for wound healing and decompression sickness. Our preliminary data and literature reports have led to the central hypothesis that HBO, delivered in the acute phases (days to weeks) after cervical spinal cord injury (SCI), attenuates diaphragm atrophy and dysfunction, reduces cervical spinal cord pathology, and improves respiratory neuromuscular recovery. The proposed mechanistic link between HBO therapy and attenuation of both muscular and neural pathology after SCI is oxidative stress. Preliminary data demonstrate that cervical contusion injury leads to substantial increases in ROS in the diaphragm and atrophy. Preliminary testing also showed that 1 hr HBO therapy for 10 days decreased diaphragm ROS formation and increased diaphragm antioxidant capacity. The HBO therapy also considerably attenuated the atrophy and contractile impairments that occurred after cervical contusion. In regards to spinal neuropathology, secondary damage (i.e., pathology that develops after the initial trauma) impairs motor recovery. Preliminary histological and molecular data demonstrate a neuroprotective impact of HBO with reduction in secondary damage in the contused cervical spinal cord. This includes attenuated neuronal loss with reduced expression of apoptotic markers and reduced inflammation after HBO therapy. Since oxidative stress contributes to secondary damage, we predict that HBO- induced upregulation of antioxidant expression underlies these effects. Collectively, the preserved diaphragm function and attenuated cervical pathology lead to our overall hypothesis that respiratory recovery will be improved by HBO therapy. Aim 1 will test the hypothesis that HBO therapy during acute through sub-acute phases after cervical SCI reduces diaphragm atrophy and improves contractility. The hypothesis will be tested with histological, molecular and functional evaluation of the diaphragm. To test oxidative mechanisms, antisense oligonucleotides will be used to block translation of specific antioxidants during HBO therapy. To determine if antioxidant mechanisms are sufficient to explain the HBO therapeutic effects, we will overexpress specific antioxidants using adeno-associated virus (AAV). Aim 2 will test the hypothesis that the neuroprotective impact of HBO therapy during acute through sub-acute phases after cervical SCI leads to improved phrenic motor recovery. The hypothesis will be tested with histological, molecular, and neurophysiological methods (direct phrenic nerve recordings and diaphragm electromyography). As in Aim 1, mechanistic studies will utilize antisense oligonucleotides and AAV strategies to modulate antioxidant formation in the spinal cord. Co-PI Dr. Smuder is an expert in diaphragm biology and mechanisms of atrophy. Co-PI Dr. Fuller has extensive experience in preclinical SCI models of respiratory dysfunction. Consultant Dr. Dean is an authority on HBO.