PERFLUOROCHEMICAL AUGMENTED INTRATRACHEAL DELIVERY OF ANTIOXIDANT ENZYMES AND GENES TO ATTENUATE OXIDATIVE STRESS-INDUCED LUNG AND RESPIRATORY MUSCLE ALTERATIONS

Abstract

Supraphysiologic concentrations of oxygen are used in the management of critically ill patients across the lifespan. However, hyperoxia (HO) results in alveolar- capillary membrane destruction, pulmonary edema, pleural effusions, infiltration and activation of inflammatory cells, altered pulmonary mechanics and gas exchange prompting increased loading of the respiratory muscle. These abnormalities of pulmonary structure and function increase the work of breathing necessitating increased respiratory muscle force production to maintain alveolar ventilation. When the load placed on the respiratory muscle pump exceeds its capacity, respiratory failure develops and is ultimately fatal unless therapeutic interventions are able to reduce the ventilatory load. The use of perfluorochemical (PFC) liquids as a respiratory medium has been effective in the treatment of respiratory distress syndrome and acute lung injury (ALI) requiring mechanical ventilation. Mechanistically, by eliminating the air-liquid interface, PFC liquids reduce surface tension enabling lung volume recruitment at low inspiratory pressures and have high respiratory gas solubility which supports gas exchange. Additionally, through mechanical as well as cytoprotective mechanisms, intrapulmonary PFC liquids reduce inflammatory cell activation and recruitment. Cell culture, animal and human studies have suggested that acute and chronic lung injury secondary to prolonged HO may be ameliorated by administration of antioxidant enzymes (AOE), with superoxide dismutases (SOD) having significant protective effects. Because the lung is exposed to the highest O2 concentrations, a logical strategy to reduce HO-induced damage is to specifically target antioxidant enzymes to the lungs. However, intratracheal delivery of AOE by vehicles like normal saline may transiently impair lung function and be poorly distributed. PFC fluids have previously been shown to be effective respiratory media for pulmonary administration of various drugs. The premise of the proposed studies are to to characterize hyperoxic lung injury in a spontaneously breathing animal model and to develop therapeutic strategies to reduce oxidatative stress and supplement endogenous AOE. With respect to the diaphragm, we reason that HO-induced lung damage and oxidative stress will increase contractile demand of the diaphragm. If AOE activity could be increased in the lungs and respiratory muscles with AOE proteins or the genes encoding these enzymes, then cell damage, inflammatory changes, damage to the lung and respiratory "pump" might be ameliorated or prevented. The results show that PFC and SOD can attenuate the HO- induced decline in lung mechanics and gas exchange, ameliorate the inflammatory and oxidative stress profiles, and promote lung and muscle structural integrity resulting in a survival benefit. These findings support the novel application of PFC liquids in a spontaneously breathing model and support the concept that PFC preconditioning and AOE supplementation play a protective role by reducing mortality and morbidity in hyperoxic lung injury.