Mitigation of Pulmonary Oxygen Toxicity in Premature Lambs with Intravenous Antioxidants

Abstract

Deficiencies of antioxidants and increased free radical generation may explain the high incidence of bronchopulmonary dysplasia in premature infants. Long-acting antioxidants such as polyethylene glycol (PEG) conjugated superoxide dismutase (SOD), and catalase might modify this process. We delivered 32 premature lambs, 16 pairs of twins, by cesarean section at 125-141 days of gestation (term 146 days) and stabilized them on ventilators in normocapnic hyperoxia for a period of 8 h. One lamb of each twin pair received an intravenous dose of 7,500-50,000 IU/kg of PEG-SOD and of 37,500-1,000,000 IU/kg of PEG-catalase at birth. Their siblings acted as controls. Mean airway pressure, arterial pressure, and heart rate were recorded continuously. Arterial blood gases and pH were obtained every 30 min. After sacrifice, standardized lung biopsies were prepared for quantitative morphometrics and electron microscopy. Administration of PEG antioxidants at birth reduced the influx of neutrophils and macrophages into the lung and damage to arterioles, bronchiolar mucosa, and type II pneumocytes without major changes in alveolar surface area or pulmonary function. These effects were dose-related and detectable even at the lowest doses of PEG antioxidants administered.

Atomic structures of wild-type and thermostable mutant recombinant human Cu,Zn superoxide dismutase.

“…These essential SOD enzymes are critical components in the physiological response to oxygen toxicity and are actively investigated as potential therapeutic agents in pathological conditions related to oxidative stress [e.g., reperfusion damage following ischemia (8,9), lung and tissue damage (10,11), and general inflammation (12)]. Recently, effective mitigation of pulmonary oxygen toxicity resulted in Food and Drug Administration designation of SOD as an orphan drug for prevention of bronchopulmonary dysplasia in premature infants, and extensions to other applications are expected (13,14). SOD is also involved in the pervasive bioregulatory functions of nitric oxide by preventing nitric oxide peroxidation by superoxide (15,16).…”

Hyperoxic Injury of Immature Guinea Pig Lung Is Mediated via Hydroxyl Radicals

“…as a significant oxidizing species in hyperoxic lung injury and provide a Imsis for understanding collagen deposition in the neonatal lung. Abbreviations CML, Ill-E-carboxyrnethy llysine FiO,, fraction of inspired air animals models with (8) or without (9) free radical scavengers have not helped ta characterize the nature of the oxygen species involved.…”