Delivering antioxidants by zip code.

PRIMARY LUNG DISEASE, the associated inflammatory response, and treatment with supplemental oxygen all result in the generation of increased amounts of reactive oxygen species (ROS), which can cause significant damage to the lung. The susceptibility of the lung to oxidative injury depends largely on the ability to upregulate protective ROS scavenging systems. Unfortunately, both intracellular and extracellular antioxidants are expressed at relatively low levels in the human lung and are often not acutely induced when exposed to oxidative stress such as hyperoxia. Premature infants are especially sensitive to oxidant injury due to a relative lack of antioxidant defenses and an excess of ROS (even room air is supraphysiological). For example, bronchopulmonary dysplasia (BPD) affects 20–60% of premature infants and is strongly associated with significant morbidity and mortality. Increasing evidence suggests that oxidative injury is intimately involved in the pathogenesis of this acute and chronic lung injury (10). Chang and colleagues (1) have shown that hyperoxia and the generation of ROS are responsible for many of the pathological features observed in a premature baboon model of BPD. In addition, animal models and clinical studies of adults with acute respiratory distress syndrome (ARDS) reveal biochemical evidence of significant ROS-induced lung injury (7). Thus developing therapeutic strategies to supplement endogenous antioxidant enzyme (AOE) activities to scavenge excess ROS represents a rational approach to minimize lung injury due to oxidant stress. AOE such as superoxide dismutase (SOD; converting toxic superoxide anion into potentially less toxic H2O2) and catalase (converting H2O2 into water) are appropriate agents for augmentation of antioxidant defenses in the lung. Over the past two decades, many investigators have delivered AOE to the lung by liposomalor viral-mediated genetic constructs or through protein supplementation in an attempt to prevent oxidant injury (5). Ilizarov and colleagues (9) have shown that pulmonary epithelial cells overexpressing AOE have significantly improved survival when exposed to oxidative stress such as hyperoxia and paraquat. Animals genetically engineered to overexpress AOE and adenovirus-mediated transfer of AOE cDNA also protect the lung against hyperoxic injury (3, 4). However, although gene transfer may provide more stable and prolonged increases in AOE activities, this method would not be efficacious in acute situations, when protective intervention is immediately required. In addition, gene delivery methods have been associated with the development of significant toxicity. Alternatively, the delivery of AOE proteins has the advantage of providing an immediate therapeutic benefit. Several groups have shown in both animal models and human trials that lung injury may be ameliorated by administration of one of these antioxidants, specifically SOD (4). Our group has studied prophylactic, intratracheal administration of recombinant human CuZnSOD (rhSOD) in premature infants to prevent oxidant-induced lung damage and BPD. Inflammatory markers were significantly reduced in tracheal aspirate samples of infants receiving rhSOD, and clinical outcome was significantly improved at a median of 1-yr corrected age (4, 6). Critically ill infants treated with rhSOD at birth had up to a 60% decrease in episodes of severe pulmonary illness (asthma, respiratory infections), emergency room visits, and hospital readmissions by 1-yr corrected age, suggesting that AOE supplementation is effective in preventing oxidant-induced pulmonary injury. It was unclear whether the antioxidant was uniformly distributed to the lung and which cell type was primarily affected. Pulmonary endothelial cells perform vital functions and are also vulnerable to oxidant injury. Intratracheal administration of AOE may not provide adequate protection to this site. Although endothelial cells are normally exposed to circulating AOE, SOD and catalase are rapidly cleared from the bloodstream when delivered intravenously, which could compromise attempts to fully protect the vascular endothelium against oxidative stress. Coupling AOE to polyethylene glycol or using liposome encapsulation can prolong the half-life of the active enzymes in vivo, increase bioavailability, and enhance the protective effect (8). However, concerns with toxicity have precluded the routine use of these administration strategies. Attempts to maximize efficacy and minimize toxicity have led to the concept of vascular immunotargeting over the past decade. Investigators have conjugated AOE with antibodies directed against endothelial surface antigens such as angiotensin-converting enzyme and adhesion molecules [ICAM-1 or platelet/endothelial cell adhesion molecule (PECAM)-1]. After intravascular administration to animals, the antibody/AOE complex binds to the endothelium, enters endothelial cells, and augments their antioxidant defenses (8). Vascular immunotargeting represents a promising approach for site-specific delivery of AOE. Address for reprint requests and other correspondence: Y. Li, CardioPulmonary Research Institute, Winthrop Univ. Hospital, State Univ. of New York at Stony Brook School of Medicine, Mineola, NY 11501 (E-mail: [email protected]). Am J Physiol Lung Cell Mol Physiol 285: L281–L282, 2003; 10.1152/ajplung.00092.2003.