DIFFERENTIAL-EFFECTS OF HYPEROXIA ON THE INDUCIBLE AND CONSTITUTIVE ISOFORMS OF NITRIC-OXIDE SYNTHASE IN THE LUNG

Hyperoxia is commonly used in the treatment of newborn respiratory dis tress. Although essential and life saving, oxygen therapy can result i n the development of lung injury. Oxygen toxicity is associated with t he production of reactive oxidant species. Nitric oxide (NO) is an oxi dant formed by the catalysis of L-arginine when acted upon by the enzy me nitric oxide synthase (NOS). We studied the differential effects of prolonged normobaric hyperoxia (FIO2 = .95, for 3, 4, and 5 days) on the two major NOS enzymes, constitutive endothelial cell NOS (ecNOS) a nd inducible NOS (iNOS). Hyperoxia led to a significant lung injury, a s measured by pulmonary compliance studies. Hyperoxia did not increase serum NO production, measured as the concentration of nitrite and nit rate. However, hyperoxia did result in a small but significant increas e in NO production in the bronchoalveolar lavage fluid, as measured by the products of nitrite and nitrate concentration. This increase in N O was not associated with an induction of whole lung iNOS, as measured by the conversion of L-[H-3]arginine to L-[H-3]citrulline or by North ern blot analysis. Hyperoxia significantly decreased ecNOS activity as measured by the conversion of L-[H-3]arginine to L-[H-3]citrulline. I n addition, administration of the NOS inhibitor N-G-nitro-L-arginine m ethyl ester worsened the injury, as measured by lung compliance and su rvival. Further studies need to be performed to determine whether this decrease in ecNOS activity during hyperoxia plays a role in the patho genesis of hyperoxia-related lung injury.