The Development of the Newborn Rat Lung in Hyperoxia: A Dose-Response Study of Lung Growth, Maturation, and Changes in Antioxidant Enzyme Activities

Abstract

Summary: To examine the dose-response relationships of oxygen-induced lung changes, newborn rats were exposed to various patterns of concentrations of hyperoxia (0.4, 0.8, and >0.95 FiO₂) for up to 12 days. Prominent findings included microscopic evidence of lung injury and retarded alveolar development (secondary septal development delayed by as much as 88%), lower whole lung DNA (50% of control), lung-to-body-weight ratios (by as much as 18%), and significantly less compliance in the lungs after exposures of 6− or 12-day durations to all concentrations of hyperoxia. Significant increases in the activities of the lung protective enzymes superoxide dismutase (129 to 160% of control), catalase (112 to 274% of control), and glutathione peroxidase (118 to 256% of control) were noted when activity was expressed on a DNA basis after 12-day exposures to the various patterns of hyperoxia. Lung changes noted after a 7-day recovery period in air included interstitial thickening (117% of control), persistance of the microscopic injury, and retarded alveolar development seen immediately after initial 6-day hyperoxic exposures. At the conclusion of a second wk of recovery in air, the lungs of hyperoxic exposed animals resembled controls in most respects, but a significantly altered compliance was exhibited by the lungs of animals initially exposed to 6 days of 0.4 or >0.95 FiO₂. The dose dependency of oxygen-induced lung injury is complex. Straightforward, stepwise dose-response adequately describes the evolution of microscopic injury and slowing of alveolar development in hyperoxia, but the dose dependency is not as clearly identified in the oxygen-induced retardation of lung growth including DNA content and in changes in antioxidant enzyme activities. Changes in lung compliance clearly do not follow expected dose-response relationships. Speculation: The toxic influence of oxygen on the lung and on lung develop ment varies depending upon the concentration and duration of oxygen exposure. In addition, individual vulnerability to the toxic effects of oxygen on the lung may vary depending upon the stage of maturation of the lung at the time of oxygen exposure. The variety of clinical presentations and morphologic features of chronic lung disease in premature infants (e.g., Wilson Mikity, chronic pulmonary insufficiency of the premature, and bronchopulmonary dysplasia) may represent a spectrum of oxygen effects on the lung rather than diseases with distinctly different pathogenesis.