Patterns of Progression and Markers of Lung Injury in Rodents and Subhuman Primates Exposed to Hyperoxia

Abstract

Exposure to high concentrations of oxygen causes injury throughout the respiratory tract. Good markers for the earliest stages of injury are not available although the course of tissue and cell responses to injury has been well characterized in a variety of animal models including rats and subhuman primates. Exposure to subacute levels of hyperoxia (40%-60% O₂) causes lung injury that is difficult to detect even after exposures of up to 7 days in duration unless animals are subsequently stressed with a second form of lung injury. Rats preexposed to 40% and 60% O₂ die sooner when exposed to 100% O₂ than do control animals, suggesting an increased susceptibility to a second injury. Rats exposed to 60% O₂ are more susceptible to development of pulmonary edema during high tidal volume mechanical ventilation, suggesting an increased susceptibility to mechanical stress. Exposures to 60% O₂ may set up chronic progressive inflammatory reactions in the lung interstitium manifested by an increase in interstitial cells and matrix occurring weeks after the hyperoxic exposure. Both rats and baboons show similar responses to acute lethal exposures to hyperoxia, although the time course is more prolonged in the baboon. Both species demonstrate increased numbers of neutrophils in the lung microvasculature as one of the earliest structural evidences of lung injury. Both species demonstrate an increase in interstitial cells, quantitative evidence of injury to alveolar epithelial cells, and a significant fall in the number of capillary endothelial cells during the late phases of hyperoxic lung injury. These changes are associated with significant decreases in the total lung capacity and residual volume, increases in pulmonary artery pressure and pulmonary vascular resistance, and tachycardia. Baboons develop a 30% reduction in cardiac output after 80 h of 100% oxygen exposure because of a diminished ejection fraction. The primary difference in the progression of lung injury between species is in the time course rather than in the basic pattern of morphologic and physiologic responses.