A B S T R A C T Exposure of rats to high oxygen tensions causes increased collagen content of lungs and alveolar enlargemnent in 3-6 wk. We tested whether cis-hydroxyproline, a proline analogue that inhibits collagen synthesis, could prevent the collagen accumulation and alveolar enlargement. Rats were exposed to hyperoxia for 60 h and then to room air and hyperoxia for alternate 24-h periods for 11.5 d. Treated oxygenexposed rats received 200 mg/kg cis-hydroxyproline twice daily over the 14-d exposure period. Control rats breathed room air. Examination of lungs on day 14 showed collagen content of oxygen-exposed lungs to be 48% greater than control (P < 0.05). The collagen content of the treated oxygen-exposed lungs was -12% of control (NS). Total lung volume was 16% greater than control in oxygen-exposed rats (P < 0.05) and 8% greater than control in treated oxygen-exposed rats (NS). Morphometric studies showed alveolar size was greater than control in oxygen-exposed rats (188± 11 [SE] vs. 143+6 gutl [P < 0.05]). Oxygenexposed, treated rats had a mean alveolar volume of 150±7 ,u,l. Lung pressure-volume curves were significantly shifted to the left of control in the oxygenexposed rats, whereas the curves of the oxygenexposed, treated group were identical to control. These data suggest that cis-hydroxyproline prevented the accumulation of collagen in the lungs in pulmonary oxygen toxicity. In addition, there was apparent protection from airspace dilatation and decreased lung elasticity, suggesting that alveolar enlargement after oxygen toxicity is linked to the deposition in (2,3). If the initial injury is not severe and the exposure is discontinued, the pathologic changes may resolve and leave no trace of permanent damage (1). If the exposure is continued beyond this point of reversibility, the pathologic changes may evolve into interstitial fibrosis (1). Pulmonary interstitial fibrosis in rats after exposure to high concentrations of oxygen is manifest on electron microscopic examination of lung tissue (3, 4) and as increased collagen content of lungs (5-8).The structural and mechanical properties ofthe lungs after recovery from oxygen toxicity are altered in a way not entirely expected from the histologic and biochemical findings of fibrosis. Several investigators have now described airspace enlargement (9)(10)(11)(12)(13)(14) and a decreased tissue elastic recoil pressure (15) in rat lung several weeks after recovery from oxygen toxicity. These results suggest decreased structural integrity of the connective tissue framework at a time when lung collagen content is increased above normal.An explanation of these paradoxical findings is suggested from experimental models of pulmonary emphysema. Weeks to months after the endotracheal instillation of proteolytic enzymes in animals, alveolar enlargement and decreased lung elasticity are found at a time when the content of collagen and elastin in the lung is normal (16,17). It has been postulated that this is due to destruction of connective tissue followed by ...