Pulmonary Structural and Extracellular Matrix Alterations in Fischer 344 Rats Following Subchronic Phosgene Exposure

Phosgene, an acylating agent, is a very potent inducer of pulmonaryedema. Subchronic effects of phosgene in laboratory animalsare not well characterized. The purpose of the study was toelucidate potential long-term effects on collagen and elastinmetabolism during pulmonary injury/recovery and obtain informationabout the concentration x time (C x T) behavior of low levelsof phosgene. Male Fischer 344 rats (60 days old) were exposedeither to clean air or phosgene, 6 hr/day: 0.1 ppm (5 days/week),0.2 ppm (5 days/week), 0.5 ppm (2 days/week), and 1.0 ppm (1day/week), for 4 or 12 weeks. A group of rats was allowed cleanair recovery for 4 weeks after 12 weeks of phosgene exposure.This exposure scenario was designed to provide equal C x T productfor all concentrations at one particular time point except for0.1 ppm (50% C x T). Phosgene exposure for 4 or 12 weeks increasedlung to body weight ratio and lung displacement volume in aconcentration-dependent manner. The increase in lung displacementvolume was significant even at 0.1 ppm phosgene at 4 weeks.Light microscopic level histopathology examination of lung wasconducted at 0.0, 0.1, 0.2, and 1.0 ppm phosgene following 4and 12 and 16 weeks (recovery). Small but clearly apparent terminalbronchiolar thickening and inflammation were evident with 0.1ppm phosgene at both 4 and 12 weeks. At 0.2 ppm phosgene, terminalbronchiolar thickening and inflammation appeared to be moreprominent when compared to the 0.1 ppm group and changes inalveolar parenchyma were minimal. At 1.0 ppm, extensive inflammationand thickening of terminal bronchioles as well as alveolar wallswere evident. Concentration rather than C x T seems to drivepathology response. Trichrome staining for collagen at the terminalbronchiolar sites indicated a slight increase at 4 weeks andmarked increase at 12 weeks in both 0.2 and 1.0 ppm groups (0.5ppm was not examined), 1.0 ppm being more intense. Wholelungprolyl hydroxylase activity and hydroxyproline, taken as anindex of collagen synthesis, were increased following 1.0 ppmphosgene exposure at 4 as well as 12 weeks, respectively. Desmosinelevels, taken as an index of changes in elastin, were increasedin the lung after 4 or 12 weeks in the 1.0 ppm phosgene group.Following 4 weeks of air recovery, lung hydroxyproline was furtherincreased in 0.5 and 1.0 ppm phosgene groups. Lung weight alsoremained significantly higher than the controls; however, desmosineand lung displacement volume in phosgene-exposed animals weresimilar to controls. In summary, terminal bronchiolar and lungvolume displacement changes occurred at very low phosgene concentrations(0.1 ppm). Phosgene concentration, rather than C x T productappeared to drive toxic responses. The changes induced by phosgene(except of collagen) following 4 weeks were not further amplifiedat 12 weeks despite continued exposure. Phosgene-induced alterationsof matrix were only partially reversible after 4 weeks of cleanair exposure.