title: Pulmonary structural and extracellular matrix alterations in Fischer 344 rats following subchronic phosgene exposure.
abstract: Phosgene, an acylating agent, is a very potent inducer of pulmonary edema. Subchronic effects of phosgene in laboratory animals are not well characterized. The purpose of the study was to elucidate potential long-term effects on collagen and elastin metabolism during pulmonary injury/recovery and obtain information about the concentration x time (C x T) behavior of low levels of phosgene. Male Fischer 344 rats (60 days old) were exposed either 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 (1 day/week), for 4 or 12 weeks. A group of rats was allowed clean air recovery for 4 weeks after 12 weeks of phosgene exposure. This exposure scenario was designed to provide equal C x T product for all concentrations at one particular time point except for 0.1 ppm (50% C x T). Phosgene exposure for 4 or 12 weeks increased lung to body weight ratio and lung displacement volume in a concentration-dependent manner. The increase in lung displacement volume was significant even at 0.1 ppm phosgene at 4 weeks. Light microscopic level histopathology examination of lung was conducted at 0.0, 0.1, 0.2, and 1.0 ppm phosgene following 4 and 12 and 16 weeks (recovery). Small but clearly apparent terminal bronchiolar thickening and inflammation were evident with 0.1 ppm phosgene at both 4 and 12 weeks. At 0.2 ppm phosgene, terminal bronchiolar thickening and inflammation appeared to be more prominent when compared to the 0.1 ppm group and changes in alveolar parenchyma were minimal. At 1.0 ppm, extensive inflammation and thickening of terminal bronchioles as well as alveolar walls were evident. Concentration rather than C x T seems to drive pathology response. Trichrome staining for collagen at the terminal bronchiolar sites indicated a slight increase at 4 weeks and marked increase at 12 weeks in both 0.2 and 1.0 ppm groups (0.5 ppm was not examined), 1.0 ppm being more intense. Whole-lung prolyl hydroxylase activity and hydroxyproline, taken as an index of collagen synthesis, were increased following 1.0 ppm phosgene exposure at 4 as well as 12 weeks, respectively. Desmosine levels, taken as an index of changes in elastin, were increased in the lung after 4 or 12 weeks in the 1.0 ppm phosgene group. Following 4 weeks of air recovery, lung hydroxyproline was further increased in 0.5 and 1.0 ppm phosgene groups. Lung weight also remained significantly higher than the controls; however, desmosine and lung displacement volume in phosgene-exposed animals were similar to controls. In summary, terminal bronchiolar and lung volume displacement changes occurred at very low phosgene concentrations (0.1 ppm). Phosgene concentration, rather than C x T product appeared to drive toxic responses. The changes induced by phosgene (except of collagen) following 4 weeks were not further amplified at 12 weeks despite continued exposure. Phosgene-induced alterations of matrix were only partially reversible after 4 weeks of clean air exposure.
authors.affiliation: Pulmonary Toxicology Branch, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
authors.forename: U P
authors.initials: UP
authors.lastname: Kodavanti
authors.forename: D L
authors.initials: DL
authors.lastname: Costa
authors.forename: S N
authors.initials: SN
authors.lastname: Giri
authors.forename: B
authors.initials: B
authors.lastname: Starcher
authors.forename: G E
authors.initials: GE
authors.lastname: Hatch
mesh_terms: D000818:Animals; D002619:Chemical Warfare Agents / Q000009:adverse effects*; D003094:Collagen / Q000378:metabolism; D003895:Desmosine / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010705:Phosgene / Q000009:adverse effects*; D011393:Procollagen-Proline Dioxygenase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
chemical_list: D002619:Chemical Warfare Agents; D003895:Desmosine; D010705:Phosgene; D003094:Collagen; D011393:Procollagen-Proline Dioxygenase; D006909:Hydroxyproline