Patterns of pulmonary structural remodeling after experimental paraquat toxicity. The morphogenesis of intraalveolar fibrosis

Abstract

For a study of the evolution of interstitial and intraalveolar fibrosis, ultrastructural and immunohistochemical observations were made of the lungs of 16 cynomolgous monkeys given 1 or 2 injections of 10 mg/kg of paraquat and sacrificed 2 days to 8 weeks later. At 2-3 days, alveolar epithelial cells were denuded in many areas, and fibronectin was conspicuous in alveolar spaces. At 1 week, fibroblasts and inflammatory cells were migrating through gaps in the denuded epithelial basement membranes; Type II cells were regenerating in some areas. At 3-4 weeks, alveoli developing intraalveolar fibrosis contained many myofibroblasts, collagen fibrils, and small elastic fibers; fibrotic alveolar walls were lined by metaplastic squamous cells and bronchiolar epithelial cells. Spiraling collagen fibrils were found in interstitium but not in alveolar spaces, which suggests that they were formed from breakdown of collagen. Newly formed intraalveolar collagen was mainly Type I. At 8 weeks, intraalveolar fibrosis had led to extensive remodeling, with new glandlike alveoli lined by Type II cells; alveoli without intraalveolar fibrosis had more normal architecture. Thus, intraalveolar fibrosis in paraquattreated lung is mediated by intraalveolar migration of interstitial cells, through gaps in the epithelial basement membranes, after epithelial injury. This is followed by connective tissue synthesis on the luminal side of the epithelial basement membrane, by differentiation of interstitial cells into myofibroblasts and smooth-muscle cells, by incorporation of areas of intraalveolar fibrosis into the interstitium, and by coalescence of alveolar walls. Intraalveolar fibrosis is more important than interstitial fibrosis in the structural remodeling that occurs in paraquattreated lung, because it results in obliteration of alveoli, coalescence of alveolar walls, and loss of functional alveolar-capillary units.