Sclerosing alveolitis induced by cyclophosphamide. Ultrastructural observations on alveolar injury and repair.

Adult rats received, intraperitoneally, 20 mg/100 g body weight of cyclophosphamide and were killed 1, 2, 3, 4, 7, 14, 21, and 28 days thereafter. Lung samples were studied by light and electron microscopy. Light microscopy revealed septal and intraalveolar hemorrhages at 2 days and hyaline membranes at 4 days. At 1 to 2 weeks the alveoli were reepithelialized; beyond these intervals there was septal thickening with increased septal cells and interstitial substance. Electron microscopy showed capillary endothelial blebs, membranous pneumocyte injury and sloughing, and severe septal edema at 1 to 2 days. At 4 days some granular pneumocytes appeared altered. At 1 week the alveoli were reepithelialized by prominent granular pneumocytes. Beyond these intervals there was septal thickening with abundant septal cells, debris, collagen, elastin and microfibrils. Some septal elements showed features consistent with "contractile interstitial cells." There was also alveolar collapse indicated by "trapped" granular pneumocytes surrounded by septal cells and fibers. Occasional granular pneumocytes showed large intracytoplasmic cavities. Cyclophosphamide can induce severe injury involving all alveolar components. The partly denuded alveoli are reepithelialized by proliferating granular pneumocytes, thus confirming their importance in alveolar repair. The subsequent development of sclerosing alveolitis suggests that cyclophosphamide may offer a useful experimental model for the study of alveolar injury and repair. The role of the septal "contractile interstitial cells" in the development of septal fibrosis and the possibility that these lesions are reversible remain to be clarified.