The Pulmonary Response to Sublethal Thoracic Irradiation in the Rat

Abstract

An animal model of radiation-induced lung disease was established using male Wistar rats given sublethal bilateral thoracic irradiation (15 Gy). The rats were studied for up to 20 weeks and compared to sham-irradiated controls. Three distinct syndromes were identified. Two weeks after irradiation there was an increase in wet lung weight without an increase in dry lung weight. Interstitial edema was confirmed ultrastructurally, but aside from minor abnormalities of endothelial cells, both capillary and alveolar basement membranes were intact and there was no alveolar protein leak. At 4 weeks after irradiation, there was an abrupt increase in both wet and dry lung weights, as well as intra-alveolar macrophages, lymphocytes, polymorphs, and protein. These changes persisted for periods of up to 8 weeks. Electron microscopy at 4 weeks revealed prominent interstitial edema and severe endothelial cell damage. There was patchy thickening of the cytoplasm of type I cells as well as some cells which appeared to be transforming from type II to type I cells, suggesting previous epithelial denudation. Mast cell density increased in perivascular and peribronchial areas from 4 weeks, and this and parenchymal mast cell density peaked at 7 weeks. The total collagen content of the lungs (determined biochemically) rose by up to 50% above control values from 5 weeks after irradiation, the bulk of the increase having occurred by 12 weeks. Further increases up to 20 weeks were similar to that seen in growing control animals. Collagen deposition (as defined by electron microscopy and Picrosirius polarization) was prominent in peribronchial and perivascular areas in all animals, but in alveolar walls it was increased severalfold above controls by 20 weeks after irradiation. In summary, this model provides sequential changes of interstitial edema, alveolitis, and interstitial fibrosis which can be studied independently. The temporal relationship between the appearance of mast cells and increased collagen deposition supports the hypothesis that mast cells are intimately related to the development of fibrosis.