Development of fibrosis after lung irradiation in relation to inflammation and lung function in a mouse strain prone to fibrosis.

The development of lung fibrosis after single-dose thoracic irradiation was studied histologically in C57L/J male mice. Lung function was monitored using uptake of carbon monoxide. During the latent period (prior to 15 weeks postirradiation) mice were chosen at random, while during the early phase (15-22 weeks) mice were sacrificed when they developed a functional deficit of at least 50%. Excess mice with a deficit of 50% in the early phase were followed into the late phase and sacrificed at 31 or 40 weeks. Two scoring methods were used to quantify lung damage. Fibrotic lesions and foci of inflammation were counted for the latent period, and the proportion of nonfunctional acini was determined for the early and late phases. After a dose 1 Gy less than the LD50/180, small regions of mild inflammatory infiltration appeared at 6 weeks, and small, focal fibrotic lesions containing numerous macrophages appeared at 8 weeks postirradiation. The number of fibrotic lesions increased steadily during the latent period in a manner that is consistent with conversion of inflammatory lesions to foci of fibrosis. Mice sacrificed upon developing a 50% functional deficit during the early phase had approximately equal proportions of lung affected by fibrosis and inflammation. Those mice which developed a similar respiratory deficit in the early phase and were followed into the late phase usually showed little change in lung function. However, when sacrificed at 31 weeks they had twice as much fibrosis and very little inflammation, suggesting that the inflammatory lesions had become fibrosed. The average number of macrophages per unit area of fibrosis declined during the latent period and changed little during the early and late phases. Lymphocytes and mast cells were also quantified in fibrosed regions.