The pathogenesis of plutonium-induced pulmonary neoplasms in the rat

Ronald Austin Herbert, Purdue University

Abstract

Rats develop neoplasms in the peripheral portions of the lungs following inhalation of plutonium. Focal proliferative lesions precede the onset of the neoplasms. Their role in the development of the neoplasms is not clear, nor have the cells of origin for the proliferative lesions and neoplasms been identified. To characterize the morphologic development of the neoplasms, F344/N rats were exposed to aerosols of $\sp{239}$PuO$\sb2$ to achieve initial lung burdens of 3.7 kBq. Rats were euthanized on days 7, 30, and 90, and subsequently at 3-month intervals to 450 days after exposure. The lungs were evaluated by light microscopy, morphometry, immunohistochemistry, transmission electron microscopy, and cytokinetics. Subpleural and peribronchiolar proliferative lesions were observed by 180 days after exposure and classified histologically as alveolar epithelial hyperplasia, fibrosis, mixed, and bronchiolar-alveolar metaplasia. Pulmonary adenomas, adenocarcinomas, squamous cell carcinomas and adenosquamous carcinomas developed at later times. The alveolar epithelial hyperplasias progressed through stages of morphologic alterations developing characteristics consistent with adenomatous neoplasms. Foci of metaplastic squamous epithelium which developed within focal areas of fibrosis, expanded and developed morphologic characteristics consistent with squamous cell carcinomas. The volume density and epithelial surface density of the hyperplastic epithelial lesions increased progressively with time, in contrast to the other phenotypes of proliferative lesions. A significant percentage of the hyperplastic epithelial lesions were immunoreactive for type II pneumocyte specific antibody, but not for Clara cell antibody. The cells of the proliferative lesions and neoplasms had ultrastructural features consistent with type II pneumocytes. The proliferative rates of the normal alveolar and bronchiolar epithelia were significantly increased by 30 days after exposure. The alveolar epithelium had greater proliferative rates than the bronchiolar epithelium. The hyperplastic epithelial and metaplastic squamous lesions had greater proliferative rates than the normal alveolar and bronchiolar epithelia. The results suggest that: (1) plutonium-induced lung neoplasia develops through a progression of focal cellular alterations; (2) the hyperplastic epithelial and metaplastic squamous lesions are preneoplastic lesions for the adenocarcinomas and squamous cell carcinomar respectively; (3) the alveolar epithelial hyperplasias are the lesions most likely to progress to malignant neoplasms; and (4) plutonium-induced pulmonary neoplasms are derived primarily from type II pneumocytes.

Degree

Ph.D.

Advisors

Rebar, Purdue University.

Subject Area

Pathology

COinS