Chronic Granulomatous Pneumonia and Lymphocytic Responses Induced by Inhaled Beryllium Metal in A/J and C3H/HeJ Mice

Abstract

Inhalation of beryllium (Be) has been associated with 2 syndromes: an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD). Key to the pathogenesis of CBD is a delayed-type hypersensitivity reaction, in which Be most likely functions as a hapten and acts as a Class II-restricted antigen, stimulating local proliferation and accumulation in the lung of Be-specific CD4+ T cells. The purpose of this study was to establish a mouse model of CBD using the inhalation route of exposure. A/J (H-2^a haplotype) and C3H/HeJ (H-2^k) mice were exposed once for 90 min in nose-only exposure tubes to aerosols of Be metal. Six mo later, lung histopathologic responses were assessed. Further analyses defined the phenotypic profile of lymphocytes in pulmonary lesions and evaluated proliferation of lymphocytes in situ and in response to Be in vitro. Responses were similar in both strains of mice. The lungs of all Be-exposed mice had interstitial compact aggregates of lymphocytes, and granulomatous pneumonia characterized by vacuolated macrophages and giant cells in alveoli, neutrophils in alveoli and alveolar septa, multifocal interstitial granulomas, and interstitial infiltrates of lymphocytes, plasma cells, monocytes, and macrophages. Most Be-exposed mice had minimal to mild interstitial fibrosis. The majority of lymphocytes in interstitial infiltrates and in microgranulomas were CD4+ T cells. Interstitial compact aggregates of lymphocytes contained B cells centrally and CD4+ cells peripherally. Lymphocyte labeling indices, used to assess proliferation in situ, were significantly greater within microgranulomas compared to compact lymphocytic aggregates. Lymphocyte stimulation indices in response to BeSO₄ in vitro were not positive in blood, spleen, or tracheobronchial lymph node samples. Be-specific immune responses and nonspecific inflammatory responses to toxic and foreign-body properties of Be may have contributed to the histopathology in both strains of mice. The interstitial mononuclear cell infiltrates, presence of microgranulomas, multinucleated foreign-body and Langhans' giant cells, interstitial fibrosis, and CD4+ T-cell predominance with local proliferation are features similar to CBD in humans. The chronic lung disease induced in these mice by inhaled Be can be used to investigate the importance of variables such as dose, exposure pattern, and physicochemical form of Be in producing this disease.

Keywords

Chronic beryllium disease granulomas CD4+ T lymphocytes B lymphocytes giant cells

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