CHRONIC GRANULOMATOUS PNEUMONIA AND LYMPHOCYTIC RESPONSES INDUCED BY INHALED BERYLLIUM METAL IN A J AND C3H/HEJ MICE/

Inhalation of beryllium (Be) has been associated with 2 syndromes: an acute chemical pneumonitis and a granulomatous lung disease known as c hronic beryllium disease (CBD). Key to the pathogenesis of CBD is a de layed-type hypersensitivity reaction, in which Be most likely function s as a hapten and acts as a Class II-restricted antigen, stimulating l ocal 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 C3 H/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 res ponses were assessed. Further analyses defined the phenotypic profile of lymphocytes in pulmonary lesions and evaluated proliferation of lym phocytes in situ and in response to Be in vitro. Responses were simila r in both strains of mice. The lungs of all Be-exposed mice had inters titial compact aggregates of lymphocytes, and granulomatous pneumonia characterized by vacuolated macrophages and giant cells in alveoli, ne utrophils in alveoli and alveolar septa, multifocal interstitial granu lomas, and interstitial infiltrates of lymphocytes, plasma cells, mono cytes, and macrophages. Most Be-exposed mice had minimal to mild inter stitial fibrosis. The majority of lymphocytes in interstitial infiltra tes and in microgranulomas were CD4+ T cells. Interstitial compact agg regates of lymphocytes contained B cells centrally and CD4+ cells peri pherally. Lymphocyte labeling indices, used to assess proliferation in situ, were significantly greater within microgranulomas compared to c ompact lymphocytic aggregates. Lymphocyte stimulation indices in respo nse to BeSO4 in vitro were not positive in blood, spleen, or tracheobr onchial lymph node samples. Be-specific immune responses and nonspecif ic inflammatory responses to toxic and foreign-body properties of Be m ay have contributed to the histopathology in both strains of mice. The interstitial mononuclear cell infiltrates, presence of microgranuloma s, multinucleated foreign-body and Langhans' giant cells, interstitial fibrosis, and CD4+ T-cell predominance with local proliferation are f eatures 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.