Chronic beryllium disease (CBD) is a granulomatous lung disease that occurs after exposure to beryllium in the workplace. Beryllium stimulates an exuberant cellular immune response resulting in granuloma formation which eventually may progress to pulmonary fibrosis. The mechanism of fibrosis in the setting of T-cell mediated hypersensitivity is not well understood. Preliminary studies in CBD have found mast cells as the source of basic fibroblast growth factor (bFGF) in the formation of the fibrosis that surrounds granulomas. It is a potent activator of fibroblast and smooth muscle cell proliferation, contributing to fibrogenesis. Basic FGF is one of the key growth factors stimulated by angiotensin II. Angiotensin-converting enzyme (ACE) and its enzymatic product angiotensin II (ATII) promote fibrosis in cardiovascular disease, by an unknown mechanism. ACE activity is high in CBD. Thus, the investigators hypothesize that the local angiotensin system responds to beryllium-induced lung injury by promoting fibrosis through the production of bFGF. Furthermore, they hypothesize that this fibrotic response is counterbalanced by a cell mediated immune response to beryllium in which there is marked interferon gamma (IFN-y) production. They will conduct experiments to determine whether beryllium can increase ACE activity and ATII production in CBD bronchoalveolar lavage (BAL) cells. By examining biopsy tissues after beryllium skin patch testing, they will assess the role of beryllium in stimulating ACE, ATII, and mRNA expression for ACE and ATII receptors during granuloma formation. The investigators will link the ATII production from beryllium stimulated macrophages to fibrosis by measuring ATII stimulation of the fibrotic growth factor, bFGF, from mast cells using a human mast cell line. They will define the mechanism of bFGF upregulation by ATII. Finally, to demonstrate that the beryllium-mediated immune response inhibits this fibrotic response, they will assess the role of IFN-y in downregulating the ATII stimulated bFGF production. These studies will help establish a role for the angiotensin system in granulomatous lung disease and the path to fibrogenesis.

K08HL003887

1998-09-04

2003-08-31