Sarcoidosis is a relatively common inflammatory disease of unknown etiology and significant morbidity. Sarcoid inflammation is characterized by complex interrelationships among macrophages, T-helper lymphocytes, and cytokines (tumor necrosis factor [TNF], interferon gamma [IFNgamma] and others) which lead to formation of granulomas and variable degrees of fibrosis in the lung and other organs. Epidemiologic data (i.e. familial clustering, racial variation) strongly support a genetic role for host susceptibility (i.e. polymorphisms of regulatory genes). A potential regulator of inflammation is the nuclear transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma). This recently described, ligand-dependent transcription factor is expressed in cells of the monocyte-macrophage lineage which play a critical role in sarcoid inflammation. In experimental models of autoimmune and inflammatory diseases, PPARgamma activation antagonizes expression and actions of inflammatory mediators, many of which are known to be overexpressed in sarcoidosis. Preliminary studies indicate that PPARgamma activity and gene expression are deficient in the alveolar compartment of sarcoidosis while in contrast, activity of the inflammatory transcription factor, NF-KappaB is upregulated. Insufficient PPARgamma activity may perpetuate the chronic inflammatory injury of sarcoidosis by failing to repress NF-KappaB. Based on these observations, it is hypothesized that PPARgamma regulation is dysfunctional in sarcoidosis.
The specific aims of this study are to: (1) Evaluate intrinsic PPARgamma mRNA (by real time RT-PCR) and protein expression (by immunoblotting and immunocytochemistry) in pulmonary granuloma tissue and bronchoalveolar lavage (BAL) cells; (2) Investigate in vitro PPARgamma responses of BAL and peripheral blood cells to challenge with positive (interleukin 4 [IL-4], granulocyte-macrophage colony stimulating factor [GM-CSF]), phorbol myristate acetate [PMA]); and negative (PPARgamma ligands, IFNgamma) regulators of PPARgamma; and (3) Determine by sequence analysis whether PPARgamma polymorphisms are associated with sarcoidosis. The study will use a combination of banked open-lung biopsy specimens as well as bronchoscopically obtained fresh specimens from sarcoidosis patients vs healthy controls to characterize the status of PPARgamma in sarcoidosis. These studies are the first to focus upon the role of PPARgamma in sarcoidosis and preliminary data strongly suggest the presence of PPARgamma dysfunction. Investigation of PPARgamma involvement in sarcoidosis will be critical to better understanding the disease process and to generating novel approaches to therapy.
