Background: Although granulomatous inflammation is a central feature of many disease processes, cellular\r\nmechanisms of granuloma formation and persistence are poorly understood. Carbon nanoparticles, which can be\r\nproducts of manufacture or the environment, have been associated with granulomatous disease. This paper utilizes\r\na previously described carbon nanoparticle granuloma model to address the issue of whether peroxisome\r\nproliferator-activated receptor gamma (PPAR?), a nuclear transcription factor and negative regulator of inflammatory\r\ncytokines might play a role in granulomatous lung disease. PPAR? is constitutively expressed in alveolar\r\nmacrophages from healthy individuals but is depressed in alveolar macrophages of patients with sarcoidosis, a\r\nprototypical granulomatous disease. Our previous study of macrophage-specific PPAR? KO mice had revealed an\r\nintrinsically inflammatory pulmonary environment with an elevated pro-inflammatory cytokines profile as compared\r\nto wild-type mice. Based on such observations we hypothesized that PPAR? expression would be repressed in\r\nalveolar macrophages from animals bearing granulomas induced by MWCNT instillation.\r\nMethods: Wild-type C57Bl/6 and macrophage-specific PPAR? KO mice received oropharyngeal instillations of\r\nmultiwall carbon nanotubes (MWCNT) (100 �µg). Bronchoalveolar lavage (BAL) cells, BAL fluids, and lung tissues were\r\nobtained 60 days post-instillation for analysis of granuloma histology and pro-inflammatory cytokines (osteopontin,\r\nCCL2, and interferon gamma [IFN-?] mRNA and protein expression.\r\nResults: In wild-type mice, alveolar macrophage PPAR? expression and activity were significantly reduced in\r\ngranuloma-bearing animals 60 days after MWCNT instillation. In macrophage-specific PPAR? KO mice, granuloma\r\nformation was more extensive than in wild-type at 60 days after MWCNT instillation. PPAR? KO mice also\r\ndemonstrated elevated pro-inflammatory cytokine expression in lung tissue, laser-microdissected lung granulomas,\r\nand BAL cells/fluids, at 60 days post MWCNT exposure.\r\nConclusions: Overall, data indicate that PPAR? deficiency promotes inflammation and granuloma formation,\r\nsuggesting that PPAR? functions as a negative regulator of chronic granulomatous inflammation.
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