The role of PPARγ in carbon nanotube-elicited granulomatous lung inflammation

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)
Barbara P Barna (Creator)
Larry Dobbs (Creator)
Isham Huizar (Creator)
Anagha Malur (Creator)
Matthew McPeek (Creator)
Janki Patel (Creator)
Mary Jane Thomassen (Creator)
Christopher Wingard (Creator)
East Carolina University (ECU )
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Abstract: BACKGROUND: Although granulomatous inflammation is a central feature of many disease processes, cellular mechanisms of granuloma formation and persistence are poorly understood. Carbon nanoparticles, which can be products of manufacture or the environment, have been associated with granulomatous disease. This paper utilizes a previously described carbon nanoparticle granuloma model to address the issue of whether peroxisome proliferator-activated receptor gamma (PPAR?), a nuclear transcription factor and negative regulator of inflammatory cytokines might play a role in granulomatous lung disease. PPAR? is constitutively expressed in alveolar macrophages from healthy individuals but is depressed in alveolar macrophages of patients with sarcoidosis, a prototypical granulomatous disease. Our previous study of macrophage-specific PPAR? KO mice had revealed an intrinsically inflammatory pulmonary environment with an elevated pro-inflammatory cytokines profile as compared to wild-type mice. Based on such observations we hypothesized that PPAR? expression would be repressed in alveolar macrophages from animals bearing granulomas induced by MWCNT instillation. METHODS: Wild-type C57Bl/6 and macrophage-specific PPAR? KO mice received oropharyngeal instillations of multiwall carbon nanotubes (MWCNT) (100 µg). Bronchoalveolar lavage (BAL) cells, BAL fluids, and lung tissues were obtained 60 days post-instillation for analysis of granuloma histology and pro-inflammatory cytokines (osteopontin, CCL2, and interferon gamma [IFN-?] mRNA and protein expression. RESULTS: In wild-type mice, alveolar macrophage PPAR? expression and activity were significantly reduced in granuloma-bearing animals 60 days after MWCNT instillation. In macrophage-specific PPAR? KO mice, granuloma formation was more extensive than in wild-type at 60 days after MWCNT instillation. PPAR? KO mice also demonstrated elevated pro-inflammatory cytokine expression in lung tissue, laser-microdissected lung granulomas, and BAL cells/fluids, at 60 days post MWCNT exposure. CONCLUSIONS: Overall, data indicate that PPAR? deficiency promotes inflammation and granuloma formation, suggesting that PPAR? functions as a negative regulator of chronic granulomatous inflammation.

Additional Information

Respiratory Research; 14:1 p. 7-7
Language: English
Date: 2013

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