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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: PPAR-gamma pathways attenuate pulmonary granuloma formation in a carbon nanotube induced murine model of sarcoidosis.

Authors: McPeek, Matthew; Malur, Anagha; Tokarz, Debra A; Murray, Gina; Barna, Barbara P; Thomassen, Mary Jane

Published In Biochem Biophys Res Commun, (2018 09 05)

Abstract: Peroxisome proliferator activated receptor gamma (PPARγ), a ligand activated nuclear transcription factor, is constitutively expressed in alveolar macrophages of healthy individuals. PPARγ deficiencies have been noted in several lung diseases including the alveolar macrophages of pulmonary sarcoidosis patients. We have previously described a murine model of multiwall carbon nanotubes (MWCNT) induced pulmonary granulomatous inflammation which bears striking similarities to pulmonary sarcoidosis, including the deficiency of alveolar macrophage PPARγ. Further studies demonstrate alveolar macrophage PPARγ deficiency exacerbates MWCNT-induced pulmonary granulomas. Based on these observations we hypothesized that activation of PPARγ via administration of the PPARγ-specific ligand rosiglitazone would limit MWCNT-induced granuloma formation and promote PPARγ-dependent pathways. Results presented here show that rosiglitazone significantly limits the frequency and severity of MWCNT-induced pulmonary granulomas. Furthermore, rosiglitazone attenuates alveolar macrophage NF-κB activity and downregulates the expression of the pro-inflammatory mediators, CCL2 and osteopontin. PPARγ activation via rosiglitazone also prevents the MWCNT-induced deficiency of PPARγ-regulated ATP-binding cassette lipid transporter-G1 (ABCG1) expression. ABCG1 is crucial to pulmonary lipid homeostasis. ABCG1 deficiency results in lipid accumulation which promotes pro-inflammatory macrophage activation. Our results indicate that restoration of homeostatic ABCG1 levels by rosiglitazone correlates with both reduced pulmonary lipid accumulation, and decreased alveolar macrophage activation. These data confirm and further support our previous observations that PPARγ pathways are critical in regulating MWCNT-induced pulmonary granulomatous inflammation.

PubMed ID: 29908181 Exiting the NIEHS site

MeSH Terms: Animals; Disease Models, Animal; Dyslipidemias/etiology; Dyslipidemias/genetics; Dyslipidemias/metabolism; Dyslipidemias/pathology; Gene Expression Regulation; Granuloma/etiology; Granuloma/genetics; Granuloma/metabolism; Granuloma/pathology*; Lung Diseases/etiology; Lung Diseases/genetics; Lung Diseases/metabolism; Lung Diseases/pathology*; Lung/metabolism; Lung/pathology*; Macrophages, Alveolar/metabolism; Macrophages, Alveolar/pathology; Mice, Inbred C57BL; Nanotubes, Carbon/adverse effects; PPAR gamma/agonists; PPAR gamma/metabolism*; Sarcoidosis/etiology; Sarcoidosis/genetics; Sarcoidosis/metabolism; Sarcoidosis/pathology*; Signal Transduction*

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