Peroxisome proliferator activated receptor gamma (PPAR gamma), a ligand activated nuclear transcription factor, is constitutively expressed in alveolar macrophages of healthy individuals. PPAR gamma 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 PPAR gamma. Further studies demonstrate alveolar macrophage PPAR gamma deficiency exacerbates MWCNT-induced pulmonary granulomas. Based on these observations we hypothesized that activation of PPAR gamma via administration of the PPAR gamma-specific ligand rosiglitazone would limit MWCNT-induced granuloma formation and promote PPAR gamma-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-kappa B activity and downregulates the expression of the pro-inflammatory mediators, CCL2 and osteopontin. PPAR gamma activation via rosiglitazone also prevents the MWCNT-induced deficiency of PPAR gamma-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 PPAR gamma pathways are critical in regulating MWCNT-induced pulmonary granulomatous inflammation. (C) 2018 Elsevier Inc. All rights reserved.