| First Author | Malur A | Year | 2019 |
| Journal | Am J Respir Cell Mol Biol | Volume | 61 |
| Issue | 2 | Pages | 198-208 |
| PubMed ID | 30741559 | Mgi Jnum | J:293875 |
| Mgi Id | MGI:6452342 | Doi | 10.1165/rcmb.2018-0346OC |
| Citation | Malur A, et al. (2019) Peroxisome Proliferator-activated Receptor-gamma Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model. Am J Respir Cell Mol Biol 61(2):198-208 |
| abstractText | We established a murine model of multiwall carbon nanotube (MWCNT)-elicited chronic granulomatous disease that bears similarities to human sarcoidosis pathology, including alveolar macrophage deficiency of peroxisome proliferator-activated receptor gamma (PPARgamma). Because lymphocyte reactivity to mycobacterial antigens has been reported in sarcoidosis, we hypothesized that addition of mycobacterial ESAT-6 (early secreted antigenic target protein 6) to MWCNT might exacerbate pulmonary granulomatous pathology. MWCNTs with or without ESAT-6 peptide 14 were instilled by the oropharyngeal route into macrophage-specific PPARgamma-knockout (KO) or wild-type mice. Control animals received PBS or ESAT-6. Lung tissues, BAL cells, and BAL fluid were evaluated 60 days after instillation. PPARgamma-KO mice receiving MWCNT + ESAT-6 had increased granulomas and significantly elevated fibrosis (trichrome staining) compared with wild-type mice or PPARgamma-KO mice that received only MWCNT. Immunostaining of lung tissues revealed elevated fibronectin and Siglec F expression on CD11c(+) infiltrating alveolar macrophages in the presence of MWCNT + ESAT-6 compared with MWCNT alone. Analyses of BAL fluid proteins indicated increased levels of transforming growth factor (TGF)-beta and the TGF-beta pathway mediator IL-13 in PPARgamma-KO mice that received MWCNT + ESAT-6 compared with wild-type or PPARgamma-KO mice that received MWCNT. Similarly, mRNA levels of matrix metalloproteinase 9, another requisite factor for TGF-beta production, was elevated in PPARgamma-KO mice by MWCNT + ESAT-6. Analysis of ESAT-6 in lung tissues by mass spectrometry revealed ESAT-6 retention in lung tissues of PPARgamma-KO but not wild-type mice. These data indicate that PPARgamma deficiency promotes pulmonary ESAT-6 retention, exacerbates macrophage responses to MWCNT + ESAT-6, and intensifies pulmonary fibrosis. The present findings suggest that the model may facilitate understanding of the effects of environmental factors on sarcoidosis-associated pulmonary fibrosis. |
