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Am J Respir Cell Mol Biol ; 61(2): 198-208, 2019 08.
Article in English | MEDLINE | ID: mdl-30741559

ABSTRACT

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 γ (PPARγ). 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 PPARγ-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. PPARγ-KO mice receiving MWCNT + ESAT-6 had increased granulomas and significantly elevated fibrosis (trichrome staining) compared with wild-type mice or PPARγ-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)-ß and the TGF-ß pathway mediator IL-13 in PPARγ-KO mice that received MWCNT + ESAT-6 compared with wild-type or PPARγ-KO mice that received MWCNT. Similarly, mRNA levels of matrix metalloproteinase 9, another requisite factor for TGF-ß production, was elevated in PPARγ-KO mice by MWCNT + ESAT-6. Analysis of ESAT-6 in lung tissues by mass spectrometry revealed ESAT-6 retention in lung tissues of PPARγ-KO but not wild-type mice. These data indicate that PPARγ 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.


Subject(s)
Antigens, Bacterial/pharmacology , Bacterial Proteins/pharmacology , Macrophages, Alveolar/metabolism , PPAR gamma/deficiency , Pulmonary Fibrosis/microbiology , Sarcoidosis, Pulmonary/microbiology , Animals , Bronchoalveolar Lavage , Bronchoalveolar Lavage Fluid , CD11 Antigens/metabolism , Disease Models, Animal , Fibronectins/metabolism , Fibrosis/metabolism , Inflammation , Lung/pathology , Macrophages/metabolism , Mass Spectrometry , Mice , Mice, Inbred C57BL , Mice, Knockout , Nanotubes, Carbon/chemistry , PPAR gamma/genetics , Pulmonary Fibrosis/genetics , Sarcoidosis, Pulmonary/pathology
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