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Murine Model of MWCNT-Elicited Granulomatous Disease Combined with a Mycobacterial Antigen Exhibits Lymphadenopathy and Increased Th1 Cells Similar to Sarcoidosis
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A4817 - Murine Model of MWCNT-Elicited Granulomatous Disease Combined with a Mycobacterial Antigen Exhibits Lymphadenopathy and Increased Th1 Cells Similar to Sarcoidosis
Author Block: A. Malur1, N. Leffler1, D. Vargas1, A. Mohan1, R. Barrington2, K. Kew1, B. Muller-Borer1, G. Murray1, B. P. Barna1, M. J. Thomassen1; 1East Carolina University, Greenville, NC, United States, 2Microbiology and Immunology, University of South Alabama, Mobile, AL, United States.
We developed a murine model of multi-wall carbon nanotube (MWCNT)-elicited chronic granulomatous disease which exhibits many similarities to human sarcoidosis, a chronic granulomatous disease of unknown etiology characterized by alveolar macrophage deficiency of the nuclear transcription factor, peroxisome-proliferator-activated receptor gamma (PPARγ) (Culver et.al 2004 Am J.Respir.Cell. Mol. Bio). Because lymphocyte reactivity to mycobacterial antigens may be associated with sarcoidosis, we hypothesized that addition of mycobacterial Early Secreted Antigenic Target Protein 6 (ESAT-6) to MWCNT might exacerbate murine T effector cells and granulomatous histopathology. MWCNT with or without ESAT-6 peptide 14 (NNALQNLARTISEAG) were instilled into macrophage-specific PPARγ KO mice. Controls received only vehicle (surfactant-PBS) or ESAT-6 alone. Evaluation of granulomas at 60 days after instillation indicated that mice receiving MWCNT + ESAT-6 had increased granulomas vs those receiving MWCNT alone (p≤0.05). This differential pathology was not due to a difference in persistence of ESAT-6 peptide as ESAT-6 was detected by mass spectroscopy in lungs of all animals 60-days after receiving ESAT-6 with MWCNT treatment. Modified Ashcroft scoring of Masson’s Trichrome staining indicated that mice receiving MWCNT + ESAT-6, had minimal fibrosis at 20 days post-treatment (3, p≤0.04), but increased pulmonary fibrosis at 60 days compared to MWCNT alone-treated animals. The numbers of T lymphocytes were also increased in lung tissue sections of mice exposed to MWCNT + ESAT-6 compared to those exposed to MWCNT alone. Moreover, mice receiving MWCNT + ESAT-6 had enlarged mediastinal lymph nodes and flow cytometric analyses revealed that Th-1 lymphocytes were significantly elevated in mice receiving MWCNT + ESAT-6 compared to MWCNT alone (p≤0.05). Immunohistochemical analysis of mediastinal lymph nodes revealed increased CD11c staining and deposition of MWCNT. Taken together, these findings suggest that (a) PPARγ deficiency exacerbates ESAT-6-associated T cell activation and pulmonary histopathology; and that (b) the MWCNT + ESAT-6 model may offer new insights into the lymphocyte activation phenotype associated with sarcoidosis.
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Author Block: A. Malur1, N. Leffler1, D. Vargas1, A. Mohan1, R. Barrington2, K. Kew1, B. Muller-Borer1, G. Murray1, B. P. Barna1, M. J. Thomassen1; 1East Carolina University, Greenville, NC, United States, 2Microbiology and Immunology, University of South Alabama, Mobile, AL, United States.
We developed a murine model of multi-wall carbon nanotube (MWCNT)-elicited chronic granulomatous disease which exhibits many similarities to human sarcoidosis, a chronic granulomatous disease of unknown etiology characterized by alveolar macrophage deficiency of the nuclear transcription factor, peroxisome-proliferator-activated receptor gamma (PPARγ) (Culver et.al 2004 Am J.Respir.Cell. Mol. Bio). Because lymphocyte reactivity to mycobacterial antigens may be associated with sarcoidosis, we hypothesized that addition of mycobacterial Early Secreted Antigenic Target Protein 6 (ESAT-6) to MWCNT might exacerbate murine T effector cells and granulomatous histopathology. MWCNT with or without ESAT-6 peptide 14 (NNALQNLARTISEAG) were instilled into macrophage-specific PPARγ KO mice. Controls received only vehicle (surfactant-PBS) or ESAT-6 alone. Evaluation of granulomas at 60 days after instillation indicated that mice receiving MWCNT + ESAT-6 had increased granulomas vs those receiving MWCNT alone (p≤0.05). This differential pathology was not due to a difference in persistence of ESAT-6 peptide as ESAT-6 was detected by mass spectroscopy in lungs of all animals 60-days after receiving ESAT-6 with MWCNT treatment. Modified Ashcroft scoring of Masson’s Trichrome staining indicated that mice receiving MWCNT + ESAT-6, had minimal fibrosis at 20 days post-treatment (3, p≤0.04), but increased pulmonary fibrosis at 60 days compared to MWCNT alone-treated animals. The numbers of T lymphocytes were also increased in lung tissue sections of mice exposed to MWCNT + ESAT-6 compared to those exposed to MWCNT alone. Moreover, mice receiving MWCNT + ESAT-6 had enlarged mediastinal lymph nodes and flow cytometric analyses revealed that Th-1 lymphocytes were significantly elevated in mice receiving MWCNT + ESAT-6 compared to MWCNT alone (p≤0.05). Immunohistochemical analysis of mediastinal lymph nodes revealed increased CD11c staining and deposition of MWCNT. Taken together, these findings suggest that (a) PPARγ deficiency exacerbates ESAT-6-associated T cell activation and pulmonary histopathology; and that (b) the MWCNT + ESAT-6 model may offer new insights into the lymphocyte activation phenotype associated with sarcoidosis.
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