THE ROLE OF THE ALVEOLAR MACROPHAGE IN CARBON NANOTUBE ELICITED MURINE MODEL OF PULMONARY GRANULOMATOUS INFLAMMATION

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Matthew McPeek (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Pulmonary sarcoidosis is a debilitating inflammatory condition characterized by the presence of granulomatous lesions throughout the lung. Granulomas are a physiological response to inhaled antigens or particulate matter which cannot be properly degraded. To explore mechanisms of granuloma formation and maintenance our laboratory developed a murine model of pulmonary granulomatous inflammation elicited by multi-wall carbon nanotubes (MWCNT). We have found the MWCNT model bears striking similarities to pulmonary sarcoidosis pathophysiology , including increased expression of inflammatory mediators and decreased expression and activity of peroxisome proliferator activated receptor-gamma (PPARy) in alveolar macrophages. PPARy is a known regulator of macrophage activation and serves a crucial role in pulmonary lipid homeostasis through the regulation of macrophage ATP-binding cassette (ABC) lipid transporter-G1 (ABCG1). Further studies demonstrated that alveolar macrophages obtained from sarcoidosis patients and MWCNT instilled animals have decreased gene expression and protein levels of ABCG1 and ABCA1 , a complementary cholesterol transporter. These studies aim to further define the role of alveolar macrophage PPARy , ABCA1 and ABCG1 in pulmonary granulomatous inflammation. We hypothesized that deficiency of ABCA1 and ABCG1 would exacerbate MWCNT induced granuloma formation. To test this hypothesis , macrophage-specific ABCA1 , ABCG1 or combined ABCA1/ABCG1 knockout mice were developed and evaluated following MWCNT instillation. We found that deficiency of ABCG1 but not ABCA1 leads to a significant upregulation of pro-inflammatory mediators and promotes pulmonary granuloma formation. Interestingly , the combined deficiency of ABCA1/ABCG1 leads to an exacerbated pulmonary inflammatory phenotype. We further hypothesized that upregulation of the PPARy-ABCG1 pathway would limit MWCNT induced granuloma formation and inflammation. To test this hypothesis , we administered the PPARy-specific ligand rosiglitazone to MWCNT instilled animals and evaluated the effect on granulomatous inflammation. We found that the administration of rosiglitazone promotes the expression of alveolar macrophage ABCG1 , limits the severity of MWCNT induced granuloma formation and reduced alveolar macrophage pro-inflammatory gene expression. These studies suggest that the PPAR-ABCG1 pathway , specifically the deficiency of alveolar macrophage ABCG1 plays a significant role in pulmonary granulomatous inflammation.

Additional Information

Publication

Dissertation

Language: English

Date: 2018

Keywords

Pulmonary Sarcoidosis, Lipid Transporters

Subjects

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