THE ROLE OF THE ALVEOLAR MACROPHAGE IN CARBON NANOTUBE ELICITED MURINE MODEL OF PULMONARY GRANULOMATOUS INFLAMMATION
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.
McPeek, Matthew. (November 2018). THE ROLE OF THE ALVEOLAR MACROPHAGE IN CARBON NANOTUBE ELICITED MURINE MODEL OF PULMONARY GRANULOMATOUS INFLAMMATION (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/7055.)
McPeek, Matthew. THE ROLE OF THE ALVEOLAR MACROPHAGE IN CARBON NANOTUBE ELICITED MURINE MODEL OF PULMONARY GRANULOMATOUS INFLAMMATION. Doctoral Dissertation. East Carolina University, November 2018. The Scholarship. http://hdl.handle.net/10342/7055. September 30, 2023.
McPeek, Matthew, “THE ROLE OF THE ALVEOLAR MACROPHAGE IN CARBON NANOTUBE ELICITED MURINE MODEL OF PULMONARY GRANULOMATOUS INFLAMMATION” (Doctoral Dissertation., East Carolina University, November 2018).
McPeek, Matthew. THE ROLE OF THE ALVEOLAR MACROPHAGE IN CARBON NANOTUBE ELICITED MURINE MODEL OF PULMONARY GRANULOMATOUS INFLAMMATION [Doctoral Dissertation]. Greenville, NC: East Carolina University; November 2018.
East Carolina University