Tuberculosis is endemic among patients with AIDS and follows an aggressive course with poor localization of mycobacteria into granuloma and widespread infection. Granulomas are monocyte rich collections of cells which derive from the circulating peripheral blood monocyte (PBMC). A classical response against pathogens is the expression of cytoprotective genes including Heme-oxygenase-1 (HO-1) which allows for a regulated inflammatory response as well as inhibits apoptosis of cells. Monocytes are recruited to the site of tuberculous infection by the interaction of C-C chemokines, (mainly monocyte chemoattractant protein-1, MCP- 1) and monocyte expression of the CCR2 receptor. It is the hypothesis of this proposal that HO-1 expression in recruited monocyte-macrophages represents a critical regulatory event involved in effective anti-mycobacterial host defense in pleural tuberculosis. HO-1 depletion enhances pleural macrophage apoptosis and impedes mycobacterial clearance by causing alterations in the signaling pathways leading to apoptosis and by altering the in vivo expression of CCR2 on the peripheral blood mononuclear cells (PBMC) and pleural macrophage (PM) leading to poor granuloma formation. We have developed a model of pleural tuberculosis in HO-1 -/- and HO-1 +/+ mice to evaluate the HO-1 mediated regulation of the CR2 receptor on PBMC and pleural macrophages (PM). We will evaluate our hypothesis in our model of pleural tuberculosis in vivo as well as in vitro in PBMC and elicited pleural macrophages.
Our specific aims are:
Specific aim #1 : To evaluate gene expression profiles in peripheral blood monocytes and pleural macrophages from control HO-1 +/+ and HO-1 -/- mice, treated with H37Rv, in a murine model of TB pleurisy and in vitro Specific aim #2: To evaluate the regulatory role of HO-1 in apoptosis of peripheral blood monocytes and pleural macrophages during granuloma formation in the pleural space in tuberculous pleurisy.
Specific aim #3 : To evaluate the regulatory role of HO-1 in the expression of CCR2 on peripheral blood monocytes and pleural macrophages during granuloma formation in the pleural space in tuberculous pleurisy. Understanding the mechanisms underlying HO-1 mediated regulation of macrophage recruitment, retention and apoptosis, leading to granuloma formation is critical to the pathophysiology of pleuro-pulmonary tuberculosis seen in patients and will help develop therapeutic modalities that augment host-defense responses.
Understanding the mechanisms underlying HO-1 mediated regulation of macrophage recruitment, retention and apoptosis, leading to granuloma formation is critical to the pathophysiology of pleuro-pulmonary tuberculosis seen in patients and will help develop therapeutic modalities that augment host-defense responses.
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