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Deletion of PPAR in Alveolar Macrophages Is Associated with a Th-1 Pulmonary Inflammatory Response¹

Anagha Malur^*, Almedia J. Mccoy^*, Sergio Arce^*, Barbara P. Barna^*, Mani S. Kavuru^*, Achut G. Malur and Mary Jane Thomassen^2,*

^* Department of Internal Medicine Division of Pulmonary and Critical Care and Sleep Medicine and Department of Microbiology and Immunology, East Carolina University, Greenville, NC 27834

Peroxisome proliferator-activated receptor (PPAR) is constitutively expressed at high levels in healthy alveolar macrophages, in contrast to other tissue macrophages and blood monocytes. PPAR ligands have been shown to down-regulate IFN--stimulated inducible NO synthase (iNOS) in macrophages. Because NO is an important inflammatory mediator in the lung, we hypothesized that deletion of alveolar macrophage PPAR in vivo would result in up-regulation of iNOS and other inflammatory mediators. The loss of PPAR in macrophages was achieved by crossing floxed (+/+) PPAR mice and a transgenic mouse containing the CRE recombinase gene under the control of the murine M lysozyme promoter (PPARKO). Alveolar macrophages were harvested by bronchoalveolar lavage (BAL). Lymphocytes (CD8:CD4 ratio = 2.8) were increased in BAL of PPARKO vs wild-type C57BL6; p 0.0001. Both iNOS and IFN- expression were significantly elevated (p 0.05) in BAL cells. Th-1 associated cytokines including IL-12 (p40), MIP-1 (CCL3), and IFN inducible protein-10 (IP-10, CXCL10) were also elevated. IL-4 and IL-17A were not detected. To test whether these alterations were due to the lack of PPAR, PPAR KO mice were intratracheally inoculated with a PPAR lentivirus construct. PPAR transduction resulted in significantly decreased iNOS and IFN- mRNA expression, as well as reduced BAL lymphocytes. These results suggest that lack of PPAR in alveolar macrophages disrupts lung homeostasis and results in a Th1-like inflammatory response.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the North Carolina Biotechnology Center, Grant No. 2005-FRG-1013 awarded to M.J.T.

² Address correspondence and reprint requests to Dr. Mary Jane Thomassen, Division of Pulmonary and Critical Care Medicine, The Brody School of Medicine, East Carolina University, 3E-149 Brody Medical Sciences Building, Greenville, NC 27834. E-mail address: thomassenm{at}ecu.edu

³ Abbreviations used in this paper: PPAR, peroxisome proliferator-activated receptor-; iNOS, inducible NO synthase; WT, wild type; BAL, bronchoalveolar lavage; lenti-PPAR, lentivirus-PPAR; KO, knockout.