The key leukocytes associated with chronic inflammation are macrophages. Macrophages play an important role in the development of lung tumors from initiated cells in lung cancer and in experimental respiratory carcinogenesis. We propose a series of in vivo modulations of macrophage activation to determine how these inflammatory phenotypes affect lung tumorigenesis in mouse models. Among the manipulations are exogenous addition of cytokines, bone marrow transplants of genetically distinct marrow populations, varying the number and activation status of pulmonary macrophages during chemical carcinogenesis, as well as using conditional lung-targeted oncogene induction of neoplasia. The macrophage activation states we will examine have distinct physiological roles. M1 activation results from bacterial infection, while M2 activation is key in adaptive immunity. To distinguish between these two phenotypes, we examine arginine metabolism. M1 activation is characterized by inducible nitric oxide synthase expression which results in arginine metabolism to citruline and nitric oxide while M2 activation results in arginase expression leading to polyamine biosynthesis. We will investigate in vitro co-culture models varying lung epithelial and macrophage composition. We will thus deduce which macrophage activation states can modify lung epithelial cell behavior, and examine how epithelial cells at different states of neoplasia affect macrophages. These experiments will provide a molecular understanding of how inflammation promotes lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA132552-05
Application #
8269049
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (O1))
Program Officer
Johnson, Ronald L
Project Start
2008-06-17
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$281,979
Indirect Cost
$97,679
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Fritz, Jason M; Dwyer-Nield, Lori D; Malkinson, Alvin M (2011) Stimulation of neoplastic mouse lung cell proliferation by alveolar macrophage-derived, insulin-like growth factor-1 can be blocked by inhibiting MEK and PI3K activation. Mol Cancer 10:76
Fritz, Jason M; Dwyer-Nield, Lori D; Russell, Bridgette M et al. (2010) The Kras mutational spectra of chemically induced lung tumors in different inbred mice mimics the spectra of KRAS mutations in adenocarcinomas in smokers versus nonsmokers. J Thorac Oncol 5:254-7
Rice, Pamela L; Barrett, Bradley S; Fritz, Jason M et al. (2010) Regulation of cytokine-induced prostanoid and nitric oxide synthesis by extracellular signal–regulated kinase 1/2 in lung epithelial cells. Exp Lung Res 36:558-71
Redente, Elizabeth F; Higgins, David M; Dwyer-Nield, Lori D et al. (2010) Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation. J Leukoc Biol 88:159-68
Reynolds, Susan D; Malkinson, Alvin M (2010) Clara cell: progenitor for the bronchiolar epithelium. Int J Biochem Cell Biol 42:1-4
Redente, Elizabeth F; Dwyer-Nield, Lori D; Barrett, Bradley S et al. (2009) Lung tumor growth is stimulated in IFN-gamma-/- mice and inhibited in IL-4Ralpha-/- mice. Anticancer Res 29:5095-101