This proposal will focus on the central hypothesis that survival and accumulation of monocytes and macrophages in the lung promotes injury and fibrosis. Pathological data from mice with genetically- or drug-induced pulmonary fibrosis supports this hypothesis, as monocyte and macrophage accumulation in the lungs temporally associates with pulmonary fibrosis. Similarly, human patients with pulmonary fibrosis have increased numbers of young, activated macrophages in their alveoli that produce heightened amounts of reactive oxygen species (ROS). In small studies, antioxidants have been successfully used to treat patients with pulmonary fibrosis. We found evidence that activation of phosphatidylinositol 3-kinase, Akt and the production of ROS in response to M-CSF stimulation were important to activate NF-kB and promote cell survival in human monocytes. Inhibitors of PI 3-kinase, proteosome activity or ROS suppressed NF-kB activation and monocyte survival in M-CSF-treated cells, suggesting that these processes may be linked. Since NF-kB is a known downstream effector of activated Akt, we hypothesize that activation of NF-kB in M-CSF-treated cells may be an essential biochemical mediator of monocyte survival, and thus may regulate macrophage-mediated inflammation in lung diseases like IPF. The goal of these studies is to define molecular targets that will help patients with this devastating lung disease. To investigate the role of NF-kB in monocyte survival we will test the following Specific Aims. 1) Does M-CSF activate Akt to promote NF-kB translocation and induce the breakdown of IkB? 2) Determine how NF-kB activation is regulated and mediates survival of M-CSF-stimulated cells. 3) Determine the mechanism by which NF-kB translocation facilitates cellular survival. We will use studies in human rnonocytes, murine macrophages from animals that are genetically programmed to suffer lung fibrosis and cell lines to directly assess the contribution of NF-kB in the survival of monocytes and macrophages. These studies will initially be largely in vitro or ex vivo, which are designed to define the role and mechanisms by which NF-kB may lead to monocyte survival with particular attention focused at the serine/threonine kinase Akt and ROS. Our long-term goal is to apply information gained from these studies to reduce monocyte- and macrophage-mediated lung inflammation and offer new treatments to patients with pulmonary fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL067176-02
Application #
6537973
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Reynolds, Herbert Y
Project Start
2001-06-05
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$331,782
Indirect Cost
Name
Ohio State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Moldovan, Leni; Batte, Kara E; Trgovcich, Joanne et al. (2014) Methodological challenges in utilizing miRNAs as circulating biomarkers. J Cell Mol Med 18:371-90
Voorhees, Jeffrey L; Powell, Nicole D; Moldovan, Leni et al. (2013) Chronic restraint stress upregulates erythropoiesis through glucocorticoid stimulation. PLoS One 8:e77935
Voorhees, Jeffrey L; Tarr, Andrew J; Wohleb, Eric S et al. (2013) Prolonged restraint stress increases IL-6, reduces IL-10, and causes persistent depressive-like behavior that is reversed by recombinant IL-10. PLoS One 8:e58488
Ismail, Noura; Wang, Yijie; Dakhlallah, Duaa et al. (2013) Macrophage microvesicles induce macrophage differentiation and miR-223 transfer. Blood 121:984-95
Dakhlallah, Duaa; Batte, Kara; Wang, Yijie et al. (2013) Epigenetic regulation of miR-17~92 contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 187:397-405
Chen, Duan; Roda, Julie M; Marsh, Clay B et al. (2012) Hypoxia inducible factors-mediated inhibition of cancer by GM-CSF: a mathematical model. Bull Math Biol 74:2752-77
Nuovo, Gerard J; Hagood, James S; Magro, Cynthia M et al. (2012) The distribution of immunomodulatory cells in the lungs of patients with idiopathic pulmonary fibrosis. Mod Pathol 25:416-33
Folcik, Virginia A; Broderick, Gordon; Mohan, Shunmugam et al. (2011) Using an agent-based model to analyze the dynamic communication network of the immune response. Theor Biol Med Model 8:1
Wang, Yijie; Mo, Xiaokui; Piper, Melissa G et al. (2011) M-CSF induces monocyte survival by activating NF-?B p65 phosphorylation at Ser276 via protein kinase C. PLoS One 6:e28081
Fischer, Sara N; Johnson, Jed K; Baran, Christopher P et al. (2011) Organ-derived coatings on electrospun nanofibers as ex vivo microenvironments. Biomaterials 32:538-46

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