This proposal will seek to further define the fundamental immunological and biochemical events that lead to pulmonary fibrosis. In animal models and humans with pulmonary fibrosis, monocyte recruitment and survival in the lung and activation of TGF-beta appear to be important components of the remodeling and fibrosis, however, the specific mechanisms involved have not been well elucidated. To address this issue, we found that in addition to promoting monocyte survival, macrophage colony-stimulating factor (M-CSF) also induces monocytes to release soluble factor(s) capable of activating latent TGF-beta. Since activation of TGF-beta appears to be casually associated with lung fibrosis, we will seek to identify the specific factor(s) released by M-CSF-stimulated monocytes that cleave latent TGF-beta and define the biochemical pathways responsible for stimulating the production of these factor(s). We will then focus on defining if active TGF-beta can facilitate monocyte survival directly or through inducing M-CSF release by fibroblasts. Finally, we will focus on """"""""proof-of-concept"""""""" studies to define if monocyte proteases are critical in the activation of latent TGF-beta to assess the potential therapeutic application for agents that block these factors. The short-term goals of this proposal are to define the mechanisms by which monocyte recruitment and survival facilitate tissue remodeling and fibrosis. The long-term goal of this project is to better define the pathological events regulating the genesis of pulmonary fibrosis and to define novel targets to direct innovative therapies to suppress lung destruction and fibrosis associated with this devastating lung disease.
| 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 |
| Ezzie, Michael E; Piper, Melissa G; Montague, Christine et al. (2011) Thrombospondin-1-deficient mice are not protected from bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 44:556-61 |
| Bringardner, Benjamin D; Baran, Christopher P; Eubank, Timothy D et al. (2008) The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis. Antioxid Redox Signal 10:287-301 |
| Ali, Naeem A; Gaughan, Alice A; Orosz, Charles G et al. (2008) Latency associated peptide has in vitro and in vivo immune effects independent of TGF-beta1. PLoS One 3:e1914 |
| Baran, Christopher P; Opalek, Judy M; McMaken, Sara et al. (2007) Important roles for macrophage colony-stimulating factor, CC chemokine ligand 2, and mononuclear phagocytes in the pathogenesis of pulmonary fibrosis. Am J Respir Crit Care Med 176:78-89 |
| Wang, Yijie; Zeigler, Mandy M; Lam, Gregory K et al. (2007) The role of the NADPH oxidase complex, p38 MAPK, and Akt in regulating human monocyte/macrophage survival. Am J Respir Cell Mol Biol 36:68-77 |
| Montague, Christine R; Hunter, Melissa G; Gavrilin, Mikhail A et al. (2006) Activation of estrogen receptor-alpha reduces aortic smooth muscle differentiation. Circ Res 99:477-84 |
| Varadharaj, Saradhadevi; Steinhour, Emily; Hunter, Melissa G et al. (2006) Vitamin C-induced activation of phospholipase D in lung microvascular endothelial cells: regulation by MAP kinases. Cell Signal 18:1396-407 |
| Wu, Haifeng M; Jin, Ming; Marsh, Clay B (2005) Toward functional proteomics of alveolar macrophages. Am J Physiol Lung Cell Mol Physiol 288:L585-95 |
| Baran, Christopher P; Zeigler, Mandy M; Tridandapani, Susheela et al. (2004) The role of ROS and RNS in regulating life and death of blood monocytes. Curr Pharm Des 10:855-66 |
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