The long term objective of this project is to uncover key mechanisms in pulmonary inflammation and fibrosis.
The specific aims are designed to study the mechanisms governing the process by which the lung inflammatory response is initiated and how it relates to the subsequent fibrotic process in a rodent bleomycin (BLM) induced model. The guiding hypothesis is that early lung inflammation is induced by the noxious stimulus itself, in this case BLM, by stimulating production of cytokines with inflammatory and fibrogenic properties. These cytokines could then further amplify subsequent production of the same and other cytokines in both autocrine and paracrine fashion. Support for this is provided by recent evidence that BLM can directly stimulate secretion of monocyte chemotactic activity and other cytokines such as interleukin-1 (IL-1) by alveolar macrophages. Delayed sequential increases in production of other cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) in lungs of animals with BLM-induced pulmonary fibrosis also suggest such a scenario. Preliminary studies show that lung endothelial cells and fibroblasts could also play active roles in regulating pulmonary fibrosis, by secretion of cytokines. Based on these studies and other preliminary data, both these cells, in addition to the macrophage, appear to be capable of upregulating their production of key mediators with inflammatory and fibrogenic activities which could participate in regulation of pulmonary fibrosis in paracrine as well as autocrine fashion. In view of these findings, the specific aims to test this hypothesis are: 1) to analyse regulation of cytokine (TGF-beta, IL-1, TNF-alpha, growth factor, neutrophil and monocyte chemotactic activities) production by rat pulmonary artery endothelial cells and lung fibroblasts by BLM, IL-1 and/or TNF-alpha, 2) to analyse modulation of this response by eicosanoids, 3) to compare cytokine production in lung fibroblasts from control rats versus those with BLM-induced pulmonary fibrosis, 4) to analyse for BLM receptors and associated cellular signal transduction pathways, 5) to assess i vivo lung cytokine (IL-1, TNF-alpha and TGF-beta) production and identify the cellular source(s) by immunohistochemistry and in situ hybridization, during BLM-induced pulmonary fibrosis, and 6) to confirm the in vivo role of TNF-alpha, TGF-beta and IL-1 by examining the effects of their depletion by treatment with specific anticytokine antibodies. In this manner clarification of the mechanisms underlying initiation of lung inflammation and fibrosis, and the increased production of key cytokines and identification of their cellular source, will be accomplished. This in turn could contribute to efforts at developing more effective therapeutic approaches for arresting, and perhaps even reversing the progression of many related interstitial lung diseases to their usual fatal outcome.
| Hu, Biao; Liu, Jianhua; Wu, Zhe et al. (2015) Reemergence of hedgehog mediates epithelial-mesenchymal crosstalk in pulmonary fibrosis. Am J Respir Cell Mol Biol 52:418-28 |
| Liu, Tianju; Yu, Hongfeng; Ullenbruch, Matthew et al. (2014) The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis. PLoS One 9:e88362 |
| Liu, Tianju; Ullenbruch, Matthew; Young Choi, Yoon et al. (2013) Telomerase and telomere length in pulmonary fibrosis. Am J Respir Cell Mol Biol 49:260-8 |
| Ding, Lin; Dolgachev, Vladilsav; Wu, Zhuang et al. (2013) Essential role of stem cell factor-c-Kit signalling pathway in bleomycin-induced pulmonary fibrosis. J Pathol 230:205-14 |
| Hu, Biao; Wu, Zhe; Hergert, Polla et al. (2013) Regulation of myofibroblast differentiation by poly(ADP-ribose) polymerase 1. Am J Pathol 182:71-83 |
| Hu, Biao; Phan, Sem H (2013) Myofibroblasts. Curr Opin Rheumatol 25:71-7 |
| Nakashima, Taku; Liu, Tianju; Yu, Hongfeng et al. (2013) Lung bone marrow-derived hematopoietic progenitor cells enhance pulmonary fibrosis. Am J Respir Crit Care Med 188:976-84 |
| Hu, Biao; Wu, Zhe; Nakashima, Taku et al. (2012) Mesenchymal-specific deletion of C/EBPýý suppresses pulmonary fibrosis. Am J Pathol 180:2257-67 |
| Hinz, Boris; Phan, Sem H; Thannickal, Victor J et al. (2012) Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 180:1340-55 |
| Phan, Sem H (2012) Genesis of the myofibroblast in lung injury and fibrosis. Proc Am Thorac Soc 9:148-52 |
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