and specific aims): Pulmonary fibrosis is a common end result of diverse forms of lung injury and interstitial lung diseases. Despite recent progress, the identity of cells responsible for elaboration of mediators driving the fibrosis process remains uncertain. The eosinophil has recently been identified as a major source for several key cytokines with fibrogenic activities, including monocyte chemotactic protein-1 (MCP-1) and transforming growth factor beta (TGF-b). It has also been identified as an important source of these and other cytokines in fibrotic lesions, while the importance of interleukin-5 (IL-5) in eosinophil recruitment have been demonstrated in allergic diseases. Human pulmonary fibrosis and fibrosis of the airway walls in asthma are associated with significant influx of eosinophils, and an increase in lung eosinophils indicates a worst prognosis and resistance to treatment in idiopathic pulmonary fibrosis. Despite this abundant suggestive evidence, direct demonstration of a role for eosinophils in pulmonary fibrosis is lacking. The central hypothesis of this project is that recruitment of eosinophils into the lung and their activation by IL-5 and other cytokines result in increased expression of fibrogenic cytokines such as TGF-b, which will in turn cause the recruitment, proliferation and activation of fibroblasts, which are ultimately responsible for the increased deposition of extracellular matrix in the fibrotic lung. To test this hypothesis, four specific aims are proposed: 1) measure lung eosinophil kinetics in a murine model of bleomycin-induced pulmonary fibrosis; 2) identify the chemotactic factors responsible for eosinophil recruitment and activation; 3) assess lung IL-5 expression, its regulation, and identify the cells responsible for IL-5 expression; 4) examine the role of IL-5 in pulmonary fibrosis by examining the effects of, a) neutralizing antibody to IL-5 and b) exogenous IL-5 administration.
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| 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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