Pulmonary fibrosis is a common end result of diverse forms of lung injury and interstitial lung diseases. A complex interplay between certain lung cells is known to be important in the fibrotic process, although the exact identity of the cells and their precise in vivo roles have not been unequivocally determined. The eosinophil is found in many fibrotic conditions and lesions, and is known to express several key cytokines with fibrogenic activities, including monocyte chemotactic protein-l (MCP-1), and transforming growth factors a (TGFa) and b (TGFb). It thus represents a potentially important source of such cytokines in these fibrotic lesions, thus identifying a potential role for eosinophils in fibrogenesis. Tissue recruitment of eosinophils is found to be dependent on interleukin-5 (IL-5) and several CC type chemokines, especially eotaxin. 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 suggestive evidence, the role of eosinophils in pulmonary fibrosis requires further elucidation. The central hypothesis of this proposal is that recruitment of eosinophils into the lung and their activation by certain chemokines/cytokines result in increased expression of fibrogenic cytokines such as TGFb, which will in turn cause the recruitment, proliferation and activation of fibroblasts with differentiation to myofibroblasts. These latter cells are ultimately responsible for the increased deposition of extracellular matrix in the fibrotic lung. To test this hypothesis, four specific aims are proposed: 1) characterize the elaboration of eotaxin and related CC chemokines in a rodent model of bleomycin-induced pulmonary fibrosis and identify the cells responsible for elaboration of injury-induced chemokines, and examination of associated regulatory mechanisms; 2) determine the role of these chemokines in pulmonary fibrosis and eosinophil recruitment, activation and apoptosis, using neutralizing antibodies (to chemokines and cognate receptors) and transgenic knockout mice; 3) analyze the regulatory role of eosinophils on fibroblast activation and myofibroblast differentiation in vitro, and identify the mediators involved; and 4) examine the ability of exogenous eotaxin and/or IL-5 treatment (as well as by IL-5 transgenic over-expression), and transferred eosinophils from fibrotic lungs, to exacerbate pulmonary fibrosis. A combination of immunohistochemical, histochemical and in situ hybridization methods will be used to identify cells and expression of specific cytokines by these cells in tissues from diseased and control animals. This overall approach will allow direct assessment of the in vivo role of these cells and combine them with in vitro studies using isolated cells for direct confirmation and more precise and quantitative delineation of mechanisms.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Reynolds, Herbert Y
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
Zip Code
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

Showing the most recent 10 out of 107 publications