Chronic progressive fibrotic lung diseases, such as idiopathic pulmonary fibrosis, remain essentially untreatable with urgent need for elucidating mechanisms to aid in discovery of novel effective therapy. These diseases involve complex and intricate interactions between both endogenous lung as well as bone marrow derived cells via a myriad of mediators, the full spectrum of which has not yet been identified. RELM? (resistin-like molecule ?)/FIZZ1 (Found in Inflammatory Zone 1), a member of the resistin family of molecules is recently found to be highly induced in an animal model of lung fibrosis, and shown to activate fibroblasts with promotion of myofibroblast differentiation and enhancing their resistance to apoptotic stimuli. It is predominantly expressed by lung epithelial cells, which can be potently induced by Th2 cytokines via STAT6. Deficiency of these elements in mice diminishes lung RELM? expression that correlates with diminished lung fibrosis. Despite this suggestive evidence for a role in fibrosis, the precise in vivo roles of RELM? in fibrosis remain unclear. The central hypothesis of this project is that RELM? and its homologous second family member, RELM?/FIZZ2, are induced in epithelial cells during lung injury resulting in activation of adjacent fibroblasts and promotion of myofibroblast differentiation, as well as participate in recruitment o bone marrow-derived cells. Interaction between these cellular elements initiated by these mediators leads to the promotion of fibrosis and its progression.
The Aims are to, 1) analyze effects of RELM?/? deficiency and overexpression on normal and injured lung, 2) evaluate the role of RELM?/? in bone marrow-derived fibroblast-like progenitor cell recruitment and consequent impact on fibrosis, 3) identify their cellular receptors, primary downstream signaling pathways and regulated target genes, and 4) examine the regulation of RELM? gene expression in lung type II alveolar epithelial cells. The approaches will exploit a combination of biochemical and molecular tools to dissect the molecular mechanisms involved in regulating their expression, and will use the already available transgenic murine strains necessary to confirm their importance in vivo. Bone marrow chimera mice will be used to assess cell recruitment to the lung.
The proposed studies will shed more light into the mediators regulating processes that are important in fibrotic lung diseases, such as idiopathic pulmonary fibrosis. Novel molecules such as FIZZ1 and FIZZ2 appear to play important roles in fibrosis by activation and recruitment of certain cells in the lung and their further elucidation may help improve on management and treatment of chronic fibrotic lung diseases.
|Hu, Biao; Phan, Sem H (2016) Notch in fibrosis and as a target of anti-fibrotic therapy. Pharmacol Res 108:57-64|
|Ding, Lin; Liu, Tianju; Wu, Zhe et al. (2016) Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis. J Immunol 197:303-12|
|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; Ding, Lin et al. (2015) Conditional Knockout of Telomerase Reverse Transcriptase in Mesenchymal Cells Impairs Mouse Pulmonary Fibrosis. PLoS One 10:e0142547|
|Martins, Vanessa; Gonzalez De Los Santos, Francina; Wu, Zhe et al. (2015) FIZZ1-induced myofibroblast transdifferentiation from adipocytes and its potential role in dermal fibrosis and lipoatrophy. Am J Pathol 185:2768-76|
|Hu, Biao; Wu, Zhe; Bai, David et al. (2015) Mesenchymal deficiency of Notch1 attenuates bleomycin-induced pulmonary fibrosis. Am J Pathol 185:3066-75|
|Xia, Hong; Bodempudi, Vidya; Benyumov, Alexey et al. (2014) Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis. Am J Pathol 184:1369-83|
|Liu, Tianju; Yu, Hongfeng; Ullenbruch, Matthew et al. (2014) The in vivo fibrotic role of FIZZ1 in pulmonary fibrosis. PLoS One 9:e88362|
|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|
|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|
Showing the most recent 10 out of 12 publications