Idiopathic pulmonary fibrosis (IPF) is one of the most pernicious forms of lung fibrogenesis and currently has no clearly effective treatments. Whereas the etiology of IPF remains enigmatic, there is evidence of dysregulations of several major molecular pathways in lung fibroblasts of IPF patients, including apoptosis/survival pathways as well as TGF-?, Akt, and MAPK signaling. In our preliminary studies, we found that the expression of miR-21 is upregulated in the lungs of mice with bleomycin-induced lung fibrosis and in the lungs of patients with IPF. Target predictions as well as previous studies demonstrate that miR-21 regulates the expression of PDCD4, Smad7, Spry1, and PTEN. These proteins are critical negative regulators of cell proliferation and survival as well as TGF-?, PI3K, and MAPK signaling. This information, together with our preliminary data, suggests that miR-21 may play an important role as an integrator in initiation and progression of IPF. Therefore, miR-21 appears to be a potential target for developing novel therapeutics to treat IPF. Our preliminary data showing that sequestering miR-21 by anti-miR-21 probes diminishes the severity of bleomycin induced lung fibrosis lend a strong support to this hypothesis. In this proposal, we aim to 1) characterize miR-21 expression in human lung fibroblasts, in the lungs of mice with bleomycin induced pulmonary fibrosis and in the lungs of patients with IPF;2) delineate the role of miR-21 in vivo during bleomycin induced lung fibrosis;3) delineate the mechanisms by which miR-21 regulates lung fibrosis;4) delineate the role of miR-21 in modulating the ex vivo pathological properties of lung fibroblasts from IPF patients.

Public Health Relevance

MicroRNAs are important regulators of many essential cellular and developmental events. Deregulations of microRNA expression have been shown to be involved in a number of diseases, such as cancer, cardiovascular diseases, and diabetes. However, whether microRNAs regulate lung injury and repair, processes that occur in idiopathic pulmonary fibrosis (IPF) has not been elucidated. We found that the expression of miR-21 is upregulated in mouse lungs with bleomycin induced lung fibrosis and lungs of patients with IPF and miR-21 promotes the fibrogenic activity of TGF-? in human fibroblasts. The studies proposed in this application should not only improve understanding of the roles of miR-21 in the pathogenesis of lung fibrosis, but also are likely to suggest novel therapeutic interventions aimed at decreasing the severity of lung fibrosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Eu, Jerry Pc
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions. Am J Physiol Lung Cell Mol Physiol 312:L415-L424
Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence. Am J Respir Cell Mol Biol 56:168-178
Cui, Huachun; Banerjee, Sami; Xie, Na et al. (2016) MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation. Am J Respir Cell Mol Biol 54:843-52
Bernard, Karen; Logsdon, Naomi J; Ravi, Saranya et al. (2015) Metabolic Reprogramming Is Required for Myofibroblast Contractility and Differentiation. J Biol Chem 290:25427-38
Tan, Zheng; Xie, Na; Cui, Huachun et al. (2015) Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J Immunol 194:6082-9
Xie, Na; Tan, Zheng; Banerjee, Sami et al. (2015) Glycolytic Reprogramming in Myofibroblast Differentiation and Lung Fibrosis. Am J Respir Crit Care Med 192:1462-74
Zhou, Yong; Chen, Huaping; Ambalavanan, Namasivayam et al. (2015) Noninvasive imaging of experimental lung fibrosis. Am J Respir Cell Mol Biol 53:8-13
Xie, Na; Liu, Gang (2015) ncRNA-regulated immune response and its role in inflammatory lung diseases. Am J Physiol Lung Cell Mol Physiol 309:L1076-87
Huang, Shengping; Liu, Shufeng; Fu, Jia J et al. (2015) Monocyte Chemotactic Protein-induced Protein 1 and 4 Form a Complex but Act Independently in Regulation of Interleukin-6 mRNA Degradation. J Biol Chem 290:20782-92
Tan, Zheng; Xie, Na; Banerjee, Sami et al. (2015) The monocarboxylate transporter 4 is required for glycolytic reprogramming and inflammatory response in macrophages. J Biol Chem 290:46-55

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