Angiogenesis and aberrant cellular redox state are the hallmarks of the pathogenesis of idiopathic pulmonary fibrosis (IPF), but the mechanisms underlying these pathologic alterations are poorly understood. Failure to understand and target such critical mechanisms directly limits the effectiveness of the therapeutic efforts against this disease. The long-term goal of this study is to develop an effective therapeutic strategy against pulmonary fibrosis and is directly relevant to the mission of National Heart, Lung and Blood Institute. The overall objective of this proposal is to investigate the contribution of oxidative stress-regulated angiogenesis in the pathogenesis of bleomycin (BLM)-induced pulmonary fibrosis. In spite of a strong positive correlation between the angiogenic mediator vascular endothelial growth factor (VEGF) and pulmonary fibrosis, the role of VEGF in pulmonary fibrosis is poorly understood.
Aim 1 is designed to establish the role of VEGF in the pathogenesis of pulmonary fibrosis and test the hypothesis that phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway regulates VEGF via hypoxia inducible factor (HIF)-11 in BLM-induced pulmonary fibrosis. Although pro-angiogenic environment is known to co-exist with progressive fibrosis, the contribution of neovascularization to the progression of fibrosis is understudied. The preliminary data demonstrates a significant increase in angiogenesis in vascular endothelial cells in response to BLM treatment.
Aim 2 is designed to establish the involvement of angiogenesis in BLM-induced pulmonary fibrosis and test the hypothesis that angiogenesis during BLM-induced pulmonary fibrosis is dependent, in part, upon Akt mediated upregulation of the angiogenic mediator VEGF. Gene knockout and pharmacological approaches will be used to elucidate the role of Akt and identify its specific isoform(s) involved in the process. Increased oxidative stress have been implicated in lung injury and fibrosis and its inhibition has shown to offer significant protection against pulmonary fibrosis in animal models.
Aim 3 is designed to evaluate if antioxidants such as manganese superoxide dismutase (MnSOD) mediate lung fibrosis by regulating the angiogenic (PI3K/Akt->HIF-1->VEGF) pathway. The preliminary data shows that Mn(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP), an MnSOD mimetic, significantly blocked BLM-induced angiogenic and fibrogenic response. We hypothesize that MnTBAP might be effective in suppressing pulmonary fibrosis by modulating the angiogenic pathway. The proposed study will be important for the increased understanding of the molecular mechanisms involved in the pathogenesis of pulmonary fibrosis. The study will also aid in identifying key molecular targets, which may serve as novel biomarkers and provide alternative avenues for the development of potential therapeutic and preventive strategies for this fatal disease.

Public Health Relevance

The proposed study will explore the modalities that dictate pathogenesis of pulmonary fibrosis. The overall objective of this proposal is to elucidate the role of some of the characteristic features such as angiogenesis and oxidative stress that have been implicated in pulmonary fibrosis but are understudied. The idea of angiogenic mediators regulating lung fibrosis represents a paradigm shift in the present understanding of this disease, and will pave way for tackling fibrosis using a new and different approach. The proposed study will be important not only to the increased understanding of the molecular mechanisms of lung fibrosis but also in the development of potential therapeutic and preventive strategies for this fatal disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Enhancement Award (SC1)
Project #
5SC1HL112630-03
Application #
8473917
Study Section
Special Emphasis Panel (ZGM1-MBRS-X (NP))
Program Officer
Eu, Jerry Pc
Project Start
2011-09-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$237,488
Indirect Cost
$74,825
Name
Hampton University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
003135068
City
Hampton
State
VA
Country
United States
Zip Code
23668
Kulkarni, Yogesh M; Dutta, Sucharita; Iyer, Anand Krishnan V et al. (2018) A Lipidomics Approach to Identifying Key Lipid Species Involved in VEGF-Inhibitor Mediated Attenuation of Bleomycin-Induced Pulmonary Fibrosis. Proteomics Clin Appl 12:e1700086
Wright, Clayton; Iyer, Anand Krishnan V; Kaushik, Vivek et al. (2017) Anti-Tumorigenic Potential of a Novel Orlistat-AICAR Combination in Prostate Cancer Cells. J Cell Biochem 118:3834-3845
Wright, Clayton; Iyer, Anand Krishnan V; Wang, Liying et al. (2017) Effects of titanium dioxide nanoparticles on human keratinocytes. Drug Chem Toxicol 40:90-100
Yakisich, Juan Sebastian; Azad, Neelam; Kaushik, Vivek et al. (2017) Cancer Cell Plasticity: Rapid Reversal of Chemosensitivity and Expression of Stemness Markers in Lung and Breast Cancer Tumorspheres. J Cell Physiol 232:2280-2286
Yakisich, Juan Sebastian; Kulkarni, Yogesh; Azad, Neelam et al. (2017) Selective and Irreversible Induction of Necroptotic Cell Death in Lung Tumorspheres by Short-Term Exposure to Verapamil in Combination with Sorafenib. Stem Cells Int 2017:5987015
Venkatadri, Rajkumar; Iyer, Anand Krishnan V; Ramesh, Vani et al. (2017) MnTBAP Inhibits Bleomycin-Induced Pulmonary Fibrosis by Regulating VEGF and Wnt Signaling. J Cell Physiol 232:506-516
Kaushik, Vivek; Yakisich, Juan Sebastian; Azad, Neelam et al. (2016) Anti-Tumor Effects of Cardiac Glycosides on Human Lung Cancer Cells and Lung Tumorspheres. J Cell Physiol :
Yakisich, Juan Sebastian; Azad, Neelam; Venkatadri, Rajkumar et al. (2016) Digitoxin and its synthetic analog MonoD have potent antiproliferative effects on lung cancer cells and potentiate the effects of hydroxyurea and paclitaxel. Oncol Rep 35:878-86
Yakisich, Juan Sebastian; Venkatadri, Rajkumar; Azad, Neelam et al. (2016) Chemoresistance of lung and breast cancer cells growing under prolonged periods of serum starvation. J Cell Physiol :
Kulkarni, Yogesh M; Kaushik, Vivek; Azad, Neelam et al. (2016) Autophagy-Induced Apoptosis in Lung Cancer Cells by a Novel Digitoxin Analog. J Cell Physiol 231:817-28

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