title: A proteomics approach to identifying key protein targets involved in VEGF inhibitor mediated attenuation of bleomycin-induced pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a life expectancy of less than 5 years post diagnosis for most patients. Poor molecular characterization of IPF has led to insufficient understanding of the pathogenesis of the disease, resulting in lack of effective therapies. In this study, we have integrated a label-free LC-MS based approach with systems biology to identify signaling pathways and regulatory nodes within protein interaction networks that govern phenotypic changes that may lead to IPF. Ingenuity Pathway Analysis of proteins modulated in response to bleomycin treatment identified PI3K/Akt and Wnt signaling as the most significant profibrotic pathways. Similar analysis of proteins modulated in response to vascular endothelial growth factor (VEGF) inhibitor (CBO-P11) treatment identified natural killer cell signaling and PTEN signaling as the most significant antifibrotic pathways. Mechanistic/mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinase (ERK) were identified to be key mediators of pro- and antifibrotic response, where bleomycin (BLM) treatment resulted in increased expression and VEGF inhibitor treatment attenuated expression of mTOR and ERK. Using a BLM mouse model of pulmonary fibrosis and VEGF inhibitor CBO-P11 as a therapeutic measure, we identified a comprehensive set of signaling pathways and proteins that contribute to the pathogenesis of pulmonary fibrosis that can be targeted for therapy against this fatal disease.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Yogesh M
authors.initials: YM
authors.lastname: Kulkarni
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.|Leroy T. Canoles Jr, Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: Sucharita
authors.initials: S
authors.lastname: Dutta
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Anand Krishnan V
authors.initials: AK
authors.lastname: Iyer
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Venkatadri
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kaushik
authors.affiliation: Department of Obstetrics and Gynecology, The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: Vani
authors.initials: V
authors.lastname: Ramesh
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Clayton A
authors.initials: CA
authors.lastname: Wright
authors.affiliation: Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.|Leroy T. Canoles Jr, Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: Oliver John
authors.initials: OJ
authors.lastname: Semmes
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Juan S
authors.initials: JS
authors.lastname: Yakisich
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Neelam
authors.initials: N
authors.lastname: Azad
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D001761:Bleomycin; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000494:pharmacology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D060066:Protein Interaction Maps / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D060449:Wnt Signaling Pathway / Q000187:drug effects; D000099200:Scaffold Protein ILK
chemical_list: D001761:Bleomycin; D016228:Endothelial Growth Factors; D051059:PTEN Phosphohydrolase; D010456:Peptides, Cyclic; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D042461:Vascular Endothelial Growth Factor A; D000099200:Scaffold Protein ILK; C478485:cyclo-VEGI; C494929:PTEN protein, human
keywords: BLM mouse model; High-throughput proteomics; Ingenuity Pathway Analysis; Pulmonary fibrosis; Systems biology; VEGF inhibitor