title: MnTBAP Inhibits Bleomycin-Induced Pulmonary Fibrosis by Regulating VEGF and Wnt Signaling.
abstract: Cellular oxidative stress is implicated not only in lung injury but also in contributing to the development of pulmonary fibrosis. We demonstrate that a cell-permeable superoxide dismutase (SOD) mimetic and peroxynitrite scavenger, manganese (III) tetrakis (4-benzoic acid) porphyrin chloride (MnTBAP) significantly inhibited bleomycin-induced fibrogenic effects both in vitro and in vivo. Further investigation into the underlying mechanisms revealed that MnTBAP targets canonical Wnt and non-canonical Wnt/Ca2+ signaling pathways, both of which were upregulated by bleomycin treatment. The effect of MnTBAP on canonical Wnt signaling was significant in vivo but inconclusive in vitro and the non-canonical Wnt/Ca2+ signaling pathway was observed to be the predominant pathway regulated by MnTBAP in bleomycin-induced pulmonary fibrosis. Furthermore, we show that the inhibitory effects of MnTBAP involve regulation of VEGF which is upstream of the Wnt signaling pathway. Overall, the data show that the superoxide scavenger MnTBAP attenuates bleomycin-induced pulmonary fibrosis by targeting VEGF and Wnt signaling pathways. J. Cell. Physiol. 232: 506-516, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pharmaceutical Sciences, Hampton University, Hampton, Virginia.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Venkatadri
authors.affiliation: Department of Pharmaceutical Sciences, Hampton University, Hampton, Virginia.
authors.forename: Anand Krishnan V
authors.initials: AK
authors.lastname: Iyer
authors.affiliation: Department of Obstetrics and Gynecology, The Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia.
authors.forename: Vani
authors.initials: V
authors.lastname: Ramesh
authors.affiliation: Department of Pharmaceutical Sciences, Hampton University, Hampton, Virginia.
authors.forename: Clayton
authors.initials: C
authors.lastname: Wright
authors.affiliation: Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Castro
authors.affiliation: Department of Pharmaceutical Sciences, Hampton University, Hampton, Virginia.
authors.forename: Juan S
authors.initials: JS
authors.lastname: Yakisich
authors.affiliation: Department of Pharmaceutical Sciences, Hampton University, Hampton, Virginia.
authors.forename: Neelam
authors.initials: N
authors.lastname: Azad
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D008665:Metalloporphyrins / Q000494:pharmacology* / Q000627:therapeutic use*; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D008665:Metalloporphyrins; D042461:Vascular Endothelial Growth Factor A; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D001761:Bleomycin