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.

Radiation-Mediated Tumor Growth Inhibition Is Significantly Enhanced with Redox-Active Compounds That Cycle with Ascorbate

“…6 and 7). While a fair amount of data exist on the ability of MnTBAP 3to reduce normal tissue injuries (9,12,53,61,64), this MnP may not have the potential as an anticancer therapeutic.…”

MnTBAP Reverses Pulmonary Vascular Remodeling and Improves Cardiac Function in Experimentally Induced Pulmonary Arterial Hypertension

“…As a cell-permeable superoxide dismutase mimetic, MnTBAP has been found to show beneficial effects in multiple disease models related to oxidative damages, including bleomycin-induced pulmonary fibrosis [27], carrageenan-induced pleurisy [28], lung contusion [26], renal fibrosis [29] and renal injury [24,30]. More interestingly, a previous study revealed that MnTBAP treatment regressed PH in Fawn hooded rats (FHR) by acting on PAMSCs [41].…”

“…Manganese (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP), a synthetic metalloporphyrin with antioxidant [21][22][23] and anti-inflammatory [23][24][25][26] effects, has been shown to inhibit the turn-over of BMPR2 in human umbilical vein endothelial cells (HUVECs) [25]. Moreover, MnTBAP offers beneficial effects in bleomycin-induced pulmonary fibrosis [27], carrageenan-induced pleurisy [28], lung contusion [26], renal fibrosis [29] and renal injury [24,30].…”

Feixian Recipe inhibits pulmonary fibrosis by targeting pulmonary microvascular endothelial cells and VEGF/VEGFR2 signaling pathway

“…14,15 Many studies suggest that a comprehensive set of signaling pathways and proteins that contribute to the pathogenesis of pulmonary fibrosis can be inhibited by targeting VEGF/VEGFR2 signaling pathway. 16,17 Our experiment has suggested that FXR could inhibit the progress of PF through inhibiting the migration of PMVECs, decreasing the angiogenesis, and reducing the expression of VEGF and VEGFR2. PI3K can be activated by various cytokines in vivo, such as VEGF, transforming growth factor-β (TGF-β), connective tissue growth factor and so on.…”