Olodaterol shows anti‐fibrotic efficacy in <i>in vitro</i> and <i>in vivo</i> models of pulmonary fibrosis

Herrmann, Franziska; Wollin, Lutz; Wirth, Johannes; Gantner, Florian; Lämmle, Bärbel; Wex, Eva

doi:10.1111/bph.13982

Cited by 16 publications

(13 citation statements)

References 51 publications

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“…TGF-β1 is recognized as a focus fibrogenic factor in pulmonary fibrosis, which could promote fibroblast proliferation and collagen deposition. Numerous studies employed TGF-β1 as the pulmonary fibrosis inducer in cell experiments [ 16 , 17 ]. In the present study, to better understand the biological function of miR-1224-5p, we treated fibroblast cell line (NIH/3T3, MRC-5) with various doses of TGF-β1 for 24 and 48 h. We observed that miR-1224-5p levels were significantly increased ( Figure 3 A,B), and α-SMA and Vimentin protein levels were increased compared with those in the control group ( Figure S2A,B ).…”

Section: Resultsmentioning

confidence: 99%

miR-1224-5p Mediates Mitochondrial Damage to Affect Silica-Induced Pulmonary Fibrosis by Targeting BECN1

Liu

et al. 2017

IJMS

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Silicosis is associated with fibroblast proliferation and extracellular matrix deposition in lung tissues. The dysregulation of miR-1224-5p has been implicated in several human cancers; however, the expression and function of miR-1224-5p in silicosis is unknown. The mitochondrial dysfunctions play critical roles in some diseases, but how these processes are regulated in silicosis remains limited. Here, we explored the role of miR-1224-5p in a mouse model of silicosis. We showed that the expression of miR-1224-5p is increased both in lung tissues of silica-induced pulmonary fibrosis and fibroblasts exposed to TGF-β1. Repression of miR-1224-5p expression attenuated silica-induced fibrotic progression in vivo and TGF-β1-induced myofibroblast differentiation in vitro. Additionally, we demonstrated that miR-1224-5p facilitated silica-induced pulmonary fibrosis primarily by repressing one of target genes, BECN1, thereby blocking PARK2 translocation to mitochondria and inducing the accumulation of damaged mitochondria. Furthermore, the activation of PDGFR signal mediated by mitochondrial damage and insufficient mitophagy resulted in myofibroblast differentiation. Collectively, these data indicated that miR-1224-5p exerts key functions in silica-induced pulmonary fibrosis and may represent a potential therapeutic target for silicosis.

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Section: Resultsmentioning

confidence: 99%

miR-1224-5p Mediates Mitochondrial Damage to Affect Silica-Induced Pulmonary Fibrosis by Targeting BECN1

Liu

et al. 2017

IJMS

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“…4000 primary human lung fibroblasts were seeded per well for α-SMA Western blot replacement and cytotoxicity assays. Determination of α-SMA expression was performed as previously described [33]. In brief, cells were starved in serum-free DMEM for 24 h, pre-treated with different concentrations of Compound 408 for 20 min and stimulated with TGF-β1 (5 ng/ mL) for 48 h. Lysates were assayed in a Western blot replacement assay [Meso Scale Discovery (MSD), Rockville, MD, USA].…”

Section: Methodsmentioning

confidence: 99%

Human lung fibroblast-to-myofibroblast transformation is not driven by an LDH5-dependent metabolic shift towards aerobic glycolysis

et al. 2019

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Background Idiopathic pulmonary fibrosis (IPF) is a fatal respiratory disease characterized by aberrant fibroblast activation and progressive fibrotic remodelling of the lungs. Though the exact pathophysiological mechanisms of IPF remain unknown, TGF-β1 is thought to act as a main driver of the disease by mediating fibroblast-to-myofibroblast transformation (FMT). Recent reports have indicated that a metabolic shift towards aerobic glycolysis takes place during FMT and that metabolic shifts can directly influence aberrant cell function. This has led to the hypothesis that inhibition of lactate dehydrogenase 5 (LDH5), an enzyme responsible for converting pyruvate into lactate, could constitute a therapeutic concept for IPF. Methods In this study, we investigated the potential link between aerobic glycolysis and FMT using a potent LDH5 inhibitor (Compound 408, Genentech). Seahorse analysis was performed to determine the effect of Compound 408 on TGF-β1-driven glycolysis in WI-38 fibroblasts. TGF-β1-mediated FMT was measured by quantifying α-smooth muscle actin (α-SMA) and fibronectin in primary human lung fibroblasts following treatment with Compound 408. Lactate and pyruvate levels in the cell culture supernatant were assessed by LC-MS/MS. In addition to pharmacological LDH5 inhibition, the effect of siRNA-mediated knockdown of LDHA and LDHB on FMT was examined. Results We show that treatment of lung fibroblasts with Compound 408 efficiently inhibits LDH5 and attenuates the TGF-β1-mediated metabolic shift towards aerobic glycolysis. Additionally, we demonstrate that LDH5 inhibition has no significant effect on TGF-β1-mediated FMT in primary human lung fibroblasts by analysing α-SMA fibre formation and fibronectin expression. Conclusions Our data strongly suggest that while LDH5 inhibition can prevent metabolic shifts in fibroblasts, it has no influence on FMT and therefore glycolytic dysregulation is unlikely to be the sole driver of FMT. Electronic supplementary material The online version of this article (10.1186/s12931-019-1058-2) contains supplementary material, which is available to authorized users.

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“…Upregulation of COL3A1 is frequently correlated with the fibrotic phenotype of the prostate and an active TGF-β1 signaling pathway [ 9 , 10 , 11 ]. Moreover, downregulation of COL3A1, using anti-fibrotic agents, has been correlated with the attenuation of the fibrotic phenotype in different organs [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Therefore, COL3A1 could potentially serve as marker for the fibrotic phenotype in the tissues and organs of the pelvis exposed to radiation.…”

Section: Introductionmentioning

confidence: 99%

The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues

et al. 2017

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Pelvic radiation for cancer therapy can damage a variety of normal tissues. In this study, we demonstrate that radiation causes acute changes to pelvic fibroblasts such as the transformation to myofibroblasts and the induction of senescence, which persist months after radiation. The addition of the manganese porphyrin, MnTE-2-PyP, resulted in protection of these acute changes in fibroblasts and this protection persisted months following radiation exposure. Specifically, at two months post-radiation, MnTE-2-PyP inhibited the number of α-smooth muscle actin positive fibroblasts induced by radiation and at six months post-radiation, MnTE-2-PyP significantly reduced collagen deposition (fibrosis) in the skin and bladder tissues of irradiated mice. Radiation also resulted in changes to T cells. At two months post-radiation, there was a reduction of Th1-producing splenocytes, which resulted in reduced Th1:Th2 ratios. MnTE-2-PyP maintained Th1:Th2 ratios similar to unirradiated mice. At six months post-radiation, increased T cells were observed in the adipose tissues. MnTE-2-PyP treatment inhibited this increase. Thus, MnTE-2-PyP treatment maintains normal fibroblast function and T cell immunity months after radiation exposure. We believe that one of the reasons MnTE-2-PyP is a potent radioprotector is due to its protection of multiple cell types from radiation damage.

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Olodaterol shows anti‐fibrotic efficacy in in vitro and in vivo models of pulmonary fibrosis

Cited by 16 publications

References 51 publications

miR-1224-5p Mediates Mitochondrial Damage to Affect Silica-Induced Pulmonary Fibrosis by Targeting BECN1

miR-1224-5p Mediates Mitochondrial Damage to Affect Silica-Induced Pulmonary Fibrosis by Targeting BECN1

Human lung fibroblast-to-myofibroblast transformation is not driven by an LDH5-dependent metabolic shift towards aerobic glycolysis

The SOD Mimic, MnTE-2-PyP, Protects from Chronic Fibrosis and Inflammation in Irradiated Normal Pelvic Tissues

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