scholarly journals The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes

2020 ◽  
Vol 21 (16) ◽  
pp. 5595
Author(s):  
Paul Cheresh ◽  
Seok-Jo Kim ◽  
Long Shuang Huang ◽  
Satoshi Watanabe ◽  
Nikita Joshi ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Sphingosine Kinase ◽  
Lung Epithelial Cell ◽  
Lung Fibroblasts ◽  
Sphingosine Kinase 1 ◽  
Mtdna Damage ◽  
Lung Epithelial ◽  
Monocyte Recruitment

Idiopathic pulmonary fibrosis (IPF) is a chronic disease for which novel approaches are urgently required. We reported increased sphingosine kinase 1 (SPHK1) in IPF lungs and that SPHK1 inhibition using genetic and pharmacologic approaches reduces murine bleomycin-induced pulmonary fibrosis. We determined whether PF543, a specific SPHK1 inhibitor post bleomycin or asbestos challenge mitigates lung fibrosis by reducing mitochondrial (mt) DNA damage and pro-fibrotic monocyte recruitment—both are implicated in the pathobiology of pulmonary fibrosis. Bleomycin (1.5 U/kg), crocidolite asbestos (100 µg/50 µL) or controls was intratracheally instilled in Wild-Type (C57Bl6) mice. PF543 (1 mg/kg) or vehicle was intraperitoneally injected once every two days from day 7−21 following bleomycin and day 14−21 or day 30−60 following asbestos. PF543 reduced bleomycin- and asbestos-induced pulmonary fibrosis at both time points as well as lung expression of profibrotic markers, lung mtDNA damage, and fibrogenic monocyte recruitment. In contrast to human lung fibroblasts, asbestos augmented lung epithelial cell (MLE) mtDNA damage and PF543 was protective. Post-exposure PF543 mitigates pulmonary fibrosis in part by reducing lung epithelial cell mtDNA damage and monocyte recruitment. We reason that SPHK1 signaling may be an innovative therapeutic target for managing patients with IPF and other forms of lung fibrosis.

The Oncogene ECT2 Contributes to a Hyperplastic, Proliferative Lung Epithelial Cell Phenotype in Idiopathic Pulmonary Fibrosis

2019 ◽  
Vol 61 (6) ◽  
pp. 713-726 ◽  
Author(s):  
Henrik M. Ulke ◽  
Kathrin Mutze ◽  
Mareike Lehmann ◽  
Darcy E. Wagner ◽  
Katharina Heinzelmann ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Lung Epithelial Cell ◽  
Cell Phenotype ◽  
Lung Epithelial

ID: 116: ADNIBISTRATION OF SPHINGOSINE KINASE 1 INHIBITOR POST-BLEOMYCIN CHALLENGE ATTENUATES BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN MICE: ROLE OF YAP1

2016 ◽  
Vol 64 (4) ◽  
pp. 966.2-966
Author(s):  
L Huang ◽  
V Natarajan
Keyword(s):  
Pulmonary Fibrosis ◽  
Human Lung ◽  
Nuclear Translocation ◽  
Sphingosine Kinase ◽  
Lung Fibroblasts ◽  
Therapeutic Drug ◽  
Mrna Levels ◽  
Sphingosine Kinase 1 ◽  
Human Lung Fibroblast

RationaleWe have earlier reported that sphingosine kinase 1 (SphK1) is up-regulated in lung tissues from idiopathic pulmonary fibrosis (IPF) patients and SphK1/sphingosine-1-phosphate (S1P) signaling axis plays a key role in bleomycin- and radiation-induced pulmonary fibrosis in mice. Further, SphK1 mRNA levels in PBMCs from IPF patients directly and significantly correlated with pulmonary function outcomes and overall survival. In this study, we investigated the effect of administration of PF-543, a specific SphK1 inhibitor, 7 days post-bleomycin (BLM) challenge on the development of pulmonary fibrosis in mice.ObjectivesTo determine the efficacy of PF-543 in attenuating pulmonary fibrosis in mice post BLM challenge.MethodsSphK1 inhibitor PF-543 (5 mg/kg body weight, i.p.; twice a week) was administered to control and BLM (1.5 U/kg, intratracheal) challenged mice on day 7 post BLM challenge, and development of pulmonary fibrosis was determined on day 21 by Mason-Trichrome staining of lung tissues, total collagen, fibronectin and α-SMA protein levels in lung tissues. In vitro, the effect of PF-543 on TGF-β (5 ng/ml) induced Yap1 activation, and differentiation, contraction, and proliferation of human lung fibroblast were assessed.ResultsAdministration of PF-543 to BLM treated mice on day 7 post challenge, dramatically inhibited BLM-induced lung injury, and attenuated collagen deposition and expression of fibronectin, α-SMA and TGF-β in lung tissues on day 21 post-BLM challenge. In vitro, PF-543 inhibited TGF-β induced differentiation, contraction and proliferation of human lung fibroblasts, as well as blocked TGF-β induced expression and nuclear translocation of YAP, a transcriptional co-factor involved in pulmonary fibrosis. Additionally, siRNA knockdown of YAP1 inhibited TGF-β induced fibroblast differentiation.ConclusionThese studies demonstrate ability of SphK1 inhibitor, PF-543 to ameliorate BLM-induced pulmonary fibrosis in mice when administered on day 7 after BLM challenge. Also, PF-543 blocked YAP1 activation, a co-transcriptional factor involved in pulmonary fibrosis development. Thus, PF-543 may serve as a potential therapeutic drug in treating pulmonary fibrosis. This work was supported by P01 HL098050 (VN).

scholarly journals Mitochondrial 8-oxoguanine DNA glycosylase mitigates alveolar epithelial cell PINK1 deficiency, mitochondrial DNA damage, apoptosis, and lung fibrosis

2020 ◽  
Vol 318 (5) ◽  
pp. L1084-L1096 ◽  
Author(s):  
Seok-Jo Kim ◽  
Paul Cheresh ◽  
Renea P. Jablonski ◽  
Lyudmila Rachek ◽  
Anjana Yeldandi ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Excision Repair ◽  
Alveolar Epithelial Cell ◽  
Mitochondrial Protein ◽  
Dna Glycosylase ◽  
Alveolar Type ◽  
Mtdna Damage ◽  
Alveolar Epithelial

Alveolar epithelial cell (AEC) apoptosis, arising from mitochondrial dysfunction and mitophagy defects, is important in mediating idiopathic pulmonary fibrosis (IPF). Our group established a role for the mitochondrial (mt) DNA base excision repair enzyme, 8-oxoguanine-DNA glycosylase 1 (mtOGG1), in preventing oxidant-induced AEC mtDNA damage and apoptosis and showed that OGG1-deficient mice have increased lung fibrosis. Herein, we determined whether mice overexpressing the mtOGG1 transgene ( mtOgg1tg) are protected against lung fibrosis and whether AEC mtOGG1 preservation of mtDNA integrity mitigates phosphatase and tensin homolog-induced putative kinase 1 (PINK1) deficiency and apoptosis. Compared with wild type (WT), mtOgg1tg mice have diminished asbestos- and bleomycin-induced pulmonary fibrosis that was accompanied by reduced lung and AEC mtDNA damage and apoptosis. Asbestos and H2O2 promote the MLE-12 cell PINK1 deficiency, as assessed by reductions in the expression of PINK1 mRNA and mitochondrial protein expression. Compared with WT, Pink1-knockout ( Pink1-KO) mice are more susceptible to asbestos-induced lung fibrosis and have increased lung and alveolar type II (AT2) cell mtDNA damage and apoptosis. AT2 cells from Pink1-KO mice and PINK1-silenced (siRNA) MLE-12 cells have increased mtDNA damage that is augmented by oxidative stress. Interestingly, mtOGG1 overexpression attenuates oxidant-induced MLE-12 cell mtDNA damage and apoptosis despite PINK1 silencing. mtDNA damage is increased in the lungs of patients with IPF as compared with controls. Collectively, these findings suggest that mtOGG1 maintenance of AEC mtDNA is crucial for preventing PINK1 deficiency that promotes apoptosis and lung fibrosis. Given the key role of AEC apoptosis in pulmonary fibrosis, strategies aimed at preserving AT2 cell mtDNA integrity may be an innovative target.

scholarly journals Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung Fibroblasts

2020 ◽  
Vol 21 (6) ◽  
pp. 2064 ◽  
Author(s):  
Long Shuang Huang ◽  
Tara Sudhadevi ◽  
Panfeng Fu ◽  
Prasanth-Kumar Punathil-Kannan ◽  
David Lenin Ebenezer ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Pulmonary Fibrosis ◽  
Smooth Muscle Actin ◽  
Reactive Oxygen ◽  
Sphingosine Kinase ◽  
Lung Fibroblasts ◽  
Mouse Lung ◽  
Oxygen Species ◽  
Sphingosine Kinase 1 ◽  
Mitochondrial Reactive Oxygen Species

The sphingosine kinase 1 (SPHK1)/sphingosine–1–phosphate (S1P) signaling axis is emerging as a key player in the development of idiopathic pulmonary fibrosis (IPF) and bleomycin (BLM)-induced lung fibrosis in mice. Recent evidence implicates the involvement of the Hippo/Yes-associated protein (YAP) 1 pathway in lung diseases, including IPF, but its plausible link to the SPHK1/S1P signaling pathway is unclear. Herein, we demonstrate the increased co-localization of YAP1 with the fibroblast marker FSP1 in the lung fibroblasts of BLM-challenged mice, and the genetic deletion of Sphk1 in mouse lung fibroblasts (MLFs) reduced YAP1 localization in fibrotic foci. The PF543 inhibition of SPHK1 activity in mice attenuated YAP1 co-localization with FSP1 in lung fibroblasts. In vitro, TGF-β stimulated YAP1 translocation to the nucleus in primary MLFs, and the deletion of Sphk1 or inhibition with PF543 attenuated TGF-β-mediated YAP1 nuclear localization. Moreover, the PF543 inhibition of SPHK1, or the verteporfin inhibition of YAP1, decreased the TGF-β- or BLM-induced mitochondrial reactive oxygen species (mtROS) in human lung fibroblasts (HLFs) and the expression of fibronectin (FN) and alpha-smooth muscle actin (α-SMA). Furthermore, scavenging mtROS with MitoTEMPO attenuated the TGF-β-induced expression of FN and α-SMA. The addition of the S1P antibody to HLFs reduced TGF-β- or S1P-mediated YAP1 activation, mtROS, and the expression of FN and α-SMA. These results suggest a role for SPHK1/S1P signaling in TGF-β-induced YAP1 activation and mtROS generation, resulting in fibroblast activation, a critical driver of pulmonary fibrosis.

scholarly journals miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions

2017 ◽  
Vol 312 (3) ◽  
pp. L415-L424 ◽  
Author(s):  
Huachun Cui ◽  
Jing Ge ◽  
Na Xie ◽  
Sami Banerjee ◽  
Yong Zhou ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Critical Role ◽  
Lung Epithelial Cells ◽  
Lung Fibroblasts ◽  
Aged Population ◽  
Age Related ◽  
Micro Rnas ◽  
Lung Epithelial

Idiopathic pulmonary fibrosis is a well-known age-related disease. However, much less recognized has been the aging associated pathogenesis of this disorder. As we and others previously showed that dysregulation of micro-RNAs (miRNAs) was an important mechanism involved in pulmonary fibrosis, the role of these molecules in this pathology in the aged population has not been investigated (Cushing L, Kuang PP, Qian J, Shao F, Wu J, Little F, Thannickal VJ, Cardoso WV, Lü J. Am J Respir Cell Mol Biol 45: 287–294, 2011; Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, Kaminski N, Abraham E. J Exp Med 207: 1589–1597, 2010; Pandit KV, Corcoran D, Yousef H, Yarlagadda M, Tzouvelekis A, Gibson KF, Konishi K, Yousem SA, Singh M, Handley D, Richards T, Selman M, Watkins SC, Pardo A, Ben-Yehudah A, Bouros D, Eickelberg O, Ray P, Benos PV, Kaminski N. Am J Respir Crit Care Med 182: 220–229, 2010). In this study, by using a lung fibrosis model established in old mice, we found that ablation of miR-34a protected aged animals from developing experimental lung fibrosis. miR-34a was upregulated in lung epithelial cells, but not in lung fibroblasts of aged mice, and miR-34a expression was further increased in epithelial cells of the fibrotic lungs of these old animals. We found that miR-34a induced dysfunctions in alveolar epithelial cells (AECs), as evidenced by increased cellular senescence and apoptosis and mitochondrial aberrations. More importantly, these abnormalities were attenuated in AECs of the fibrotic lungs of aged miR-34a−/− mice. We found that miR-34a targeted Sirt1, a master anti-aging regulator, and two key cell cycle modulators, E2F3 and cyclin E2, in lung epithelial cells, and the repression of these targets was relieved in miR-34a-deficient AECs. In summary, our data suggest that elevated AEC miR-34a plays a critical role in the pathogenesis of pulmonary fibrosis in the aged population. Our study also indicates miR-34a to be a more precise miRNA target for treating this disease that overwhelmingly affects people of advanced age.

Sign in / Sign up

Export Citation Format

Share Document