PMID- 32192225
OWN - NLM
STAT- MEDLINE
DCOM- 20201204
LR  - 20211204
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 6
DP  - 2020 Mar 17
TI  - Sphingosine Kinase 1/S1P Signaling Contributes to Pulmonary Fibrosis by 
      Activating Hippo/YAP Pathway and Mitochondrial Reactive Oxygen Species in Lung 
      Fibroblasts.
LID - 10.3390/ijms21062064 [doi]
LID - 2064
AB  - 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-beta 
      stimulated YAP1 translocation to the nucleus in primary MLFs, and the deletion of 
      Sphk1 or inhibition with PF543 attenuated TGF-beta-mediated YAP1 nuclear 
      localization. Moreover, the PF543 inhibition of SPHK1, or the verteporfin 
      inhibition of YAP1, decreased the TGF-beta- or BLM-induced mitochondrial reactive 
      oxygen species (mtROS) in human lung fibroblasts (HLFs) and the expression of 
      fibronectin (FN) and alpha-smooth muscle actin (alpha-SMA). Furthermore, scavenging 
      mtROS with MitoTEMPO attenuated the TGF-beta-induced expression of FN and alpha-SMA. The 
      addition of the S1P antibody to HLFs reduced TGF-beta- or S1P-mediated YAP1 
      activation, mtROS, and the expression of FN and alpha-SMA. These results suggest a 
      role for SPHK1/S1P signaling in TGF-beta-induced YAP1 activation and mtROS 
      generation, resulting in fibroblast activation, a critical driver of pulmonary 
      fibrosis.
FAU - Huang, Long Shuang
AU  - Huang LS
AD  - Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL 
      60612, USA.
FAU - Sudhadevi, Tara
AU  - Sudhadevi T
AD  - Departments of Pediatrics, University of Illinois at Chicago, Chicago, IL 60612, 
      USA.
FAU - Fu, Panfeng
AU  - Fu P
AD  - Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL 
      60612, USA.
FAU - Punathil-Kannan, Prasanth-Kumar
AU  - Punathil-Kannan PK
AD  - Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL 
      60612, USA.
FAU - Ebenezer, David Lenin
AU  - Ebenezer DL
AD  - Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL 
      60612, USA.
FAU - Ramchandran, Ramaswamy
AU  - Ramchandran R
AD  - Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL 
      60612, USA.
FAU - Putherickal, Vijay
AU  - Putherickal V
AD  - Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL 
      60612, USA.
FAU - Cheresh, Paul
AU  - Cheresh P
AD  - Department of Medicine, Division of Pulmonary & Critical care Medicine, Jesse 
      Brown VA Medical Center, Chicago, IL 60612, USA.
AD  - Department of Medicine, Northwestern University Feinberg School of Medicine, 
      Chicago, IL 60611, USA.
FAU - Zhou, Guofei
AU  - Zhou G
AD  - Departments of Pediatrics, University of Illinois at Chicago, Chicago, IL 60612, 
      USA.
FAU - Ha, Alison W
AU  - Ha AW
AD  - Departments of Biochemistry and Molecular genetics, University of Illinois at 
      Chicago, Chicago, IL 60612, USA.
FAU - Harijith, Anantha
AU  - Harijith A
AD  - Departments of Pediatrics, University of Illinois at Chicago, Chicago, IL 60612, 
      USA.
FAU - Kamp, David W
AU  - Kamp DW
AD  - Department of Medicine, Division of Pulmonary & Critical care Medicine, Jesse 
      Brown VA Medical Center, Chicago, IL 60612, USA.
AD  - Department of Medicine, Northwestern University Feinberg School of Medicine, 
      Chicago, IL 60611, USA.
FAU - Natarajan, Viswanathan
AU  - Natarajan V
AUID- ORCID: 0000-0002-5132-8212
AD  - Departments of Pharmacology, University of Illinois at Chicago, Chicago, IL 
      60612, USA.
AD  - Departments of Medicine, University of Illinois at Chicago, Chicago, IL 60612, 
      USA.
LA  - eng
GR  - P01 HL060678/HL/NHLBI NIH HHS/United States
GR  - P01 HL126609/HL/NHLBI NIH HHS/United States
GR  - T32 HL007829/HL/NHLBI NIH HHS/United States
GR  - P01 077806, P01 126609, R01 127342, HD 090887/National Institutes of Health, 
      HLBI/
PT  - Journal Article
DEP - 20200317
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Cell Cycle Proteins)
RN  - 0 (Fibronectins)
RN  - 0 (Lysophospholipids)
RN  - 0 (PF-543)
RN  - 0 (Pyrrolidines)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sulfones)
RN  - 0 (Transcription Factors)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (YAP-Signaling Proteins)
RN  - 0 (YAP1 protein, human)
RN  - 0 (YY1AP1 protein, human)
RN  - 11056-06-7 (Bleomycin)
RN  - 26993-30-6 (sphingosine 1-phosphate)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - NGZ37HRE42 (Sphingosine)
RN  - Y4S76JWI15 (Methanol)
SB  - IM
MH  - Active Transport, Cell Nucleus
MH  - Adaptor Proteins, Signal Transducing
MH  - Alveolar Epithelial Cells/metabolism
MH  - Animals
MH  - Bleomycin/adverse effects
MH  - Cell Cycle Proteins/*metabolism
MH  - Fibroblasts/metabolism
MH  - Fibronectins/genetics/metabolism
MH  - Gene Deletion
MH  - Gene Expression
MH  - Hippo Signaling Pathway
MH  - Humans
MH  - Idiopathic Pulmonary Fibrosis/etiology/*metabolism
MH  - Immunohistochemistry
MH  - Lysophospholipids/*metabolism
MH  - Methanol/analogs & derivatives/pharmacology
MH  - Mice
MH  - Mitochondria/*metabolism
MH  - Phosphotransferases (Alcohol Group Acceptor)/antagonists & 
      inhibitors/genetics/*metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Pyrrolidines/pharmacology
MH  - Reactive Oxygen Species/*metabolism
MH  - *Signal Transduction
MH  - Sphingosine/*analogs & derivatives/metabolism
MH  - Sulfones
MH  - Transcription Factors/*metabolism
MH  - Transforming Growth Factor beta1/metabolism
MH  - YAP-Signaling Proteins
PMC - PMC7139883
OTO - NOTNLM
OT  - BLM
OT  - S1P
OT  - SPHK1
OT  - TGF-beta
OT  - YAP signaling
OT  - lung fibroblast
OT  - pulmonary fibrosis
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2020/03/21 06:00
MHDA- 2020/12/15 06:00
PMCR- 2020/03/01
CRDT- 2020/03/21 06:00
PHST- 2020/01/29 00:00 [received]
PHST- 2020/03/12 00:00 [revised]
PHST- 2020/03/13 00:00 [accepted]
PHST- 2020/03/21 06:00 [entrez]
PHST- 2020/03/21 06:00 [pubmed]
PHST- 2020/12/15 06:00 [medline]
PHST- 2020/03/01 00:00 [pmc-release]
AID - ijms21062064 [pii]
AID - ijms-21-02064 [pii]
AID - 10.3390/ijms21062064 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Mar 17;21(6):2064. doi: 10.3390/ijms21062064.