Evidence map›Paper›PMID 32736525›Full record

ArticleMolecular medicine (Cambridge, Mass.)2020

FK506 induces lung lymphatic endothelial cell senescence and downregulates LYVE-1 expression, with associated decreased hyaluronan uptake.

Shikshya Shrestha, Woohyun Cho, Benjamin Stump, Jewel Imani, Anthony M Lamattina, Pierce H Louis, James Pazzanese, Ivan O Rosas, Gary Visner, Mark A Perrella and 1 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular medicine (Cambridge, Mass.), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.3field-weighted citation impact, top 39% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 9 citations in OpenAlex.

  1. Article
  2. Review
  3. Review
  4. Modeling lymphangiogenesis: Pairing in vitro and in vivo metrics.Microcirculation (New York, N.Y. : 1994) · 2023
    Review
  5. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 2 institutions in 2 countries.

Shikshya ShresthaDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Woohyun ChoDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Benjamin StumpDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Jewel ImaniDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Anthony M LamattinaDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Pierce H LouisDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
James PazzaneseDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Ivan O RosasDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Gary VisnerDeparmtent of Pediatrics, Boston Children Hospital, Harvard Medical School, Boston, MA, USA.
Mark A PerrellaDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Souheil El-ChemalyDivision of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. Sel-chemaly@bwh.harvard.edu.ORCID 0000-0003-2929-5589
Brigham and Women's Hospital · USBoston Children's Hospital · US

Funding

RESPIRATORY RESEARCHT32HL007633 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI George R Washko · 1985 to 2026
$14.9M
Lymphatics and Lung Allograft RejectionR01HL130275 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI EL-CHEMALY, SOUHEIL · 2016 to 2020
$2.2M
Glycogen Synthase Kinase (GSK)-3b inhibition Mediates Lymphangiogenesis to Ameliorate Experimental Fibrosis.F32HL140859 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI STUMP, BENJAMIN · 2018 to 2018
$52k
NHLBI NIH HHS F32 HL140859NHLBI NIH HHS R01 HL130275NHLBI NIH HHS T32 HL007633
6 · The paper itself

Abstract

backgroundTherapeutic lymphangiogenesis in an orthotopic lung transplant model has been shown to improve acute allograft rejection that is mediated at least in part through hyaluronan drainage. Lymphatic vessel endothelial hyaluronan receptor (LYVE-1) expressed on the surface of lymphatic endothelial cells plays important roles in hyaluronan uptake. The impact of current immunosuppressive therapies on lung lymphatic endothelial cells is largely unknown. We tested the hypothesis that FK506, the most commonly used immunosuppressant after lung transplantation, induces lung lymphatic endothelial cell dysfunction.

methodsLung lymphatic endothelial cells were cultured in vitro and treated with FK506. Telomerase activity was measured using the TRAP assay. Protein expression of LYVE-1 and senescence markers p21 and β-galactosidase was assessed with western blotting. Matrigel tubulation assay were used to investigate the effects of FK506 on TNF-α-induced lymphangiogenesis. Dual luciferase reporter assay was used to confirm NFAT-dependent transcriptional regulation of LYVE-1. Flow cytometry was used to examine the effects of FK506 on LYVE-1 in precision-cut-lung-slices ex vivo and on hyaluronan uptake in vitro.

resultsIn vitro, FK506 downregulated telomerase reverse transcriptase expression, resulting in decreased telomerase activity and subsequent induction of p21 expression and cell senescence. Treatment with FK506 decreased LYVE-1 mRNA and protein levels and resulted in decreased LEC HA uptake. Similar result showing reduction of LYVE-1 expression when treated with FK506 was observed ex vivo. We identified a putative NFAT binding site on the LYVE-1 promoter and cloned this region of the promoter in a luciferase-based reporter construct. We showed that this NFAT binding site regulates LYVE-1 transcription, and mutation of this binding site blunted FK506-dependent downregulation of LYVE-1 promoter-dependent transcription. Finally, FK506-treated lymphatic endothelial cells show a blunted response to TNF-α-mediated lymphangiogenesis.

conclusionFK506 alters lymphatic endothelial cell molecular characteristics and causes lymphatic endothelial cell dysfunction in vitro and ex vivo. These effects of FK506 on lymphatic endothelial cell may impair the ability of the transplanted lung to drain hyaluronan macromolecules in vivo. The implications of our findings on the long-term health of lung allografts merit more investigation.

Indexed as

AnimalsBiological TransportCells, CulturedCellular SenescenceEndothelial CellsGene Expression RegulationHumansHyaluronic AcidLymphangiogenesisMiceNFATC Transcription FactorsProtein BindingTacrolimusTelomeraseVesicular Transport ProteinsHyaluronic AcidLYVE1 protein, humanNFATC Transcription FactorsTacrolimusTelomeraseTERT protein, humanVesicular Transport ProteinsEndothelial cellsFk506HyaluronanLung lymphaticLYVE-1SenescenceTERT

Identifiers

PMID32736525
PMCPMC7395348
OpenAlexW3046336923

What OpenQuestion holds

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LicenceCC BY
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.