title: Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury.
abstract: Outcomes for lung transplantation are the worst of any solid organ, and ischemia-reperfusion injury (IRI) limits both short- and long-term outcomes. Presently no therapeutic agents are available to prevent IRI. Sphingosine 1-phosphate (S1P) modulates immune function through binding to a set of G protein-coupled receptors (S1PR1-5). Although S1P has been shown to attenuate lung IRI, the S1P receptors responsible for protection have not been defined. The present study tests the hypothesis that protection from lung IRI is primarily mediated through S1PR1 activation. Mice were treated with either vehicle, FTY720 (a nonselective S1P receptor agonist), or VPC01091 (a selective S1PR1 agonist and S1PR3 antagonist) before left lung IR. Function, vascular permeability, cytokine expression, neutrophil infiltration, and myeloperoxidase levels were measured in lungs. After IR, both FTY720 and VPC01091 significantly improved lung function (reduced pulmonary artery pressure and increased pulmonary compliance) vs. vehicle control. In addition, FTY720 and VPC01091 significantly reduced vascular permeability, expression of proinflammatory cytokines (IL-6, IL-17, IL-12/IL-23 p40, CC chemokine ligand-2, and TNF-α), myeloperoxidase levels, and neutrophil infiltration compared with control. No significant differences were observed between VPC01091 and FTY720 treatment groups. VPC01091 did not significantly affect elevated invariant natural killer T cell infiltration after IR, and administration of an S1PR1 antagonist reversed VPC01091-mediated protection after IR. In conclusion, VPC01091 and FTY720 provide comparable protection from lung injury and dysfunction after IR. These findings suggest that S1P-mediated protection from IRI is mediated by S1PR1 activation, independent of S1PR3, and that selective S1PR1 agonists may provide a novel therapeutic strategy to prevent lung IRI.
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Stone
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Ashish K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Charles
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Huerter
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia; and.
authors.forename: William F
authors.initials: WF
authors.lastname: Johnston
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia; and.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Lynch
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia; and laubach@virginia.edu.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Laubach
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D003517:Cyclopentanes / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000494:pharmacology; D055370:Lung Injury / Q000517:prevention & control*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011409:Propylene Glycols / Q000494:pharmacology*; D049349:Receptors, Lysosphingolipid / Q000819:agonists* / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: D003517:Cyclopentanes; D016207:Cytokines; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C579735:rac-((1R*,3S*)-1-amino-3-(4-octylphenyl)cyclopentyl)methanol hydrochloride; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: barrier function; inflammation; invariant natural killer T cells; lung transplantation; primary graft dysfunction