Resolution of post-lung transplant ischemia-reperfusion injury is modulated via Resolvin D1-FPR2 and Maresin 1-LGR6 signaling

J Heart Lung Transplant. 2023 May;42(5):562-574. doi: 10.1016/j.healun.2022.12.013. Epub 2022 Dec 21.

Abstract

Background: Dysregulation of inflammation-resolution pathways leads to postlung transplant (LTx) ischemia-reperfusion (IR) injury and allograft dysfunction. Our hypothesis is that combined treatment with specialized pro-resolving lipid mediators, that is, Resolvin D1 (RvD1) and Maresin-1 (MaR1), enhances inflammation-resolution of lung IR injury.

Methods: Expression of RvD1 and MaR1 was analyzed in bronchoalveolar lavage (BAL) fluid of patients on days 0, 1, and 7 post-LTx. Lung IR injury was evaluated in C57BL/6 (WT), FPR2-/-, and LGR6 siRNA treated mice using a hilar-ligation model with or without administration with RvD1 and/or MaR1. A donation after circulatory death and murine orthotopic lung transplantation model was used to evaluate the protection by RvD1 and MaR1 against lung IR injury. In vitro studies analyzed alveolar macrophages and type II epithelial cell activation after treatment with RvD1 or MaR1.

Results: RvD1 and MaR1 expressions in BAL from post-LTx patients was significantly increased on day 7 compared to days 0 and 1. Concomitant RvD1 and MaR1 treatment significantly mitigated early pulmonary inflammation and lung IR injury in WT mice, which was regulated via FPR2 and LGR6 receptors. In the murine orthotopic donation after cardiac death LTx model, RvD1 and MaR1 treatments significantly attenuated lung IR injury and increased PaO2 levels compared to saline-treated controls. Mechanistically, RvD1/FPR2 signaling on alveolar macrophages attenuated HMGB1 and TNF-α secretion and upregulated uptake of macrophage-dependent apoptotic neutrophils (efferocytosis), whereas MaR1/LGR6 signaling mitigated CXCL1 secretion by epithelial cells.

Conclusions: Bioactive proresolving lipid mediator-dependent signaling that is, RvD1/FPR2 and MaR1/LGR6- offers a novel therapeutic strategy in post-LTx injury.

Keywords: efferocytosis; inflammation-resolution; ischemia-reperfusion injury; lung transplantation; maresin 1; resolvin D1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Alveolar Epithelial Cells / drug effects
  • Animals
  • Bronchoalveolar Lavage Fluid / chemistry
  • Docosahexaenoic Acids* / analysis
  • Docosahexaenoic Acids* / pharmacology
  • Docosahexaenoic Acids* / therapeutic use
  • Inflammation / drug therapy
  • Inflammation / etiology
  • Inflammation / genetics
  • Inflammation / metabolism
  • Lung Diseases* / drug therapy
  • Lung Diseases* / etiology
  • Lung Diseases* / metabolism
  • Lung Diseases* / surgery
  • Lung Transplantation* / adverse effects
  • Macrophages, Alveolar / drug effects
  • Mice
  • Mice, Inbred C57BL
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Reperfusion Injury* / drug therapy
  • Reperfusion Injury* / etiology
  • Reperfusion Injury* / genetics
  • Reperfusion Injury* / metabolism

Substances

  • 7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid
  • Docosahexaenoic Acids
  • formyl peptide receptor 2, mouse
  • Lgr6 protein, mouse
  • Receptors, G-Protein-Coupled
  • resolvin D1
  • RNA, Small Interfering