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
Abbreviations:
SPMs (Specialized pro-resolving lipid mediators), RvD1 (Resolvin D1), MaR1 (Maresin 1), FPR2 (Formyl peptide receptor 2), LGR6 (Leucine-rich repeat containing G-protein coupled receptor 6.)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: December 21, 2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 International Society for Heart and Lung Transplantation. All rights reserved.
