New therapeutic concepts against ischemia-reperfusion injury in organ transplantation - PubMed (original) (raw)

Review

New therapeutic concepts against ischemia-reperfusion injury in organ transplantation

Kenneth J Dery et al. Expert Rev Clin Immunol. 2023 Jul-Dec.

Abstract

Introduction: Ischemia-reperfusion injury (IRI) involves a positive amplification feedback loop that stimulates innate immune-driven tissue damage associated with organ procurement from deceased donors and during transplantation surgery. As our appreciation of its basic immune mechanisms has improved in recent years, translating putative biomarkers into therapeutic interventions in clinical transplantation remains challenging.

Areas covered: This review presents advances in translational/clinical studies targeting immune responses to reactive oxygen species in IRI-stressed solid organ transplants, especially livers. Here we focus on novel concepts to rejuvenate suboptimal donor organs and improve transplant function using pharmacologic and machine perfusion (MP) strategies. Cellular damage induced by cold ischemia/warm reperfusion and the latest mechanistic insights into the microenvironment's role that leads to reperfusion-induced sterile inflammation is critically discussed.

Expert opinion: Efforts to improve clinical outcomes and increase the donor organ pool will depend on improving donor management and our better appreciation of the complex mechanisms encompassing organ IRI that govern the innate-adaptive immune interface triggered in the peritransplant period and subsequent allo-Ag challenge. Computational techniques and deep machine learning incorporating the vast cellular and molecular mechanisms will predict which peri-transplant signals and immune interactions are essential for improving access to the long-term function of life-saving transplants.

Keywords: CEACAM1; NETs; TLR; inflammation; ischemia-reperfusion injury; machine perfusion; organ transplantation; oxygen stress.

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Conflict of interest statement

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Figures

Figure 1:

Ischemia-reperfusion injury (IRI) is a classic positive feedback loop that leads to an amplified cascade response in liver transplant patients. It is characterized by three phases that involve the interplay between necrotic tissue damage and alternations in the microcirculatory environment. Phase 1 involves parenchymal cell death resulting from ischemic stress that stimulates danger molecules, such as HMGB1 and DNA fragments. Phase 2 consists of the activation of PMNs by cytokine/chemokines such as IL-23, MCP1, TNFα, and IL-8. Phase 3 is characterized by the activation of host innate and adaptive immune cells, like inflammatory cytokine IL-23, which causes gd T cells to secrete IL-17A, recruiting the circulating monocytes and neutrophils to the expanding inflammatory milieu that causes more parenchymal damage, Phase 1 (large black arrow, right-side panel). Extrapolated from studies in liver and renal injury models [113,200]. Adapted from [13] with copyright permission to reuse and created using

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Figure 2.

Warm but not cold ischemic stress of cytokine-stimulated primary-derived hepatocytes causes the up-regulation of HO-1 by HuR protein. (A) Representative immunohistochemical detection of hepatocyte HuR and HO-1 after 12 hours of CM conditioning (n = 3/group; original magnification, ×40). Act, actin; Dapi, 4′,6-diamidino-2-phenylindole. Primary-derived hepatocytes were cultured in serum-free medium incubated under acute (1.5 hours) (B) warm or (C) cold hypoxia conditions followed by standard normoxia incubation for the indicated times. Total lysates were probed by western blot for differences between HO-1, HuR, HIF-1α, BMP4, Bcl-xL, and β-Act, as a loading control. Bottom: data below figures show unpaired two-tailed Student _t_-test of representative samples showing HIF-1α, HO-1, and HuR calculated relative to β-Act expression. Data shown are mean ± SEM, n = 2 (repeated at least three times). Adapted from [87], with permission for copyright from John Wiley & Sons Ltd.

Figure 3.

Newly discovered signaling pathway modifiers associated with tissue IRI in organ transplantation. TLR4/NF-kB signaling pathway in macrophages can be activated by various ligands, including DAMPs and others, resulting in the activation of neutrophils, leading to inflammatory cytokine release and tissue damage. Recent studies revealed that many modalities, such as carvedilol, salidroside, propionic acid, thrombomodulin, CD47mAb, TIP1, rAIM, and liraglutide, could potentially block this pathway. TIP1 may also decrease Th17 cells and increase Tregs. IL-1R8 may drive macrophage polarization toward the “cytoprotective” M2 phenotype. As for T-cells, anti-CD4 mAb could mitigate neutrophil/macrophage infiltration and proinflammatory gene expression programs. While NK cell involvement in organ IRI is known to be IL-15 signaling-dependent, no specific inhibitor has been reported.

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New therapeutic concepts against ischemia-reperfusion injury in organ transplantation - PubMed (original) (raw)