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Review
. 2011 Nov 7;17(11):1391-401.
doi: 10.1038/nm.2507.

Ischemia and reperfusion--from mechanism to translation

Holger K Eltzschig  1 , Tobias Eckle
Affiliations
Review

Ischemia and reperfusion--from mechanism to translation

Holger K Eltzschig et al. Nat Med. .

Abstract

Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality in a wide range of pathologies, including myocardial infarction, ischemic stroke, acute kidney injury, trauma, circulatory arrest, sickle cell disease and sleep apnea. Ischemia-reperfusion injury is also a major challenge during organ transplantation and cardiothoracic, vascular and general surgery. An imbalance in metabolic supply and demand within the ischemic organ results in profound tissue hypoxia and microvascular dysfunction. Subsequent reperfusion further enhances the activation of innate and adaptive immune responses and cell death programs. Recent advances in understanding the molecular and immunological consequences of ischemia and reperfusion may lead to innovative therapeutic strategies for treating patients with ischemia and reperfusion-associated tissue inflammation and organ dysfunction.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Biological processes implicated in ischemia and reperfusion.
Figure 2
Figure 2
Injury and resolution during ischemia and reperfusion. (a) Ischemia and reperfusion is associated with a pathological activation of the immune system. Tissue hypoxia during the ischemic period results in TLR-dependent stabilization of the transcription factor NF-κB, leading to transcriptional activation of inflammatory gene programs. TLR4 expression can be increased by ROS and can be activated by endogenous ligands such as HMGB1. TLR3 can be activated by RNA released from necrotic cells. After reperfusion, granulocytes such as neutrophils adhere to the vasculature and infiltrate the tissue, and platelets can ‘piggyback’ on neutrophils. Activated platelets can interact with vascular endothelia at the site of injury; this interaction depends on a shift of platelet integrins from a low-affinity state to a high-affinity state (integrin activation or priming), which requires Kindlin-3. Activated platelets release inorganic polyphosphate that directly binds to and activates the plasma protease factor XII, contributing to proinflammatory and procoagulant activation during ischemia and reperfusion. CD4+, CD8+ and γδ T cells contribute to tissue injury; for example, by the release of IL-17 from γδ T cells. (b) Ischemia and reperfusion activates endogenous mechanisms of injury resolution. Tissue hypoxia results in the inhibition of oxygen-sensing PHD enzymes and stabilization of the HIF transcription factor, activating a wide range of transcriptional programs involved in injury resolution, including the production of extracellular adenosine that signals through receptors such as ADORA2B (A2B). In addition, hypoxia-elicited inhibition of PHDs results in NF-κB activation, which contributes to the resolution phase by preventing apoptosis. Regulatory T cells and dendritic cells are important sources of IL-10, which has a crucial role in dampening inflammation and attenuating reactive oxygen production. Splenic reservoir monocytes are recruited from the spleen to the site of tissue energy where they participate in wound healing. Breakdown products from fibrinogen, such as fibrin-derived peptide Bβ15–42, protect the myocardium from injury. NMHC-II, non-muscle myosin heavy chain type II; DC, dendritic cell; EC, endothelial cell; Poly P, polyphosphate; TF, tissue factor; VSMC, vascular smooth muscle cell.
Figure 3
Figure 3
Therapeutic gases for the treatment of ischemia and reperfusion. CO, NO and H2S are considered to be endogenous gas transmitters. The predominant pathway for endogenous CO production involves the conversion of the erythrocyte-derived porphyrin molecule heme to biliverdin by the action of heme oxygenase, liberating CO as a byproduct. CO has been implicated in attenuating inflammation and tissue injury through the stabilization of HIF. NO is produced predominantly from the endogenous metabolism of l-arginine to citrulline by NO synthase, which is expressed in multiple cell types, including vascular endothelia and neurons (not shown). Inhaled NO has been therapeutically used to attenuate hypoxic pulmonary vasoconstriction or to dampen apoptosis during ischemia and reperfusion. H2S is produced endogenously through the metabolism of l-cysteine by the action of either cystathionine β-synthase (CBS) (expressed predominantly in the brain, nervous system, liver and kidney) or cystathionine γ-lyase (CSE) (expressed predominantly in liver and in vascular and nonvascular smooth muscle). Therapeutic use of inhaled H2S has been shown to induce a suspended-animation–like state characterized by hypothermia and stable cardiovascular hemodynamics, and to have protective effects during ischemia and reperfusion. In contrast to endogenous gas transmitters, no biological pathway for the generation of H2 has been described in mammalian cell systems. Therapeutic use of inhaled H2 has been shown to attenuate ischemia and reperfusion–associated accumulation of ROS and to preserve mitochondrial function. EC, endothelial cell; VSMC, vascular smooth muscle cell.
Figure 4
Figure 4
Nucleotide and nucleoside signaling during ischemia and reperfusion. Multiple cell types release ATP during ischemia and reperfusion (for example, spillover from necrotic cells or controlled release through pannexin hemichannels from apoptotic cells or connexin hemichannels from activated inflammatory cells),,. Subsequent binding of ATP to P2 receptors enhances pathological inflammation and tissue injury, for example, through P2X7-dependent Nlrp3 inflammasome activation and P2Y6-dependent enhancement of vascular inflammation. ATP can be rapidly converted to adenosine through the ecto-apyrase CD39 (conversion of ATP to AMP) and subsequently by the ecto-5′ nucleotidase CD73 (conversion of AMP to adenosine). Adenosine signaling dampens sterile inflammation, enhances metabolic adaptation to limited oxygen availability and promotes the resolution of injury through activation of A2A adenosine receptors expressed on inflammatory cells and activation of A2B adenosine receptors expressed on tissue-resident cells (for example, cardiac myocytes, vascular endothelia or intestinal epithelia). EC, endothelial cell; VSMC, vascular smooth muscle cell.
Figure 5
Figure 5
MiRNA pathways implicated in myocardial ischemia and reperfusion. miR-92a (encoded by the miR-17-92a cluster) is highly expressed in vascular endothelia, and blocks ischemic angiogenesis by inhibition of proangiogenic proteins such as the α5 integrin (encoded by ITGA5). In contrast, miR-499 and miR-24 levels are repressed in cardiac tissue following ischemia and reperfusion. MiR-499 suppresses myocyte apoptosis by direct repression of calcineurin subunit synthesis, leading to decreased calcineurin-mediated dephosphorylation of DRP1, thereby interfering with DRP1-mediated activation of the pro-apoptotic mitochondrial fission program. MiR-24 inhibits myocyte apoptosis by direct repression of BIM synthesis. Accordingly, decreasing miR-92a levels (therapeutic inhibition) or increasing miR-499 or miR-24 levels (therapeutic enhancement) might have beneficial effects in the setting of myocardial ischemia and reperfusion. CN, calcineurin; EC, endothelial cell.
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