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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Ischemia and reperfusion—from mechanism to translation

Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds. These factors may induce acute and/or chronic inflammatory responses in the heart, pancreas, liver, kidney, lung, brain, intestinal tract and reproductive system, potentially leading to tissue damage or disease. Both infectious and non-infectious agents and cell damage activate inflammatory cells and trigger inflammatory signaling pathways, most commonly the NF-κB, MAPK, and JAK-STAT pathways. Here, we review inflammatory responses within organs, focusing on the etiology of inflammation, inflammatory response mechanisms, resolution of inflammation, and organ-specific inflammatory responses.

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Inflammatory responses and inflammation-associated diseases in organs

Acute myocardial infarction (MI) is a major cause of death and disability worldwide. In patients with MI, the treatment of choice for reducing acute myocardial ischemic injury and limiting MI size is timely and effective myocardial reperfusion using either thombolytic therapy or primary percutaneous coronary intervention (PPCI). However, the process of reperfusion can itself induce cardiomyocyte death, known as myocardial reperfusion injury, for which there is still no effective therapy. A number of new therapeutic strategies currently under investigation for preventing myocardial reperfusion injury have the potential to improve clinical outcomes in patients with acute MI treated with PPCI.

https://dm5migu4zj3pb.cloudfront.net/manuscripts/62000/62874/JCI62874.v1.pdf

Myocardial ischemia-reperfusion injury: a neglected therapeutic target

Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.

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Cell Biology of Ischemia/Reperfusion Injury

Mitochondria play an important role in cell death and cardioprotection. During ischemia, when ATP is progressively depleted, ion pumps cannot function resulting in a rise in calcium (Ca2+), which f...

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Mechanisms Underlying Acute Protection From Cardiac Ischemia-Reperfusion Injury

Over the past 2 to 3 decades, several phenomena have been identified that provide powerful protection against myocardial infarction and other sequelae of ischemia/reperfusion1: myocardial hibernation that is related to stunning,2 ischemic preconditioning,3 delayed or second-window ischemic preconditioning,4 ischemic postconditioning,5 and their pharmacological recruitment. Stunning and hibernation share contractile function as an end point. In stunning, reduced postischemic contractile function is viewed as reversible injury, whereas in hibernation dysfunction is viewed as an adaptive response. Ischemic preconditioning is characterized by infarct size reduction as its most robust end point but shares with hibernation the underlying idea of a regulated protective response. These phenomena have been confirmed in patients with coronary artery disease.2,6–8 Nitric oxide (NO) and mitochondria also are important in patients with coronary artery disease. Nitroglycerin induces delayed protection against periinterventional ischemic ECG alterations, contractile dysfunction, and pain sensation,7 and cyclosporin A, which inhibits opening of the mitochondrial permeability transition pore (MPTP), attenuates reperfusion injury in patients with acute myocardial infarction.9

Articles pp 1961 and 1970 

The “new ischemic syndromes” have intrigued scientists and clinicians trying to understand their underlying pathophysiology and to recruit their cardioprotective potential. This initial enthusiasm has not materialized into translational medicine.10 Why is that? There has been a long but ultimately fruitless debate as to whether the phenotype of hibernating myocardium is the result of ongoing ischemia with reduced baseline coronary blood flow or repetitive cycles of ischemia/reperfusion and consequent stunning without reduced baseline flow. Clearly, perfusion-contraction matching cannot be maintained for >12 hours. Conversely, repetitive cycles of ischemia/reperfusion with subsequent stunning finally result in hibernating myocardium with reduced contractile function and baseline blood flow.2 Thus, the cumulative effect of stunning is a progression to hibernation. True stunning, if seen at all, is …

Cardioprotection Nitric Oxide, Protein Kinases, and Mitochondria

Extracellular ATP liberated during hypoxia and inflammation can either signal directly on purinergic receptors or can activate adenosine receptors following phosphohydrolysis to adenosine. Given the association of polymorphonuclear leukocytes (PMNs) with adenine-nucleotide/nucleoside signaling in the inflammatory milieu, we hypothesized that PMNs are a source of extracellular ATP. Initial studies using high-performance liquid chromatography and luminometric ATP detection assays revealed that PMNs release ATP through activation-dependent pathways. In vitro models of endothelial barrier function and neutrophil/endothelial adhesion indicated that PMN-derived ATP signals through endothelial adenosine receptors, thereby promoting endothelial barrier function and attenuating PMN/endothelial adhesion. Metabolism of extracellular ATP to adenosine required PMNs, and studies addressing these metabolic steps revealed that PMN express surface ecto-apyrase (CD39). In fact, studies with PMNs derived from cd39(-/-) mice showed significantly increased levels of extracellular ATP and lack of ATP dissipation from their supernatants. After excluding lytic ATP release, we used pharmacological strategies to reveal a potential mechanism involved in PMN-dependent ATP release (eg, verapamil, dipyridamole, brefeldin A, 18-alpha-glycyrrhetinic acid, connexin-mimetic peptides). These studies showed that PMN ATP release occurs through connexin 43 (Cx43) hemichannels in a protein/phosphatase-A-dependent manner. Findings in human PMNs were confirmed in PMNs derived from induced Cx43(-/-) mice, whereby activated PMNs release less than 15% of ATP relative to littermate controls, whereas Cx43 heterozygote PMNs were intermediate in their capacity for ATP release (P<0.01). Taken together, our results identify a previously unappreciated role for Cx43 in activated PMN ATP release, therein contributing to the innate metabolic control of the inflammatory milieu.

ATP Release From Activated Neutrophils Occurs via Connexin 43 and Modulates Adenosine-Dependent Endothelial Cell Function

The myocardial JAK/STAT pathway: from protection to failure.

The signal transducer and activator of transcription 3 (STAT3) contributes to cardioprotection by ischemic pre- and postconditioning. Mitochondria are central elements of cardioprotective signaling, most likely by delaying mitochondrial permeability transition pore (MPTP) opening, and STAT3 has recently been identified in mitochondria. We now characterized the mitochondrial localization of STAT3 and its impact on respiration and MPTP opening. STAT3 was mainly present in the matrix of subsarcolemmal and interfibrillar cardiomyocyte mitochondria. STAT1, but not STAT5 was also detected in mitochondria under physiological conditions. ADP-stimulated respiration was reduced in mitochondria from mice with a cardiomyocyte-specific deletion of STAT3 (STAT3-KO) versus wildtypes and in rat mitochondria treated with the STAT3 inhibitor Stattic (STAT3 inhibitory compound, 6-Nitrobenzo[b]thiophene 1,1-dioxide). Mitochondria from STAT3-KO mice and Stattic-treated rat mitochondria tolerated less calcium until MPTP opening occurred. STAT3 co-immunoprecipitated with cyclophilin D, the target of the cardioprotective agent and MPTP inhibitor cyclosporine A (CsA). However, CsA reduced infarct size to a similar extent in wildtype and STAT3-KO mice in vivo. Thus, STAT3 possibly contributes to cardioprotection by stimulation of respiration and inhibition of MPTP opening.

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Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion

Not only the prevalence, but also the mortality due to ischaemic cardiovascular disease is higher in older than in young humans, and the demographic shift towards an ageing population will further increase the prevalence of age-related cardiovascular disease. In order to develop strategies aimed to limit reversible and irreversible myocardial damage in older patients, there is a need to better understand age-induced alterations in protein expression and cell signalling. Cardioprotective phenomena such as ischaemic and pharmacological pre and postconditioning attenuate ischaemia/reperfusion injury in young hearts. Whether or not pre and postconditioning are still effective in aged organs, animals, or patients, i.e. under conditions where such cardioprotection is most relevant, is still a matter of debate; most studies suggest a loss of protection in aged hearts. The present review discusses changes in protein expression and cell signalling important to ischaemia/reperfusion injury with myocardial ageing. The efficacy of cardioprotective manoeuvres, e.g. ischaemic pre and postconditioning in aged organs and animals will be discussed, and the development of strategies aimed to antagonize the age-induced loss of protection will be addressed.

Kerstin Boengler

Papers

Cardioprotection Nitric Oxide, Protein Kinases, and Mitochondria

ATP Release From Activated Neutrophils Occurs via Connexin 43 and Modulates Adenosine-Dependent Endothelial Cell Function

The myocardial JAK/STAT pathway: from protection to failure.

Inhibition of permeability transition pore opening by mitochondrial STAT3 and its role in myocardial ischemia/reperfusion

Loss of cardioprotection with ageing.