Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury

Vinten‐Johansen, Jakob

doi:10.1016/j.cardiores.2003.10.011

Cited by 593 publications

(457 citation statements)

References 201 publications

(157 reference statements)

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“…Third, we show that MSC‐mediated adenosine prevents significant increases in ROS formation following injury. While this effect is likely attributable to reduction of ROS formation from several cell sources (ie, myocytes and fibroblasts), neutrophils are a known significant source of H 2 O 2 and superoxide in vivo 53. Finally, we show that MSCs require CD73‐mediated adenosine production to improve cardiac function following MI/R injury.…”

Section: Discussionmentioning

confidence: 70%

“…By day 3, however, cell necrosis decreases substantially and may deprive MSCs of the extracellular AMP substrate necessary to continue generating adenosine. Despite this time‐limited effect, adenosine appears to be a potent signaling molecule within the first 24 hours of injury, which serves to blunt the rapid and robust infiltration of circulating leukocytes, a process that has been well documented to propagate myocardial necrosis 2, 53. While the duration of effect for APCP on MSCs after in vivo implantation is not completely clear, Figure 3 would suggest it is temporary since innate immune cell infiltration is significantly reduced at day 1 but not at day 3, by eMSC‐treated animals compared with those treated with APCP‐eMSCs post‐MI/R injury.…”

Section: Discussionmentioning

confidence: 99%

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Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

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BackgroundDuring myocardial ischemia/reperfusion (MI/R) injury, there is extensive release of immunogenic metabolites that activate cells of the innate immune system. These include ATP and AMP, which upregulate chemotaxis, migration, and effector function of early infiltrating inflammatory cells. These cells subsequently drive further tissue devitalization. Mesenchymal stromal cells (MSCs) are a potential treatment modality for MI/R because of their powerful anti‐inflammatory capabilities; however, the manner in which they regulate the acute inflammatory milieu requires further elucidation. CD73, an ecto‐5′‐nucleotidase, may be critical in regulating inflammation by converting pro‐inflammatory AMP to anti‐inflammatory adenosine. We hypothesized that MSC‐mediated conversion of AMP into adenosine reduces inflammation in early MI/R, favoring a micro‐environment that attenuates excessive innate immune cell activation and facilitates earlier cardiac recovery.Methods and ResultsAdult rats were subjected to 30 minutes of MI/R injury. MSCs were encapsulated within a hydrogel vehicle and implanted onto the myocardium. A subset of MSCs were pretreated with the CD73 inhibitor, α,β‐methylene adenosine diphosphate, before implantation. Using liquid chromatography/mass spectrometry, we found that MSCs increase myocardial adenosine availability following injury via CD73 activity. MSCs also reduce innate immune cell infiltration as measured by flow cytometry, and hydrogen peroxide formation as measured by Amplex Red assay. These effects were dependent on MSC‐mediated CD73 activity. Finally, through echocardiography we found that CD73 activity on MSCs was critical to optimal protection of cardiac function following MI/R injury.Conclusions MSC‐mediated conversion of AMP to adenosine by CD73 exerts a powerful anti‐inflammatory effect critical for cardiac recovery following MI/R injury.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Shin

Wang

Zemskova

et al. 2018

JAHA

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“…However, these cells were not identifiable as apoptotic. The Evans blue stained cardiomyocytes may have received a lethal mechanical injury at the time of exposure, although briefly delayed injury may have occurred from communication via gap junctions (GarciaDorado et al 2004), or by the activity of the infiltrating inflammatory cells (Vinten-Johansen, 2004), which are processes implicated in cardiomyocyte injury. The Evans blue staining indicated permeabilization of the cardiomyocyte plasma membrane, which apparently led to gradual degeneration, necrosis and removal by the normal inflammatory and phagocytic healing process after about 1-2 d. A photomicrograph of a section of a heart sample 4 hr after MCE and stained using the ApopTag® system, which shows TUNEL positive cardiomyocyte nuclei (A).…”

Section: Discussionmentioning

confidence: 99%

Evans Blue Staining of Cardiomyocytes Induced by Myocardial Contrast Echocardiography in Rats: Evidence for Necrosis Instead of Apoptosis

Miller

Peng

Dou

et al. 2007

Ultrasound in Medicine & Biology

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High Mechanical Index (MI) echocardiography with contrast agent has been shown to induce Evans blue staining of cardiomyocytes, seen one day after exposure, in addition to contraction band necrosis, seen immediately after exposure. This research examined the roles of necrosis vs. apoptosis in these bioeffects. Myocardial contrast echocardiography at high MI with 1:4 ECG triggering was performed in anesthetized rats at 1.5 MHz. Histologically observable cell injury was accumulated by infusing a high dose of 50 μl/kg Definity® via tail vein for 5 min at the start of 10 min of scanning. Evans blue dye or propidium iodide was injected as an indicator of cardiomyocyte plasma membrane integrity. Histological sections were stained using the TUNEL method for labeling nuclei with DNA degradation (e.g. apoptosis). Evans blue fluorescent cells were counted on frozen sections or on hematoxylin-stained and TUNEL labeled paraffin sections. In addition, transmission electron microscopy was used to assess potential apoptotic nuclei. Hypercontraction and propidium iodide staining were observed immediately after imaging-exposure. Although TUNEL positive cells were evident after 4 h, these also had indications of contraction band necrosis and features of apoptosis were not confirmed by electron microscopy. Inflammatory cell infiltration was evident after 24 h. A second, more subtle injury was recognized by Evans blue staining, with minimal inflammatory cell infiltration at the morphologically intact stained cells after 24 h. Apoptosis was not detected by the TUNEL method in the cardiomyocytes stained with Evans blue at 24 h. However, Evans blue stained cell numbers declined after 48 h, with continued inflammatory cell infiltration. The initial insult for Evans blue stained cardiomyocytes apparently induced partial permeability of the plasma membrane, which led to gradual degeneration (but not apoptosis) and necrosis after 24-48 h.

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“…In vitro experiments suggested that the mechanism of neutrophil-cardiomyocyte adhesion is dependent on CD18 integrin activation on neutrophils and on expression of ICAM-1, one of the primary ligands for the CD18 integrins [208], by injured cardiomyocytes. However, the in vivo significance of neutrophil-induced cardiomyocyte injury remains unknown [209]. Neutrophil depletion in animals undergoing reperfused myocardial infarction led to a marked decrease in infarct size [210,211] suggesting that a significant amount of myocardial injury induced by coronary artery occlusion followed by reperfusion may be neutrophil-dependent [212].…”

Section: The Concept Of Neutrophil-mediated Cardiomyocyte Injurymentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

572

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury

Cited by 593 publications

References 201 publications

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

Evans Blue Staining of Cardiomyocytes Induced by Myocardial Contrast Echocardiography in Rats: Evidence for Necrosis Instead of Apoptosis

The immune system and cardiac repair

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