Platelets in cardiac ischaemia/reperfusion injury: a promising therapeutic target

Ziegler, Melanie; Wang, Xiaowei; Peter, Karlheinz

doi:10.1093/cvr/cvz070

Cited by 95 publications

(102 citation statements)

References 132 publications

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“…We speculate, here, on how these results can be interpreted in the context of clinical pathologies that are characterized by platelet activation and inflammation. The newly-emerging role of platelets as immune regulators in sepsis [11], cardiac ischaemia/reperfusion (I/R) injury [17, 20] and acute lung injury (ALI) [50] is often juxtaposed against their well-established role in promoting leukocyte-mediated inflammation in these inflammatory diseases. An emerging working hypothesis is that platelets can elicit dual, potentially sequential, roles in inflammation [11, 20].…”

Section: Discussionmentioning

confidence: 99%

“…The ability of platelets to propagate and resolve inflammation is particularly important in acute myocardial infarction (AMI) and I/R injury, where the resolution of inflammation in a timely manner is required for optimal myocardial healing and long-term repair [60]. In both conditions, platelets are known to have both pro-inflammatory [17, 61] and pro-resolving [20, 62] effects. In a clinical setting, anti-platelet agents are administered as a cornerstone of intervention in AMI.…”

Section: Discussionmentioning

confidence: 99%

“…In light of these findings, platelets are increasingly appreciated as immune regulators, rather than purely pro-inflammatory cells. Interestingly, this regulatory response has been characterized in a number of inflammatory diseases where platelets are also known to be predominant drivers of leukocyte infiltration and leukocyte-mediated inflammation [17–19]. The dynamicity in platelet responses may be a mechanism to enhance, and then temper, an inflammatory response [20] to prevent rampant host damage [11] and is also both context- and stimulus-dependent [11, 21].…”

Section: Introductionmentioning

confidence: 99%

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Platelets modulate multiple markers of neutrophil function in response to in vitro Toll-like receptor stimulation

et al. 2019

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IntroductionIn addition to their role in facilitating leukocyte-mediated inflammation, platelets can dampen leukocyte pro-inflammatory responses in some contexts. Consequently, platelets are increasingly appreciated as regulators of inflammation. Together, platelets and neutrophils play a role in inflammation through Toll-like receptor (TLR) expression, although we do not fully understand how platelets shape neutrophil responses to TLR stimulation. Here, we aimed to determine the extent to which platelets can modulate neutrophil function in response to in vitro stimulation with TLR4, TLR2/1, and TLR2/6 agonists.MethodsNeutrophils from 10 healthy individuals were cultured alone or with autologous platelets. Neutrophils ± platelets were left unstimulated or were stimulated with 1 or 100 ng/mL lipopolysaccharide (LPS; a TLR4 agonist), Pam3CSK4 (a TLR2/1 agonist) and fibroblast-stimulating lipopeptide (FSL)-1 (a TLR2/6 agonist). Neutrophil activation and phagocytic activity were assessed by flow cytometry, and elastase and interleukin-8 secretion were assessed by ELISA.ResultsThe addition of platelets attenuated neutrophil CD66b and CD11b expression in response to various doses of Pam3CSK4 and FSL-1. Furthermore, platelet co-culture was associated with higher CD62L expression (indicating reduced CD62L shedding) in response to these TLR agonists. Platelets also reduced elastase secretion in unstimulated cultures and in response to low-dose TLR stimulation. Conversely, platelet co-culture increased neutrophil phagocytosis in unstimulated cultures and in response to low-dose Pam3CSK4 and FSL-1. Platelets also increased IL-8 secretion in response to low-dose LPS.ConclusionPlatelets are complex immunomodulators that can attenuate some, and simultaneously augment other, neutrophil functions. This modulation can occur both in the absence and presence of TLR stimulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Platelets modulate multiple markers of neutrophil function in response to in vitro Toll-like receptor stimulation

et al. 2019

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“…It is possible that successful treatment of pathogenetic mechanisms associated with reperfusion would reduce the severity of RMI. Conversely, improvement in microvascular flow by reduction of RMI may enhance the efficacy of therapeutic strategies directed at specific aspects of potentially lethal reperfusion injury 152–154…”

Section: Limitationsmentioning

confidence: 99%

<p>Reperfusion Microvascular Ischemia After Prolonged Coronary Occlusion: Implications And Treatment With Local Supersaturated Oxygen Delivery</p>

Spears¹

2019

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Following a prolonged coronary arterial occlusion, heterogeneously scattered, focal regions of low erythrocyte flow are commonly found throughout the reperfused myocardium. Experimental studies have also demonstrated the presence of widespread, focally patchy regions of microvascular ischemia during reperfusion (RMI). However, the potential contribution of RMI to tissue viability and function has received little attention in the absence of practical clinical methods for its detection. In this review, the anatomic/functional basis of RMI is summarized, along with the evidence for its presence in reperfused myocardium. Advances in microcirculation research related to obstructive responses of vascular endothelial cells and blood elements to the effects of hypoxia and low shear stress are discussed, and a potential cycle of intensification of RMI from such responses and progressive loss of functional capillary density is presented. In capillaries with impaired erythrocyte flow, compensatory increases in the delivery of oxygen, because of its low solubility in plasma, are effective only at high partial pressures. As discussed herein, attenuation of the cycle with oxygen at hyperbaric levels in plasma is, very likely, responsible for improved tissue level perfusion noted experimentally. Observed clinical benefits from intracoronary SuperSaturated oxygen (SSO2) delivery, including infarct size reduction, can be attributed to attenuation of RMI with improvement in microvascular blood flow.

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“…However, platelet involvement in myocarditis was not described yet. It is well known that platelets play an important role in inflammatory and ischemic processes 19 – 21 . Hints for platelet involvement in myocarditis were given by another molecular imaging study, which used an ultrasound contrast agent against P-selectin 22 .…”

Section: Introductionmentioning

confidence: 99%

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice

Braig

Jakob

Bienert

et al. 2020

Sci Rep

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MRI sensitivity for diagnosis and localization of early myocarditis is limited, although it is of central clinical interest. The aim of this project was to test a contrast agent targeting activated platelets consisting of microparticles of iron oxide (MPIO) conjugated to a single-chain antibody directed against ligand-induced binding sites (LIBS) of activated glycoprotein IIb/IIIa (= LIBS-MPIO). Myocarditis was induced by subcutaneous injection of an emulsion of porcine cardiac myosin and complete Freund's adjuvant in mice. 3D 7 T in-vivo MRI showed focal signal effects in LIBS-MPIO injected mice 2 days after induction of myocarditis, whereas in control-MPIO injected mice no signal was detectable. Histology confirmed CD41-positive staining, indicating platelet involvement in myocarditis in mice as well as in human specimens with significantly higher LIBS-MPIO binding compared to control-MPIO in both species. Quantification of the myocardial MRI signal confirmed a signal decrease after LIBS-MPIO injection and significant less signal in comparison to control-MPIO injection. These data show, that platelets are involved in inflammation during the course of myocarditis in mice and humans. They can be imaged non-invasively with LIBS-MPIO by molecular MRI at an early time point of the inflammation in mice, which is a valuable approach for preclinical models and of interest for both diagnostic and prognostic purposes. Besides myocardial ischemia, myocarditis is one of the most common causes of heart failure. The prevalence among young patients with sudden cardiac death is described within a range of 2-42%, and among patients with non-ischemic dilated cardiomyopathy within a range of 9-16%. The prognosis of progressing myocarditis is poor, symptoms are unspecific and diagnosis is challenging 1. Myocarditis is defined as an inflammatory process of the myocardium established by histological and immunohistochemical criteria associated with cardiac dysfunction. Several pathophysiological causes for myocarditis are known including infectious agents such as viruses, immune-mediated and toxic causes. Clinical symptoms, laboratory values, ECG and echocardiography are very often unspecific or inconclusive 1. To date, the diagnostic gold standard for diagnosis of myocarditis is endomyocardial biopsy (EMB). The Dallas criteria define myocarditis as histological evidence of inflammatory infiltrates within the myocardium associated with myocyte degeneration and necrosis of non-ischemic origin 2. There are also immunohistochemical criteria, namely abnormal inflammatory infiltrate defined as ≥ 14 leucocytes/mm 2 , including up to 4 monocytes/mm 2 with the presence of CD3 positive T-lymphocytes ≥ 7 cells/mm 21 .

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Platelets in cardiac ischaemia/reperfusion injury: a promising therapeutic target

Abstract: Graphical Abstract Graphical Abstract

Cited by 95 publications

References 132 publications

Platelets modulate multiple markers of neutrophil function in response to in vitro Toll-like receptor stimulation

Platelets modulate multiple markers of neutrophil function in response to in vitro Toll-like receptor stimulation

<p>Reperfusion Microvascular Ischemia After Prolonged Coronary Occlusion: Implications And Treatment With Local Supersaturated Oxygen Delivery</p>

Molecular magnetic resonance imaging of activated platelets allows noninvasive detection of early myocarditis in mice

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