Neutrophil stunning by metoprolol reduces infarct size

García‐Prieto, Jaime; Villena-Gutiérrez, Rocío; Gómez, Mónica; Bernardo, Esther; Pun-García, Andrés; García‐Lunar, Inés; Crainiciuc, Georgiana; Fernández‐Jiménez, Rodrigo; Sreeramkumar, Vinatha; Bourio-Martínez, Rafael; García-Ruiz, José M.; Valle, Alfonso; Sanz-Rosa, David; Pizarro, Gonzalo; Fernández‐Ortíz, Antonio; Hidalgo, Andrés; Fuster, Valentín; Ibáñez, Borja

doi:10.1038/ncomms14780

Cited by 178 publications

(162 citation statements)

References 56 publications

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“…The migration of neutrophils from the blood stream into inflamed tissues is a tightly regulated process essential for the rapid development of an effective immune response against injury and invading pathogens. This phenomenon, extensively studied during physiological responses in healthy tissues , is also a key element in the development of many acute and life‐threatening inflammatory pathologies , such as I/R injury . Several therapeutic strategies have been tested both in preclinical and clinical studies of inflammatory conditions to inhibit neutrophil recruitment and/or functions through the use of natural or synthetic (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…These innate immune cells, whilst vital for host defense against pathogens, are implicated in the pathogenesis of many disorders due to their capacity to release a wide range of proinflammatory mediators , reactive oxygen species (ROS) and destructive proteolytic enzymes. Clear evidence for the involvement of neutrophils in I/R injury has been provided by both preclinical and clinical studies in which neutrophil depletion was protective against further tissue damage . Similarly, blocking neutrophil interaction with blood vessel walls within reperfused areas of ischemic tissues improves disease outcome in patients .…”

Section: Introductionmentioning

confidence: 99%

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Neutrophil elastase plays a non‐redundant role in remodeling the venular basement membrane and neutrophil diapedesis post‐ischemia/reperfusion injury

Voisin

Leoni

Woodfin

et al. 2019

The Journal of Pathology

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Ischemia/reperfusion (I/R) injury is a severe inflammatory insult associated with numerous pathologies, such as myocardial infarction, stroke and acute kidney injury. I/R injury is characterized by a rapid influx of activated neutrophils secreting toxic free radical species and degrading enzymes that can irreversibly damage the tissue, thus impairing organ functions. Significant efforts have been invested in identifying therapeutic targets to suppress neutrophil recruitment and activation post‐I/R injury. In this context, pharmacological targeting of neutrophil elastase (NE) has shown promising anti‐inflammatory efficacy in a number of experimental and clinical settings of I/R injury and is considered a plausible clinical strategy for organ care. However, the mechanisms of action of NE, and hence its inhibitors, in this process are not fully understood. Here we conducted a comprehensive analysis of the impact of NE genetic deletion on neutrophil infiltration in four murine models of I/R injury as induced in the heart, kidneys, intestine and cremaster muscle. In all models, neutrophil migration into ischemic regions was significantly suppressed in NE−/− mice as compared with wild‐type controls. Analysis of inflamed cremaster muscle and mesenteric microvessels by intravital and confocal microscopy revealed a selective entrapment of neutrophils within venular walls, most notably at the level of the venular basement membrane (BM) following NE deletion/pharmacological blockade. This effect was associated with the suppression of NE‐mediated remodeling of the low matrix protein expressing regions within the venular BM used by transmigrating neutrophils as exit portals. Furthermore, whilst NE deficiency led to reduced neutrophil activation and vascular leakage, levels of monocytes and prohealing M2 macrophages were reduced in tissues of NE−/− mice subjected to I/R. Collectively our results identify a vital and non‐redundant role for NE in supporting neutrophil breaching of the venular BM post‐I/R injury but also suggest a protective role for NE in promoting tissue repair. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neutrophil elastase plays a non‐redundant role in remodeling the venular basement membrane and neutrophil diapedesis post‐ischemia/reperfusion injury

Voisin

Leoni

Woodfin

et al. 2019

The Journal of Pathology

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“…Surprisingly, studies in murine models of myocardial injury have shown that adrenergic signalling directly on leucocytes modulates inflammation. Although different forms of β‐adrenergic receptors are expressed on neutrophils, β1‐AR was found to be critical in early stages of myocardial injury: an antagonist for this receptor impaired the migration of neutrophils towards chemotactic stimuli in vitro and hematopoietic‐specific deficiency in the receptor protected from acute injury during the early stages of infarction . Interestingly, inhibition of this receptor leads to aberrant morphology of intravascular neutrophils and reduced motility, similar to that found upon disruption of platelet‐neutrophil interactions .…”

Section: Adrenergic Signalling During Vascular Inflammationmentioning

confidence: 91%

Neutrophils as effectors of vascular inflammation

Gómez-Moreno

Adrover

Hidalgo

2018

Eur J Clin Investigation

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Vascular inflammation underlies most forms of cardiovascular disease, which remains a prevalent cause of death among the global population. Advances in the biology of neutrophils, as well as insights into their dynamics in tissues, have revealed that these cells are prominent drivers of vascular inflammation though derailed activation within blood vessels. The development of powerful imaging techniques, as well as identification of cells and molecules that regulate their activation within vessels, including platelets and catecholamines, has been instrumental to better understand the mechanisms through which neutrophils protect or damage the organism. Other advances in our understanding of how these leucocytes exert detrimental functions on neighbouring cells, including the formation of DNA-based extracellular traps, constitute milestones in defining neutrophil-driven inflammation. Here, we review emerging mechanisms that regulate intravascular activation and effector functions of neutrophils, and discuss specific pathologies in which these processes are relevant. We argue that identification of pathways and mechanisms specifically engaged within the vasculature may provide effective therapies to treat this prevalent group of pathologies.

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“…Furthermore, the METOCARD trial showed benefit of periprocedural β‐blocker administration on infarct size and MVO . No significant differences in IMH occurrence ( P =0.36) or IMH extent ( P =0.097) were found between patients with and without intravenous periprocedural β‐blockers in the METOCARD trial.…”

Section: Discussionmentioning

confidence: 90%

Predictors of Intramyocardial Hemorrhage After Reperfused ST‐Segment Elevation Myocardial Infarction

Amier

Tijssen

Teunissen

et al. 2017

JAHA

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BackgroundFindings from recent studies show that microvascular injury consists of microvascular destruction and intramyocardial hemorrhage (IMH). Patients with ST‐segment elevation myocardial infarction (STEMI) with IMH show poorer prognoses than patients without IMH. Knowledge on predictors for the occurrence of IMH after STEMI is lacking. The current study aimed to investigate the prevalence and extent of IMH in patients with STEMI and its relation with periprocedural and clinical variables.Methods and ResultsA multicenter observational cohort study was performed in patients with successfully reperfused STEMI with cardiovascular magnetic resonance examination 5.5±1.8 days after percutaneous coronary intervention. Microvascular injury was visualized using late gadolinium enhancement and T2‐weighted cardiovascular magnetic resonance imaging for microvascular obstruction and IMH, respectively. The median was used as the cutoff value to divide the study population with presence of IMH into mild or extensive IMH. Clinical and periprocedural parameters were studied in relation to occurrence of IMH and extensive IMH, respectively. Of the 410 patients, 54% had IMH. The presence of IMH was independently associated with anterior infarction (odds ratio, 2.96; 95% CI, 1.73–5.06 [P<0.001]) and periprocedural glycoprotein IIb/IIIa inhibitor treatment (odds ratio, 2.67; 95% CI, 1.49–4.80 [P<0.001]). Extensive IMH was independently associated with anterior infarction (odds ratio, 3.76; 95% CI, 1.91–7.43 [P<0.001]). Presence and extent of IMH was associated with larger infarct size, greater extent of microvascular obstruction, larger left ventricular dimensions, and lower left ventricular ejection fraction (all P<0.001).ConclusionsOccurrence of IMH was associated with anterior infarction and glycoprotein IIb/IIIa inhibitor treatment. Extensive IMH was associated with anterior infarction. IMH was associated with more severe infarction and worse short‐term left ventricular function in patients with STEMI.

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Neutrophil stunning by metoprolol reduces infarct size

Cited by 178 publications

References 56 publications

Neutrophil elastase plays a non‐redundant role in remodeling the venular basement membrane and neutrophil diapedesis post‐ischemia/reperfusion injury

Neutrophil elastase plays a non‐redundant role in remodeling the venular basement membrane and neutrophil diapedesis post‐ischemia/reperfusion injury

Neutrophils as effectors of vascular inflammation

Predictors of Intramyocardial Hemorrhage After Reperfused ST‐Segment Elevation Myocardial Infarction

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