scholarly journals Lung exposure to lipopolysaccharide causes atherosclerotic plaque destabilisation

2016 ◽  
Vol 48 (1) ◽  
pp. 205-215 ◽  
Author(s):  
Jen Erh Jaw ◽  
Masashi Tsuruta ◽  
Yeni Oh ◽  
John Schipilow ◽  
Yuki Hirano ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lung Inflammation ◽  
Cardiovascular Events ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Saline Control ◽  
Atheromatous Plaque ◽  
Vascular Events ◽  
Plaque Instability ◽  
Brachiocephalic Trunk

Epidemiological studies have implicated lung inflammation as a risk factor for acute cardiovascular events, but the underlying mechanisms linking lung injury with cardiovascular events are largely unknown.Our objective was to develop a novel murine model of acute atheromatous plaque rupture related to lung inflammation and to investigate the role of neutrophils in this process.Lipopolysaccharide (LPS; 3 mg·kg−1) or saline (control) was instilled directly into the lungs of male apolipoprotein E-null C57BL/6J mice following 8 weeks of a Western-type diet. 24 h later, atheromas in the right brachiocephalic trunk were assessed for stability ex vivo using high-resolution optical projection tomography and histology. 68% of LPS-exposed mice developed vulnerable plaques, characterised by intraplaque haemorrhage and thrombus, versus 12% of saline-exposed mice (p=0.0004). Plaque instability was detectable as early as 8 h post-intratracheal LPS instillation, but not with intraperitoneal instillation. Depletion of circulating neutrophils attenuated plaque rupture.We have established a novel plaque rupture model related to lung injury induced by intratracheal exposure to LPS. In this model, neutrophils play an important role in both lung inflammation and plaque rupture. This model could be useful for screening therapeutic targets to prevent acute vascular events related to lung inflammation.

scholarly journals Targeting macrophage necroptosis for therapeutic and diagnostic interventions in atherosclerosis

2016 ◽  
Vol 2 (7) ◽  
pp. e1600224 ◽  
Author(s):  
Denuja Karunakaran ◽  
Michele Geoffrion ◽  
Lihui Wei ◽  
Wei Gan ◽  
Laura Richards ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Density Lipoprotein ◽  
Necrotic Core ◽  
Atherosclerotic Plaques ◽  
Core Formation ◽  
Macrophage Cell ◽  
Plaque Instability

Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. Hence, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell necrosis regulated by RIP3 and MLKL kinases that, in contrast to apoptosis, induces a proinflammatory state. We show herein that necroptotic cell death is activated in human advanced atherosclerotic plaques and can be targeted in experimental atherosclerosis for both therapeutic and diagnostic interventions. In humans with unstable carotid atherosclerosis, expression of RIP3 and MLKL is increased, and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced atheromas. Investigation of the molecular mechanisms underlying necroptosis showed that atherogenic forms of low-density lipoprotein increase RIP3 and MLKL transcription and phosphorylation—two critical steps in the execution of necroptosis. Using a radiotracer developed with the necroptosis inhibitor necrostatin-1 (Nec-1), we show that 123I-Nec-1 localizes specifically to atherosclerotic plaques in Apoe−/− mice, and its uptake is tightly correlated to lesion areas by ex vivo nuclear imaging. Furthermore, treatment of Apoe−/− mice with established atherosclerosis with Nec-1 reduced lesion size and markers of plaque instability, including necrotic core formation. Collectively, our findings offer molecular insight into the mechanisms of macrophage cell death that drive necrotic core formation in atherosclerosis and suggest that this pathway can be used as both a diagnostic and therapeutic tool for the treatment of unstable atherosclerosis.

Abstract 3: Targeting Macrophage Necroptosis for Therapeutic and Diagnostic Interventions to Treat Atherosclerosis

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Denuja Karunakaran ◽  
Michele Geoffrion ◽  
Lihui Wei ◽  
Wei Gan ◽  
Ljubica Perisic ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Oxidized Ldl ◽  
Combined Treatment ◽  
Necrotic Core ◽  
Core Formation ◽  
Macrophage Cell ◽  
Plaque Instability

Background: Atherosclerosis results from maladaptive inflammation driven primarily by macrophages, whose recruitment and proliferation drive plaque progression. In advanced plaques, macrophage death contributes centrally to the formation of plaque necrosis, which underlies the instability that promotes plaque rupture and myocardial infarction. As such, targeting macrophage cell death pathways may offer promise for the stabilization of vulnerable plaques. Necroptosis is a recently discovered pathway of programmed cell necrosis regulated by RIP3 and MLKL kinases that in contrast to apoptosis, induces a pro-inflammatory state. We hypothesize that atherogenic ligands within the plaque promote macrophage necroptosis and this process underlies necrotic core formation and drives atherosclerotic plaque instability. Results: In humans with unstable carotid atherosclerosis, expression of RIP3 and MLKL is increased and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced atheromas. Investigation of the molecular mechanisms underlying plaque necroptosis showed that macrophages treated with oxidized LDL have increased expression of necroptotic genes RIP3 and MLKL through ROS-dependent activation of the promoter region and increased RIP3 and MLKL phosphorylation. Combined treatment with oxLDL and DAMPs (damage associated molecular patterns) amplified macrophage necroptotic cell death, indicating that additional inflammatory stimuli present in the lesion could act synergistically to promote necroptosis. Using a radiotracer developed with the necroptosis inhibitor Nec-1, we show that 123 I-Nec1 localizes specifically to atherosclerotic plaques in Apoe-/- mice, and its uptake is tightly correlated to lesion areas by ex vivo nuclear imaging. Furthermore, treatment of Apoe-/- mice with established atherosclerosis with Nec-1 reduced lesion size and markers of plaque instability, including necrotic core formation. Conclusions: Our findings offer molecular insight into the mechanisms of macrophage cell death that drive necrotic core formation in atherosclerosis and suggest that this pathway can be used as both a diagnostic and therapeutic tool for the treatment of unstable atherosclerosis.

Management of acute coronary syndrome

2020 ◽  
pp. 3626-3655
Author(s):  
Rajesh K. Kharbanda ◽  
Keith A.A. Fox
Keyword(s):  
Acute Coronary Syndrome ◽  
Cardiovascular Events ◽  
Plaque Rupture ◽  
Atheromatous Plaque ◽  
Coronary Syndrome ◽  
Clinical Consequences ◽  
Prehospital Cardiac Arrest ◽  
Infarction Heart ◽  
Term Management

Acute coronary syndrome (ACS) is precipitated by an abrupt change in an atheromatous plaque and/or thrombotic occlusion. This results in increased obstruction to perfusion and ischaemia or infarction in the territory supplied by the affected vessel. The clinical consequences of plaque rupture can range from a clinically silent episode, through to unstable symptoms of ischaemia without infarction, to profound ischaemia complicated by progressive infarction, heart failure, arrhythmia, and risk of sudden death. Clinical presentation with an ACS identifies a patient at high risk of further cardiovascular events requiring a defined acute and long-term management strategy. Prompt relief of pain is important, not only for humanitarian reasons, but also because pain is associated with sympathetic activation, vasoconstriction, and increased myocardial work. The management of prehospital cardiac arrest requires special attention: at least as many lives can be saved by prompt resuscitation and defibrillation as by reperfusion.

Management of acute coronary syndrome

2010 ◽  
pp. 2911-2935
Author(s):  
Keith A.A. Fox ◽  
Rajesh K. Kharbanda
Keyword(s):  
Heart Failure ◽  
Acute Coronary Syndrome ◽  
Cardiovascular Events ◽  
Plaque Rupture ◽  
Atheromatous Plaque ◽  
Coronary Syndrome ◽  
Clinical Consequences ◽  
Infarction Heart ◽  
Term Management

The acute coronary syndrome (ACS) is precipitated by an abrupt change in an atheromatous plaque, resulting in increased obstruction to perfusion and ischaemia or infarction in the territory supplied by the affected vessel. The clinical consequences of plaque rupture can range from an entirely silent episode, through to unstable symptoms of ischaemia without infarction, to profound ischaemia complicated by progressive infarction, heart failure, and risk of sudden death. Clinical presentation with an ACS identifies a patient at high risk of further cardiovascular events requiring a defined acute and long-term management strategy....

scholarly journals Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia

2016 ◽  
Vol 74 (4) ◽  
pp. 545-552 ◽  
Author(s):  
Friso de Beer ◽  
Wim Lagrand ◽  
Gerie J. Glas ◽  
Charlotte J. P. Beurskens ◽  
Gerard van Mierlo ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lung Injury ◽  
Complement Activation ◽  
Lung Inflammation ◽  
Lavage Fluid ◽  
Saline Control ◽  
Repeated Treatment ◽  
C1 Esterase Inhibitor ◽  
Healthy Control ◽  
Esterase Inhibitor

Abstract Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation. This was investigated in a rat model of severe Streptococcus pneumoniae pneumonia. Rats were intra–tracheally challenged with S. pneumoniae to induce pneumonia. Nebulized C1-esterase inhibitor or saline (control animals) was repeatedly administered to rats, 30 min before induction of pneumonia and every 6 h thereafter. Rats were sacrificed 20 or 40 h after inoculation with bacteria. Brochoalveolar lavage fluid and lung tissue were obtained for measuring levels of complement activation (C4b/c), lung injury and inflammation. Induction of pneumonia was associated with pulmonary complement activation (C4b/c at 20 h 1.24 % [0.56–2.59] and at 40 h 2.08 % [0.98–5.12], compared to 0.50 % [0.07–0.59] and 0.03 % [0.03–0.03] in the healthy control animals). The functional fraction of C1-INH was detectable in BALF, but no effect was found on pulmonary complement activation (C4b/c at 20 h 0.73 % [0.16–1.93] and at 40 h 2.38 % [0.54–4.19]). Twenty hours after inoculation, nebulized C1-esterase inhibitor treatment reduced total histology score, but this effect was no longer seen at 40 h. Nebulized C1-esterase inhibitor did not affect other markers of lung injury or lung inflammation. In this negative experimental animal study, severe S. pneumoniae pneumonia in rats is associated with pulmonary complement activation. Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury.

scholarly journals Neutrophil extracellular traps induce MCP-1 release from endothelial cells at the plaque rupture site in acute myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Ondracek ◽  
T.M Hofbauer ◽  
A Mangold ◽  
T Scherz ◽  
V Seidl ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Endothelial Cells ◽  
Plaque Rupture ◽  
Ex Vivo ◽  
Coronary Intervention ◽  
Neutrophil Extracellular Traps ◽  
Funding Source ◽  
Extracellular Traps

Abstract Introduction Leukocyte-mediated inflammation is crucial in acute myocardial infarction (AMI). We recently observed that neutrophil extracellular traps (NETs) are increased at the culprit site, promoting activation and differentiation of fibrocytes, cells with mesenchymal and leukocytic properties. Fibrocyte migration is mediated by monocyte chemoattractant protein (MCP)-1 and C-C chemokine receptor type 2 (CCR2). We investigated the interplay between NETs, fibrocyte function, and MCP-1 in AMI. Methods Culprit site and femoral blood of AMI patients was drawn during percutaneous coronary intervention. We characterized CCR2 expression of fibrocytes by flow cytometry. MCP-1 and the NET marker citrullinated histone H3 (citH3) were measured by ELISA. Fibrocytes were treated in vitro with MCP-1. Human coronary arterial endothelial cells (hCAECs) were stimulated with isolated NETs, and MCP-1 was measured by ELISA and qPCR. The influence of MCP-1 on NET formation in vitro was assessed using isolated neutrophils. Results We have included 50 consecutive AMI patients into the study. NETs and concentrations of MCP-1 were increased at the CLS. NET stimulation of hCAECs induced MCP-1 on mRNA and protein level. Increasing MCP-1 gradient was associated with fibrocyte accumulation at the site of occlusion. In the presence of higher MCP-1 these fibrocytes expressed proportionally less CCR2 than peripheral fibrocytes. In vitro, MCP-1 dose-dependently decreased fibrocyte CCR2 and reduced ex vivo NET release of healthy donor neutrophils. Conclusions NETs induce endothelial MCP-1 release, presumably promoting a chemotactic gradient for leukocyte and fibrocyte migration. MCP-1 mediated inhibition of NET formation could point to a negative feedback loop. These data will shed light on vascular healing. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund

scholarly journals Effects of Positive End-expiratory Pressure Titration and Recruitment Maneuver on Lung Inflammation and Hyperinflation in Experimental Acid Aspiration–induced Lung Injury

2012 ◽  
Vol 117 (6) ◽  
pp. 1322-1334 ◽  
Author(s):  
Aline M. Ambrosio ◽  
Rubin Luo ◽  
Denise T. Fantoni ◽  
Claudia Gutierres ◽  
Qin Lu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Recruitment Maneuver ◽  
Alveolar Wall ◽  
Arterial Oxygenation ◽  
Positive End Expiratory Pressure ◽  
Acid Aspiration ◽  
Recruitment Maneuvers ◽  
Alveolar Area

Background In acute lung injury positive end-expiratory pressure (PEEP) and recruitment maneuver are proposed to optimize arterial oxygenation. The aim of the study was to evaluate the impact of such a strategy on lung histological inflammation and hyperinflation in pigs with acid aspiration-induced lung injury. Methods Forty-seven pigs were randomly allocated in seven groups: (1) controls spontaneously breathing; (2) without lung injury, PEEP 5 cm H2O; (3) without lung injury, PEEP titration; (4) without lung injury, PEEP titration + recruitment maneuver; (5) with lung injury, PEEP 5 cm H2O; (6) with lung injury, PEEP titration; and (7) with lung injury, PEEP titration + recruitment maneuver. Acute lung injury was induced by intratracheal instillation of hydrochloric acid. PEEP titration was performed by incremental and decremental PEEP from 5 to 20 cm H2O for optimizing arterial oxygenation. Three recruitment maneuvers (pressure of 40 cm H2O maintained for 20 s) were applied to the assigned groups at each PEEP level. Proportion of lung inflammation, hemorrhage, edema, and alveolar wall disruption were recorded on each histological field. Mean alveolar area was measured in the aerated lung regions. Results Acid aspiration increased mean alveolar area and produced alveolar wall disruption, lung edema, alveolar hemorrhage, and lung inflammation. PEEP titration significantly improved arterial oxygenation but simultaneously increased lung inflammation in juxta-diaphragmatic lung regions. Recruitment maneuver during PEEP titration did not induce additional increase in lung inflammation and alveolar hyperinflation. Conclusion In a porcine model of acid aspiration-induced lung injury, PEEP titration aimed at optimizing arterial oxygenation, substantially increased lung inflammation. Recruitment maneuvers further improved arterial oxygenation without additional effects on inflammation and hyperinflation.

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