Leukocyte Depletion Attenuates Reperfusion Injury in Patients With Left Ventricular Hypertrophy

Sawa, Yoshiki; Taniguchi, Koichi; Kadoba, Keishi; Nishimura, Motonobu; Ichikawa, Hajime; Amemiya, Akira; Kuratani, Thoru; Matsuda, Hikaru

doi:10.1161/01.cir.93.9.1640

Cited by 65 publications

(59 citation statements)

References 26 publications

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“…Although the leukocyte contribution to myocardial reperfusion injury has been demonstrated 13,[15][16][17][18][19] and discussed 20 before, only have recent studies revealed an interaction between the leukocyte and platelet compartments as effectors of reperfusion injury. 8,21,22 In particular, the study of Lefer and coworkers 8 suggested that blockade of P-selectin and its ligands, eg, PSGL-1, reduced PMN-platelet-dependent myocardial reperfusion injury.…”

Section: Discussionmentioning

confidence: 99%

c7E3Fab Reduces Postischemic Leukocyte-Thrombocyte Interaction Mediated by Fibrinogen

Kupatt

Habazettl

Hanusch

et al. 2000

ATVB

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Abstract-Reperfusion injury after coronary occlusion is in part mediated by leukocyte activation and adhesion. Platelets may interact with polymorphonuclear granulocytes (PMNs), causing aggravated reperfusion injury. We studied whether c7E3Fab, a chimeric Fab fragment blocking platelet glycoprotein (GP) IIb/IIIa, decreases PMN-platelet-dependent myocardial dysfunction after ischemia. Isolated guinea pig hearts (nϭ5 per group) perfused at a constant flow of 5 mL/min were subjected to ischemia (15 minutes, 37°C) and reperfusion. Human PMNs (10ϫ10 6 cells, 3 mL), platelets (400ϫ10 6 , 3 mL), and fibrinogen (1 mg/mL) were infused for 3 minutes after 2 minutes of reperfusion, with or without c7E3Fab. Flow cytometry detected GPIIb/IIIa (platelets) and MAC-1 (aM␤2, PMNs) as well as coaggregates of both in the effluent, whereas double-fluorescence microscopy visualized intracoronary PMN-platelet coaggregates. Postischemic recovery of pressure-volume work (12-cm H 2 O preload and 60 -mm Hg afterload) was defined as the ratio of postischemic to preischemic external heart work (meanϮSEM). c7E3Fab reduced platelet GPIIb/IIIa detection to 10% of controls, blocked a transcoronary MAC-1 increase (ϩ25% without versus Ϫ23% with c7E3Fab), and inhibited PMN-platelet coaggregation in the effluent (49Ϯ12% without versus 17Ϯ2% with c7E3Fab) as well as in the hearts themselves (5.0Ϯ0.7/cm 2 without versus 1.2Ϯ0.3/cm 2 surface area with c7E3Fab). Postischemic recovery of external heart work (83Ϯ5% in cell-free hearts) declined to 46Ϯ4% after postischemic PMN-platelet infusion, but not in the presence of c7E3Fab (74Ϯ11%) or LPM19c (71Ϯ6%). We conclude that c7E3Fab inhibits formation of PMN-platelet aggregates during myocardial reperfusion, an effect that protects against PMN-platelet-dependent stunning. Key Words: abciximab Ⅲ polymorphonuclear neutrophils Ⅲ platelets Ⅲ myocardial stunning Ⅲ microcirculation Ⅲ fibrinogen P harmacological and interventional strategies aimed at reperfusion of an occluded coronary artery are standard therapeutic regimens, although a certain percentage of treatments remain unsuccessful. Aimed at reducing this margin, inhibitors of the platelet fibrinogen receptor protein, glycoprotein (GP) IIb/IIIa (␣2b/␤3, CD41/CD61), have been introduced, eg, a Fab fragment of the chimeric monoclonal antibody 7E3 (c7E3Fab, Abciximab [Centocor]) against human GPIIb/IIIa. 1-3 Besides improving coronary flow reserve, c7E3Fab protects from myocardial stunning in humans, which is expressed as regional wall shortening of the reperfused myocardium. 4 Factors beyond inhibition of platelet aggregation might contribute to the improvement in flow and myocardial function, eg, inhibition of platelet-endothelium or platelet-leukocyte interactions. Fibrinogen competition studies with monoclonal antibodies suggest that MAC-1 (␣M␤2, CD11b/CD18) is a major, if not unique, fibrinogen receptor on the polymorphonuclear neutrophil (PMN) surface. 5,6 Interestingly, MAC-1 expression decreases after application of c7E3Fab in patients undergoing pe...

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Section: Discussionmentioning

confidence: 99%

c7E3Fab Reduces Postischemic Leukocyte-Thrombocyte Interaction Mediated by Fibrinogen

Kupatt

Habazettl

Hanusch

et al. 2000

ATVB

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“…injury to a number of organs, including the heart, liver, and lung, and is thought to also contribute to the pathogenesis of chronic diseases associated with cell death (5,31,32). Therefore, it could potentially be of therapeutic benefit to block this sterile inflammatory response.…”

Section: Figurementioning

confidence: 99%

“…They also help to clear dead cells and debris and stimulate mechanisms to repair tissue damage. On the other hand, recruiting the innate defenses comes at a price (4)(5)(6). The delivery of the immune effector mechanisms is imprecise, and as a result, normal healthy cells may be caught in the line of fire and damaged.…”

Section: Introductionmentioning

confidence: 99%

Uric acid promotes an acute inflammatory response to sterile cell death in mice

Kono¹,

Chen²,

Ontiveros³

et al. 2010

J. Clin. Invest.

300

239

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Necrosis stimulates inflammation, and this response is medically relevant because it contributes to the pathogenesis of a number of diseases. It is thought that necrosis stimulates inflammation because dying cells release proinflammatory molecules that are recognized by the immune system. However, relatively little is known about the molecular identity of these molecules and their contribution to responses in vivo. Here, we investigated the role of uric acid in the inflammatory response to necrotic cells in mice. We found that dead cells not only released intracellular stores of uric acid but also produced it in large amounts postmortem as nucleic acids were degraded. Using newly developed Tg mice that have reduced levels of uric acid either intracellularly and/or extracellularly, we found that uric acid depletion substantially reduces the cell death-induced inflammatory response. Similar results were obtained with pharmacological treatments that reduced uric acid levels either by blocking its synthesis or hydrolyzing it in the extracellular fluids. Importantly, uric acid depletion selectively inhibited the inflammatory response to dying cells but not to microbial molecules or sterile irritant particles. Collectively, our data identify uric acid as a proinflammatory molecule released from dying cells that contributes significantly to the cell death-induced inflammatory responses in vivo.

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“…It is possible that patients with more than one risk factor for atherothrombosis have a smoldering inflammatory response that could have a detrimental effect on the host. These data are relevant in the era in which antileukocyte therapeutic interventions are considered [8, 9, 10]. …”

Section: Introductionmentioning

confidence: 99%

Activated Polymorphonuclear Leukocytes and Monocytes in the Peripheral Blood of Patients with Ischemic Heart and Brain Conditions Correspond to the Presence of Multiple Risk Factors for Atherothrombosis

Berliner¹,

Rogowski²,

Rotstein³

et al. 2000

Cardiology

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Objective: Risk factors like hypertension, diabetes mellitus, dyslipidemia and smoking contribute to the pathogenesis of atherothrombosis. We investigated whether the multiplicity of risk factors for atherothrombosis is associated with leukocyte activation. Methods: We examined the availability of CD11b/CD18 antigen on the surface of peripheral blood polymorphonuclear leukocytes and monocytes in patients with acute ischemic heart and brain conditions. Results: There was a highly significant (p < 0.00001) increment in the availability of the CD11b/CD18 antigen on the surface of the polymorphonuclear leukocytes in patients with multiple (2 or more) vascular risk factors [mean fluorescence intensity (MFI) ± SD, 210 ± 102] as opposed to individuals with none or 1 risk factor for atherothrombosis (MFI 159 ± 73). Similar results were observed on the monocytes: 309 ± 151 and 235 ± 97, respectively (p < 0.00001). Conclusion: The multiplicity of risk factors for atherothrombosis is associated with the up-regulation of CD11b/CD18 antigen on the surface of peripheral blood polymorphonuclear leukocytes and monocytes, suggesting the presence of an increased inflammatory response and leukocyte activation in these individuals.

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Leukocyte Depletion Attenuates Reperfusion Injury in Patients With Left Ventricular Hypertrophy

Abstract: These results demonstrate that leukocyte-depleted reperfusion is potentially beneficial as an adjunct to terminal cardioplegia during cardiac surgery to attenuate reperfusion injury in patients with left ventricular hypertrophy.

Cited by 65 publications

References 26 publications

c7E3Fab Reduces Postischemic Leukocyte-Thrombocyte Interaction Mediated by Fibrinogen

c7E3Fab Reduces Postischemic Leukocyte-Thrombocyte Interaction Mediated by Fibrinogen

Uric acid promotes an acute inflammatory response to sterile cell death in mice

Activated Polymorphonuclear Leukocytes and Monocytes in the Peripheral Blood of Patients with Ischemic Heart and Brain Conditions Correspond to the Presence of Multiple Risk Factors for Atherothrombosis

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