Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes

Lindner, Jonathan R.; Coggins, Matthew; Kaul, Sanjiv; Klibanov, Alexander L.; Brandenburger, Gary H.; Ley, Klaus

doi:10.1161/01.cir.101.6.668

Cited by 216 publications

(172 citation statements)

References 38 publications

(43 reference statements)

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“…Targeting was achieved by incorporating PS in the lipid shell, which enhances complement-mediated microbubble attachment to activated leukocytes adherent to the venular endothelium. 4,6 Because microbubbles are confined to the vascular compartment, targeted MCE provides unique information on the active intravascular recruitment of leukocytes rather than total tissue burden. In this study, the spatial extent of inflammation by MCE was similar to that measured by 99m Tc-RP517, which was administered late after reperfusion in order to minimize signal from extravasated 99m Tc-labeled neutrophils.…”

Section: Discussionmentioning

confidence: 99%

Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography

Christiansen¹,

Leong‐Poi²,

Klibanov³

et al. 2002

ACC Current Journal Review

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Background-We hypothesized that myocardial contrast echocardiography (MCE) with leukocyte-targeted microbubbles could temporally and spatially characterize the severity of postischemic myocardial inflammation. Methods and Results-In 9 open-chest dogs, either the left anterior descending or left circumflex coronary artery was occluded for 90 minutes (nϭ6), while the remaining dogs served as non-ischemic controls. During occlusion, MCE was performed to determine the risk area (RA) and regions supplied by collateral flow. Myocardial inflammation was assessed 5, 60, and 120 minutes after reflow by MCE imaging of leukocyte-targeted (phosphatidylserine-containing) lipid microbubbles. The spatial extent and severity of inflammation were also assessed by radionuclide imaging of the neutrophil-avid tracer 99m TcRP517 and tissue myeloperoxidase activity. Early after reflow, MCE detected inflammation throughout the entire risk area, the extent of which decreased over time due to reduced signal in collateral-supplied regions.The spatial extent of inflammation late after reflow was similar for MCE and radionuclide imaging. The severity of inflammation in the infarct zone, the noninfarcted risk area, and collateral-supplied territories determined by quantitative MCE correlated well with myeloperoxidase activity (rϭ0.81). Conclusions-MCE with leukocyte-targeted microbubbles can temporally assess the severity and extent of postischemic myocardial inflammation and could be used to evaluate new treatment strategies designed to limit inflammation in acute coronary syndromes. Key Words: echocardiography Ⅲ inflammation Ⅲ ischemia L eukocyte infiltration into the myocardium can play a detrimental role after myocardial ischemia/reperfusion by contributing to myocellular injury and necrosis 1,2 and to microvascular no-reflow. 3 An accurate, noninvasive method for routinely assessing inflammation is not currently available but would be valuable for further characterizing the contribution of inflammation to reperfusion injury in patients and for evaluating new treatment strategies that attenuate postischemic leukocyte recruitment.We have recently demonstrated that inflammation can be assessed using contrast-enhanced ultrasound with microbubbles that bind to activated leukocytes adherent to the venular endothelium. 4 -6 Leukocyte avidity for lipid microbubbles has been greatly enhanced by incorporating phosphatidylserine (PS) into the shell, which increases microbubble retention in inflamed tissue. 6 In this study, we hypothesized that the severity of myocardial inflammation after ischemia/ reperfusion injury could be assessed both spatially and temporally using myocardial contrast echocardiography (MCE) with leukocyte-targeted microbubbles. Methods Animal PreparationThe study was approved by the Animal Research Committee at the University of Virginia. Nine anesthetized open-chest dogs (30 to 35 kg) were studied (Haycock Kennels). Ultrasound flow probes were placed around proximal portions of the left anterior descending (LAD) and left c...

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Section: Discussionmentioning

confidence: 99%

Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography

Christiansen¹,

Leong‐Poi²,

Klibanov³

et al. 2002

ACC Current Journal Review

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“…10 Some microbubble agents initially introduced as blood flow tracers for myocardial contrast echocardiography (MCE) are adhesive to and phagocytosed by leukocytes, including macrophages. 18,19 The microbubbles interacting with leukocytes remain acoustically active and provide for ultrasound imaging of inflammation. 19 -22 Therefore, in the present study, we sought to clarify whether leukocytetargeted MCE can provide for the noninvasive detection of acute cardiac rejection and enables quantitative assessment of the magnitude of infiltration of monocyte/macrophages and T cells and the histological severity of acute cardiac rejection.…”

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confidence: 99%

Leukocyte-Targeted Myocardial Contrast Echocardiography Can Assess the Degree of Acute Allograft Rejection in a Rat Cardiac Transplantation Model

et al. 2004

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Background-Repetitive endomyocardial biopsies are necessary to monitor the effects of immunosuppressants after cardiac transplantation. Contrast ultrasound with microbubble targeting of leukocytes detects acute leukocyte infiltration. We examined whether leukocyte-targeted myocardial contrast echocardiography (MCE) could provide for the quantitative assessment of acute cardiac rejection. Methods and Results-Hearts from Brown Norway rats or Lewis rats were transplanted into other Brown Norway rats. Isografts and groups of allografts either untreated or treated with cyclosporin A (CsA) at a low dose (3 mg · kg) from 3 days before transplantation were compared at posttransplantation day 3. Echocardiography-derived left ventricular wall thickening was comparable among the 4 groups. Myocardial blood flow assessed with MCE, relating pulsing intervals with signal intensity (SI), was slightly decreased only in untreated allografts. However, myocardial SI (in gray levels) obtained after a 10-minute period allowing microbubble-leukocyte interactions after contrast injection exhibited a clear gradient in these groups (12Ϯ2 in untreated allografts, 9Ϯ5 in allografts treated with low-dose CsA, 6Ϯ3 in allografts treated with high-dose CsA, and 2Ϯ1 in isografts, PϽ0.001). The pattern of difference in SI among the groups agreed well with that in ED-1-positive cell (macrophage) count (25Ϯ7, 12Ϯ4, 5Ϯ3, and 1Ϯ0 cells per high-power field, respectively, PϽ0.001), which correlated with CD3-positive cell (T lymphocyte) count (33Ϯ5, 22Ϯ5, 9Ϯ4, and 1Ϯ0 cells per high-power field, respectively, PϽ0.001). Conclusions-Leukocyte-targeted MCE can noninvasively assess the degree of rejection in transplanted hearts by directly revealing the magnitude of intramyocardial infiltration of macrophages and T lymphocytes.

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“…Previous studies have demonstrated that the attachment of microbubbles to the vessel walls in areas of injury was partially due to a complement component (4,11,12). However, the mechanism by which this occurs early after injury (i.e.…”

Section: Discussionmentioning

confidence: 99%

Albumin-based Microbubbles Bind Up-regulated Scavenger Receptors following Vascular Injury

Anderson

Duryee

Anchan

et al. 2010

Journal of Biological Chemistry

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We have shown previously that perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind to injured vascular tissue and can be detected with ultrasound imaging techniques. Prior studies have shown that scavenger receptors (SRs) are regulators of innate and adaptive immune responses and are involved in the progression of vascular disease such as atherosclerosis. In this study, we sought to determine the molecular mechanism of PESDA binding to ballooninjured vasculature. RT-PCR analysis of angioplastied aortas demonstrated a significantly (p < 0.01) increased expression of SRs. Binding to SRs was confirmed using SR-expressing CHO cells, and this binding was blocked by competitive inhibition with the SR-binding ligands oxidized LDL and malondialdehyde-acetaldehyde-modified LDL. Confocal imaging confirmed the co-localization of PESDA microbubbles to CD36, SRB-1, and Toll-like receptor 4, but not to monocytes/macrophages. This study demonstrates that PESDA binds to SRs and that this binding is in major part dependent upon the oxidized nature of PESDA microbubble shell proteins. The extent of SR mRNA expression was increased with injury and associated with microbubble retention as defined by scanning electron microscopy and immunohistochemistry. These findings clarify the mechanisms of how albumin-based microbubbles bind to injured and inflamed vasculature and further support the potential of this imaging technique to detect early vascular innate inflammatory pathophysiologic processes.The complexities of vascular inflammation and disease are multifaceted, and although our current clinical treatments are effective, there is a need to refine patient treatment regimens and risk stratification tools. Standard risk factors for the development of coronary heart disease include age, hypertension, dyslipidemia, diabetes, and tobacco use (1). Although these measures are linked to the development of atheromatous plaques and coronary heart disease, there is an underestimation of subclinical atherosclerosis (2, 3). For example, a substantial proportion of men and women with an intermediate Framingham risk score (10 -19%, 10-year coronary heart disease risk) had a higher than predicted atherosclerotic burden (3). This limitation in the predictive power of the Framingham risk score is postulated to be secondary to the lack of representation of other risk modifiers such as inflammation (2, 3).Currently, there is no gold standard for detecting inflammation within the vascular wall. Perfluorocarbon-exposed sonicated dextrose albumin (PESDA) 2 microbubbles interact with and bind to sites of endothelial dysfunction using contrast pulse sequencing ultrasound (4, 5). However, the mechanism(s) by which albumin-based microbubbles bind and interact with the injured vascular wall has yet to be fully determined. This study details in part the nature of PESDA binding to injured vessels and how this binding may play a role in the non-invasive detection of vascular wall injury and innate inflammatory responses. EXPERIMENTAL PRO...

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Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes

Cited by 216 publications

References 38 publications

Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography

Noninvasive imaging of myocardial reperfusion injury using leukocyte-targeted contrast echocardiography

Leukocyte-Targeted Myocardial Contrast Echocardiography Can Assess the Degree of Acute Allograft Rejection in a Rat Cardiac Transplantation Model

Albumin-based Microbubbles Bind Up-regulated Scavenger Receptors following Vascular Injury

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