doi: 10.1161/CIRCULATIONAHA.107.712380
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(Circulation. 2007;116:363-365.)
© 2007 American Heart Association, Inc.
Editorial |
Tissue Plasminogen Activator–Induced Reperfusion Injury After Stroke Revisited
From the Departments of Neurology (D.M.H.) and Cardiology, Cardiovascular Center (C.M.M.), University Hospital Zurich; and Cardiovascular Research (C.M.M.), Institute of Physiology, University of Zurich, Zurich, Switzerland.
Reprint requests to Dr Dirk M. Hermann, Department of Neurology, University Hospital Zurich, Frauenklinikstr 26, CH-8091 Zürich, Switzerland. E-mail dirk.hermann{at}usz.ch
Key Words: Editorials • blood-brain barrier • inflammation • mast cells • tissue plasminogen activator
Intravenous thrombolysis with tissue plasminogen activator (tPA) is an established treatment of acute ischemic stroke in humans.1 When delivered within 3 hours after symptom onset, tPA reduces neurological deficits and improves the functional outcome of stroke patients.1 However, this improvement in recovery is achieved at the expense of an increased incidence in symptomatic intracranial hemorrhage, which occurs in 
6% of patients.1 Intracranial hemorrhage is a typical complication of thrombolysis in acute ischemic stroke. Hemorrhages markedly reduce the therapeutic benefit of tPA.
Article p 411
Parenchymal bleeding after stroke is attributed to leakiness of the blood-brain barrier.2 On acute ischemia, fine-tuned chemokine responses lead to the recruitment of T cells, macrophages, and mast cells (MCs) into the brain tissue.3 These inflammatory cells release a variety of proteolytic enzymes, including matrix metalloproteinase (MMP)-2 and MMP-9,3 that induce blood-brain barrier breakdown and facilitate vascular rupture. On release of other chemoattractant molecules, polymorphonuclear neutrophils enter the brain parenchyma, imposing massive oxidative stress on the reperfused tissue.3
tPA therapy of acute ischemic stroke increases both reperfusion damage and hemorrhage risk. As such, the thrombolytic promotes matrix degradation in the ischemic brain parenchyma via activation of MMP-9.4 Furthermore, it imposes oxidative stress by upregulation of inducible nitric oxide synthase, which is also a proinflammatory enzyme,5 and induces vascular disturbances reflected by downregulation of endothelial nitric oxide synthase.6,7 As a consequence, neuronal injury is facilitated in a caspase-8–dependent way.8 This process is controlled by activated protein C.4,8 The fact that the half-life of tPA itself is short (8 to 12 minutes)9 exemplifies the profound influence of this thrombolytic compound on acute ischemic injury. The common effectors propagating the actions of tPA remain unknown.
In this issue of Circulation, Strbian and colleagues10 report that MCs are involved in both brain hemorrhage and reperfusion injury after tPA treatment. The authors demonstrate that both pharmacological MC stabilization and genetic MC deficiency alleviate the ability of tPA to increase brain edema, polymorphonuclear neutrophil accumulation, and hemorrhage risk. Their data suggest that MCs represent a common denominator of tPA-induced reperfusion injury and brain hemorrhage. These findings may have a clinical impact in that therapeutic efforts directed at MC stabilization may help to decrease complications of thrombolysis.
MCs are involved in host defense responses to allergens and have recently been recognized to play a role in inflammatory processes such as autoimmune diseases11 and atherosclerosis.12 Considering the role of MCs, striking parallels exist between tPA-induced reperfusion injury and the rupture of atherosclerotic plaques (the Figure). In the central nervous system, MCs accumulate in inflamed brain areas,11 whereas in atherosclerosis, MCs are increased in shoulder regions of vulnerable plaques.13 Given the increased susceptibility of plaque shoulders to rupture, MCs appear well positioned as gatekeepers of plaque vulnerability. The invasion of MCs into target tissues is mediated by eotaxin, a chemoattractant that interacts with the chemokine receptor CCR3.3
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Once migrated into the tissue, activated MCs undergo degranulation, a process that is directly stimulated by tPA, as Strbian and colleagues show. Degranulating MCs release preformed substances such as the peptides histamine and bradykinin, which induce vasodilation and blood-brain barrier permeability (the Figure).14 Histamine also has thrombogenic effects, inducing tissue factor in endothelial and vascular smooth muscle cells,15 and may promote atherosclerosis (the Figure). The presence of the histamine-synthesizing enzyme histidine decarboxylase and of histamine receptors-1 and -2 (H1, H2) in atherosclerotic plaques,16 the decreased plaque formation in histidine decarboxylase–deficient mice,17 and the reduced intima proliferation after pharmacological H1 but not H2 receptor blockade18 support this notion.
Besides histamine and bradykinin, MCs release several other molecules (the Figure) such as the anticoagulant heparin, which may promote brain hemorrhage and act as growth inhibitor of vascular smooth muscle cells19; the proinflammatory cytokines tumor necrosis factor-
and interleukin-6; various chemokines that attract neutrophils, macrophages, or T cells to the site of injury11; basic fibroblast growth factor, which stimulates vascular smooth muscle cell proliferation20; and the serine proteases tryptase and chymase.12 Tryptase and chymase activate inactive MMPs to their proteolytic forms,10 thus enhancing vascular permeability and plaque vulnerability. In addition, chymase may generate active angiotensin II, another vasoactive and proinflammatory peptide, from its inactive precursor angiotensin I.
A limitation of the study by Strbian and colleagues10 with respect to future clinical applications is that the MC stabilizer cromoglycate had to be administered directly into the cerebrospinal fluid via the intraventricular route because this substance does not cross the blood-brain barrier. This approach is not applicable under clinical conditions in which the systemic (preferably intravenous) delivery of pharmacological compounds is desirable. Furthermore, Strbian et al investigated a model of mechanically induced ischemia-reperfusion injury, not of cerebral thromboembolism/thrombolysis, which would be clinically more relevant. Thus, proof-of-concept studies are required to determine whether the benefits of MC stabilization can be applied to thromboembolic stroke.
We propose that the bench-to-bedside translation of findings from experimental animals to human patients is a priority issue for the future, given that reperfusion therapies have not achieved implementation in acute ischemic stroke similar to that in acute myocardial infarction. Even in large university hospitals with excellent infrastructures, thrombolysis rates hardly exceed 5% to 10% of patients with stroke admitted to stroke units. These low thrombolysis rates in stroke can be attributed to local bleeding complications, which may result at least in part from secondary reperfusion injury triggered by tPA.
On the pathophysiological level, the striking parallels between the role of MCs in inflammatory responses in the brain and atherosclerotic plaque rupture deserve our attention. Along this line, the role of allergen-induced or IgE- or MC-mediated immune responses in atherogenesis, thrombosis, or reperfusion injury would be a promising research avenue. The data by Strbian and colleagues10 suggest that IgE receptor blockade might mimic the beneficial effects of pharmacological MC stabilizers in the stroke brain. A better understanding of the mechanisms underlying tPA-induced reperfusion injury may provide valuable tools to decrease the detrimental effects of tPA, thereby increasing its therapeutic potential in stroke patients. Such insights will cross-fertilize research concepts in the cardiovascular field.
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Acknowledgments |
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Sources of Funding
Dr Hermann has received research grants from the NCCR "Neural plasticity and repair," the University Research Priority Program Integrative Human Physiology at the University of Zürich, the Swiss National Science Foundation (3200B0–100790/1 and 3200B0–112056/1), the Swiss Heart Foundation, the Hartmann-Müller Foundation, and the Betty and David Koetser Foundation. Dr Matter holds grants from the European Union (G5RD–CT–2001–00532 and Bundesamt für Bildung und Wissenschaft), the Swiss National Science Foundation (31–114094/1 and 3100–068118), the Swiss Heart Foundation, and the University Research Priority Program Integrative Human Physiology at the University of Zürich.
Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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