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Dirk M. Hermann and Christian M. MatterInduced Reperfusion Injury After Stroke RevisitedTissue Plasminogen Activator

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is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulationdoi: 10.1161/CIRCULATIONAHA.107.712380

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Tissue Plasminogen ActivatorInduced Reperfusion InjuryAfter Stroke Revisited

Dirk M. Hermann, MD; Christian M. Matter, MD

Intravenous thrombolysis with tissue plasminogen activator(tPA) is an established treatment of acute ischemic strokein humans.1 When delivered within 3 hours after symptomonset, tPA reduces neurological deficits and improves thefunctional outcome of stroke patients.1 However, this im-provement in recovery is achieved at the expense of anincreased incidence in symptomatic intracranial hemorrhage,which occurs in6% of patients.1 Intracranial hemorrhage isa typical complication of thrombolysis in acute ischemicstroke. Hemorrhages markedly reduce the therapeutic benefitof tPA.

Article p 411

Parenchymal bleeding after stroke is attributed to leakinessof the blood-brain barrier.2 On acute ischemia, fine-tunedchemokine 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 proteolyticenzymes, including matrix metalloproteinase (MMP)-2 andMMP-9,3 that induce blood-brain barrier breakdown andfacilitate vascular rupture. On release of other chemoattrac-tant molecules, polymorphonuclear neutrophils enter thebrain parenchyma, imposing massive oxidative stress on the

reperfused tissue.3

tPA therapy of acute ischemic stroke increases both reper-fusion damage and hemorrhage risk. As such, thethrombolytic promotes matrix degradation in the ischemicbrain parenchyma via activation of MMP-9.4 Furthermore, itimposes oxidative stress by upregulation of inducible nitricoxide synthase, which is also a proinflammatory enzyme,5

and induces vascular disturbances reflected by downregula-tion of endothelial nitric oxide synthase.6,7 As a consequence,neuronal injury is facilitated in a caspase-8dependent way.8

This process is controlled by activated protein C.4,8 The factthat 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 effectorspropagating the actions of tPA remain unknown.

In this issue of Circulation, Strbian and colleagues10 reportthat MCs are involved in both brain hemorrhage and reper-fusion injury after tPA treatment. The authors demonstratethat both pharmacological MC stabilization and genetic MCdeficiency alleviate the ability of tPA to increase brainedema, polymorphonuclear neutrophil accumulation, andhemorrhage risk. Their data suggest that MCs represent acommon denominator of tPA-induced reperfusion injury andbrain hemorrhage. These findings may have a clinical impactin that therapeutic efforts directed at MC stabilization mayhelp to decrease complications of thrombolysis.

MCs are involved in host defense responses to allergensand have recently been recognized to play a role in inflam-matory processes such as autoimmune diseases11 and athero-sclerosis.12 Considering the role of MCs, striking parallelsexist between tPA-induced reperfusion injury and the ruptureof atherosclerotic plaques (the Figure). In the central nervoussystem, MCs accumulate in inflamed brain areas,11 whereasin atherosclerosis, MCs are increased in shoulder regions ofvulnerable plaques.13 Given the increased susceptibility ofplaque shoulders to rupture, MCs appear well positioned asgatekeepers of plaque vulnerability. The invasion of MCs intotarget tissues is mediated by eotaxin, a chemoattractant that

interacts with the chemokine receptor CCR3.3

Once migrated into the tissue, activated MCs undergodegranulation, a process that is directly stimulated by tPA, asStrbian and colleagues show. Degranulating MCs releasepreformed substances such as the peptides histamine andbradykinin, which induce vasodilation and blood-brain bar-rier permeability (the Figure).14 Histamine also has thrombo-genic effects, inducing tissue factor in endothelial and vas-cular smooth muscle cells,15 and may promote atherosclerosis(the Figure). The presence of the histamine-synthesizingenzyme histidine decarboxylase and of histamine receptors-1and -2 (H1, H2) in atherosclerotic plaques,16 the decreasedplaque formation in histidine decarboxylasedeficient

mice,17 and the reduced intima proliferation after pharmaco-logical H1but not H2receptor blockade18 support this notion.

Besides histamine and bradykinin, MCs release severalother molecules (the Figure) such as the anticoagulant hepa-rin, which may promote brain hemorrhage and act as growthinhibitor of vascular smooth muscle cells19; the proinflamma-tory cytokines tumor necrosis factor- and interleukin-6;various chemokines that attract neutrophils, macrophages, orT 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 andchymase activate inactive MMPs to their proteolytic forms,10

thus enhancing vascular permeability and plaque vulnerabil-ity. In addition, chymase may generate active angiotensin II,

The opinions expressed in this article are not necessarily those of theeditors or of the American Heart Association.

From the Departments of Neurology (D.M.H.) and Cardiology, Car-diovascular Center (C.M.M.), University Hospital Zurich; and Cardio-vascular Research (C.M.M.), Institute of Physiology, University ofZurich, Zurich, Switzerland.

Reprint requests to Dr Dirk M. Hermann, Department of Neurology,University Hospital Zurich, Frauenklinikstr 26, CH-8091 Zrich, Swit-zerland. E-mail [email protected]

(Circulation.2007;116:363-365.)

2007 American Heart Association, Inc.

Circulationis available at http://www.circulationaha.orgDOI: 10.1161/CIRCULATIONAHA.107.712380

363

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another vasoactive and proinflammatory peptide, from itsinactive precursor angiotensin I.

A limitation of the study by Strbian and colleagues10

with respect to future clinical applications is that the MCstabilizer cromoglycate had to be administered directlyinto the cerebrospinal fluid via the intraventricular routebecause this substance does not cross the blood-brainbarrier. This approach is not applicable under clinicalconditions in which the systemic (preferably intravenous)

delivery of pharmacological compounds is desirable. Fur-thermore, Strbian et al investigated a model of mechani-cally induced ischemia-reperfusion injury, not of cerebralthromboembolism/thrombolysis, which would be clinicallymore relevant. Thus, proof-of-concept studies are requiredto determine whether the benefits of MC stabilization canbe applied to thromboembolic stroke.

We propose that the bench-to-bedside translation offindings from experimental animals to human patients isa priority issue for the future, given that reperfusiontherapies have not achieved implementation in acute is-chemic stroke similar to that in acute myocardial infarc-tion. Even in large university hospitals with excellent

infrastructures, thrombolysis rates hardly exceed 5% to10% of patients with stroke admitted to stroke units. Theselow thrombolysis rates in stroke can be attributed to localbleeding complications, which may result at least in partfrom secondary reperfusion injury triggered by tPA.

On the pathophysiological level, the striking parallelsbetween the role of MCs in inflammatory responses in thebrain and atherosclerotic plaque rupture deserve our attention.Along this line, the role of allergen-induced or IgE- orMC-mediated immune responses in atherogenesis, thrombo-sis, or reperfusion injury would be a promising researchavenue. The data by Strbian and colleagues10 suggest that IgE

receptor blockade might mimic the beneficial effects ofpharmacological MC stabilizers in the stroke brain. A better

understanding of the mechanisms underlying tPA-inducedreperfusion injury may provide valuable tools to decrease thedetrimental effects of tPA, thereby increasing its therapeuticpotential in stroke patients. Such insights will cross-fertilizeresearch concepts in the cardiovascular field.

Sources of FundingDr Hermann has received research grants from the NCCR Neuralplasticity and repair, the University Research Priority ProgramIntegrative Human Physiology at the University of Zrich, the Swiss

National Science Foundation (3200B0 100790/1 and 3200B0112056/1), the Swiss Heart Foundation, the Hartmann-Mller Foun-dation, and the Betty and David Koetser Foundation. Dr Matter holdsgrants from the European Union (G5RDCT200100532 andBundesamt fr Bildung und Wissenschaft), the Swiss NationalScience Foundation (31114094/1 and 3100068118), the SwissHeart Foundation, and the University Research Priority ProgramIntegrative Human Physiology at the University of Zrich.

DisclosuresNone.

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ciation of outcome with early stroke treatment: pooled analysis ofATLANTIS, ECASS, and NINDS rtPA stroke trials. Lancet. 2004;363:768774.

2. Hermann DM, Bassetti CL. Implications of ATP-binding cassette trans-porters for brain pharmacotherapies. Trends Pharmacol Sci. 2007;28:128134.

3. Charo IF, Ransohoff RM. The many roles of chemokines and chemokinereceptors in inflammation. N Engl J Med. 2006;354:610621.

4. Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, Liu D,Maggirwar SB, Deane R, Fernandez JA, LaRue B, Griffin JH, Chopp M,Zlokovic BV. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med. 2006;12:12781285.

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6. Kilic E, Kilic , Matter CM, Lscher TF, Bassetti CL, Hermann DM.

Aggravation of focal cerebral ischemia by tissue plasminogen activator isreversed by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor

bradykinin

histamine

thrombosis,atherogenesis

vasodilation,

vascularpermeability

angiotensin IIactivation

MMP activation

vascular permeability and

hemorrhage, plaque rupture

vasoconstriction,

atherogenesis

++++

++

cytokines,chemokines,

bFGF

heparin

anticoagulation,brain hemorrhage

vulnerable

plaquereperfusedbrain

chymase

tryptase

t-PA

inflammation,atherogenesis,

plaque rupture

Effects of tPA in the ischemic tissuemediated by MCs. tPA promotes MCdegranulation after acute ischemic strokein both the reperfused brain parenchymaand vulnerable atherosclerotic plaques,

leading to the release of various media-tors such as the vasoactive peptides his-tamine and bradykinin, the anticoagulantheparin, various cytokines and chemo-kines, basic fibroblast growth factor(bFGF), and the proteases tryptase andchymase. These mediators exert a vari-ety of actions in the reperfused tissueaffecting vasomotion, vascular perme-ability, inflammation, thrombosis, athero-genesis, and plaque rupture, all of whichmay increase the susceptibility for sec-ondary injury and brain hemorrhage.Background figure reproduced with kindpermission from AMP Laboratory GmbH,Mainz, Germany.

364 Circulation July 24, 2007

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but does not depend on endothelial NO synthase. Stroke. 2005;36:332336.

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10. Strbian D, Karjalainen-Lindsberg M-L, Kovanen PT, Tatlisumak T,Lindsberg PJ. Mast cell stabilization reduces hemorrhage formation andmortality after administration of thrombolytics in experimental ischemicstroke. Circulation. 2007;116:411418.

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12. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease.N Engl J Med. 2005;352:16851695.

13. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cellsat the site of coronary atheromatous erosion or rupture in myocardialinfarction. Circulation. 1995;92:10841088.

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16. Murata Y, Tanimoto A, Wang KY, Tsutsui M, Sasaguri Y, De Corte F,Matsushita H. Granulocyte macrophage-colony stimulating factorincreases the expression of histamine and histamine receptors in mono-cytes/macrophages in relation to arteriosclerosis. Arterioscler ThrombVasc Biol. 2005;25:430435.

17. Sasaguri Y, Wang KY, Tanimoto A, Tsutsui M, Ueno H, Murata Y,Kohno Y, Yamada S, Ohtsu H. Role of histamine produced by bonemarrow-derived vascular cells in pathogenesis of atherosclerosis. CircRes. 2005;96:974981.

18. Miyazawa N, Watanabe S, Matsuda A, Kondo K, Hashimoto H,Umemura K, Nakashima M. Role of histamine H1 and H2 receptorantagonists in the prevention of intimal thickening. Eur J Pharmacol.1998;362:5359.

19. Edelman ER, Adams DH, Karnovsky MJ. Effect of controlled adventitialheparin delivery on smooth muscle cell proliferation following endothe-lial injury. Proc Natl Acad Sci U S A. 1990;87:37733777.

20. Lappalainen H, Laine P, Pentikainen MO, Sajantila A, Kovanen PT. Mastcells in neovascularized human coronary plaques store and secrete basicfibroblast growth factor, a potent angiogenic mediator. ArteriosclerThromb Vasc Biol. 2004;24:18801885.

KEYWORDS: Editorials blood-brain barrier inflammation mast cells tissue plasminogen activator

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