Tissue Plasminogen ActivatorInduced Reperfusion Injury After Stroke Revisited

Dirk M. Hermann and Christian M. Matter

Circulation. 2007;116:363-365
doi: 10.1161/CIRCULATIONAHA.107.712380
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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Editorial
Tissue Plasminogen ActivatorInduced Reperfusion Injury
After Stroke Revisited
Dirk M. Hermann, MD; Christian M. Matter, MD

ntravenous 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.
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
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 Zrich, Switzerland. E-mail dirk.hermann@usz.ch
(Circulation. 2007;116:363-365.)
2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.107.712380

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
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,

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364

Circulation

July 24, 2007

reperfused
brain

t-PA

vulnerable
plaque

thrombosis,
atherogenesis
histamine

vasoconstriction,
atherogenesis

bradykinin

vasodilation,
vascular
permeability

angiotensin II
activation
heparin

+
chymase

++

tryptase

MMP activation
vascular permeability and
hemorrhage, plaque rupture

cytokines,
chemokines,
bFGF

anticoagulation,
brain hemorrhage

inflammation,
atherogenesis,
plaque rupture

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

Effects of tPA in the ischemic tissue

mediated by MCs. tPA promotes MC
degranulation after acute ischemic stroke
in both the reperfused brain parenchyma
and vulnerable atherosclerotic plaques,
leading to the release of various mediators such as the vasoactive peptides histamine and bradykinin, the anticoagulant
heparin, various cytokines and chemokines, basic fibroblast growth factor
(bFGF), and the proteases tryptase and
chymase. These mediators exert a variety of actions in the reperfused tissue
affecting vasomotion, vascular permeability, inflammation, thrombosis, atherogenesis, and plaque rupture, all of which
may increase the susceptibility for secondary injury and brain hemorrhage.
Background figure reproduced with kind
permission from AMP Laboratory GmbH,
Mainz, Germany.

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.

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 Zrich, the Swiss
National Science Foundation (3200B0 100790/1 and 3200B0
112056/1), the Swiss Heart Foundation, the Hartmann-Mller Foundation, and the Betty and David Koetser Foundation. Dr Matter holds
grants from the European Union (G5RDCT2001 00532 and
Bundesamt fr Bildung und Wissenschaft), the Swiss National
Science Foundation (31114094/1 and 3100 068118), the Swiss
Heart Foundation, and the University Research Priority Program
Integrative Human Physiology at the University of Zrich.

Disclosures
None.

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KEY WORDS: Editorials blood-brain barrier
tissue plasminogen activator

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inflammation

mast cells