Published online before print August 21, 2003, doi: 10.1161/01.STR.0000091273.86523.59
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(Stroke. 2003;34:2171.)
© 2003 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Cooling Matrix Metalloproteinases to Improve Thrombolysis in Acute Ischemic Stroke
Neurovascular Research Laboratory, Stroke Unit, Vall d’Hebron Hospital, Barcelona, Spain
Although their history is only recent, the role of matrix metalloproteinases (MMPs) in ischemic stroke first began to be understood when MMP expression was found to be significantly increased and implicated in blood brain barrier (BBB) disruption, edema formation, and hemorrhagic transformation in animal models of cerebral ischemia.1 Further study demonstrated the pharmacological blocking of these enzymes and the development of an MMP-9 knockout model, showing reduced infarct volumes and confirming its deleterious role.2 Recently, the participation of MMP-9 has also been demonstrated in vivo after human stroke and shown to be related to neurological worsening, infarct size, and hemorrhagic transformation.3,4
Two innovative points are raised by Horstmann et al5: first, the global study of several MMPs, together with their inhibitors and substrates, making their deleterious role more comprehensive; and second, the modification of their temporal profiles regarding different acute stroke treatments.
Concomitant with the increase in MMP-9, Horstmann et al report an increase in laminin breakdown products. This points to proteolytic degradation of critical BBB components by MMP-9, possibly explaining its deleterious role through dissolution of the basal lamina (BL). The BL matrix is constructed from type IV collagen chains and a second polymer network derived from laminin. Entactin connects both complexes, and fibronectin connects the BL with the surrounding tissue and the extracellular matrix. Parallel losses of these BL components have been shown to contribute to loss of brain microvascular integrity6 and are now demonstrated in human stroke.
Regarding natural MMP inhibitors, a more decisive role was expected for some of these members, such as TIMP-1, in the MMP network. However, the present study fails to show that TIMP-1 blocks the response of MMP-9 to ischemia, although the level of these inhibitors during the very first hours of stroke onset was not properly explored, and therefore its definitive contribution remains unknown.
Highlights of this study include the possibility that hypothermia modulates neuroinflammation by decreasing MMP-9 plasmatic level and weakly suggests that tPA may activate MMP-9 as an unwanted side effect. The main caveat is that treatments were initiated before blood samples were obtained. This lack of pretreatment baseline values makes it difficult to measure the effect of each intervention.
In support of this "cool" finding, there is experimental evidence that moderate hypothermia suppresses the inflammatory response. The neuroprotective effect of hypothermia is related to nuclear factor-
B inhibition, reduction of endothelial adhesion molecule expression, and leukocyte infiltration.7,8 Interestingly, the MMP-9 promoter region contains a nuclear factor-B site, by which inflammation may regulate MMP-9 transcription. It is also known that neutrophils utilize this MMP for migration. Both facts are clear links to explain MMP-9 reduction after therapeutic hypothermia.
Another intriguing point is MMP-9 activation by tPA, suggested because cleaved forms of MMP-9 are present only in patients of the thrombolysis group. As plasmin is involved in the cascade that processes proMMP-9 to the active form,9 the administration of tPA may activate and promote the destructive potential of this enzyme. This hypothesis explains the reduction of tPA-induced hemorrhages after administering a MMP inhibitor (BB-94) in a rabbit model of embolic stroke.10 Similarly, a positive graded response exists between MMP-9 production and the degree and extent of brain bleeding after thrombolysis in human stroke.11
Although some authors are researching these points extensively and generating new explanations for tPA-mediated MMP-9 activation in animal stroke models,12 experiments are needed to confirm the relevance of this issue in humans, with samples obtained before and promptly after tPA infusion because of the short half-life of active MMP-9 and of tPA itself.
If hypothermia decreases MMP-9 and tPA increases the expression of this molecule, a combination of both therapeutic strategies seems to be an attractive, logical approach for limiting damage from ischemia. A pilot study has already demonstrated the safety and feasibility of this combination,13 but a limitation in clinical practice for this combination therapy might be the reduced efficacy of tPA in the temperature range proposed for hypothermic treatment of acute ischemic stroke.14
In conclusion, new studies are needed to confirm some of the interesting hypotheses proposed by Horstmann et al. Meanwhile, intensive research in the development of MMP-9 inhibitors is mandatory. At present the therapeutic time window is narrow. In the future, however, the administration of tPA to stroke patients in combination with hypothermia and MMP inhibitors even beyond 3 hours might reduce the likelihood of bleeding complications and could provide further therapeutic benefit.
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2. Asahi M, Asahi K, Jung J, del Zoppo G, Fini ME, Lo EH. Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab. 2000; 20: 1681–1689.[CrossRef][Medline] [Order article via Infotrieve]
3. Montaner J, Alvarez-Sabín J, Molina C, Anglés A, Abilleira S, Arenillas J, González MA, Monasterio J. Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke. 2001; 32: 1759–1766.
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11. Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribó M, Quintana M, Alvarez-Sabín J. Matrix metalloproteinase (MMP-9) pre-treatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation. 2003; 107: 598–603.
12. Tsuji K, Aoki T, Arai K, Tsirka S, Lo EH. Tissue plasminogen activator triggers matrix metallproteinase-9 upregulation after cerebral ischemia: pharmacologic and genetic studies. Stroke. 2003; 34: 297–298.
13. Krieger DW, De Georgia MA, Abou-Chebl A, Andrefsky JC, Sila CA, Katzan IL, Mayberg MR, Furlan AJ. Cooling for Acute Ischemic Brain Damage (COOL AID): an open pilot study of induced hypothermia in acute ischemic stroke. Stroke. 2001; 32: 1847–1854.
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