Journal of Leukocyte Biology Myeloid cells, immune suppression, tumor immunology
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Originally published online as doi:10.1189/jlb.0907606 on April 7, 2008

Published online before print April 7, 2008
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(Journal of Leukocyte Biology. 2008;84:207-214.)
© 2008 by Society for Leukocyte Biology

Tissue plasminogen activator (t-PA) promotes neutrophil degranulation and MMP-9 release

Eloy Cuadrado*,1, Laura Ortega*,1, Mar Hernández-Guillamon*, Anna Penalba*, Israel Fernández-Cadenas*, Anna Rosell*,{dagger} and Joan Montaner*,2

* Neurovascular Research Laboratory, Neurovascular Unit, Department of Neurology, Universitat Autònoma de Barcelona, Institut de Recerca, Hospital Vall d’Hebron, Barcelona, Spain; and
{dagger} Neuroprotection Research Laboratory, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA

2Correspondence: Neurovascular Research Laboratory, Neurovascular Unit, Institut de Recerca, Hospital Vall d’Hebron, Pg Vall d’Hebron 119-129, 08035 Barcelona, Spain. E-mail: 31862jmv{at}comb.es

Recombinant tissue plasminogen activator (t-PA), the only approved stroke treatment, is used for clot lysis within the occluded brain artery. Unfortunately, matrix metalloproteinase-9 (MMP-9) concentration increases after t-PA treatment and has been related to hemorrhagic transformation after ischemic stroke. Although the exact cellular source of brain MMP-9 remains unknown, invading, inflammatory cells, such as neutrophils, release MMP-9 to cross the blood brain barrier. Therefore, we hypothesize that the most feared side effect of stroke reperfusion therapy, brain hemorrhage, is related to t-PA-induced MMP-9 release by neutrophils. We show by means of ELISA that t-PA treatment promotes MMP-9, MMP-8, and tissue inhibitor metalloproteinase-2 release from human neutrophils ex vivo within 10 and 30 min. Moreover, by zymography and Western blot, we observed that neutrophils are emptied of MMP-9 content after t-PA treatment at those times. Finally, total internal reflection fluorescent imaging allowed us to observe the t-PA effect on neutrophils, showing the promotion of degranulation on these cells in vivo. Our data suggest that neutrophils are good candidates to be the main source of MMP-9 following t-PA stroke treatment and in consequence, partially responsible for thrombolysis-related brain bleedings.

Key Words: stroke • hemorrhage • TIRF • TIMP-2 • plasmin




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