Impact of the neutrophil response to granulocyte colony-stimulating factor on the risk of hemorrhage when used in combination with tissue plasminogen activator during the acute phase of experimental stroke

Journal of Neuroinflammation

Régis Bordet²  Didier Leys¹  Annabelle Dupont³  Olivier Pétrault²  Maud Laprais²  Catherine Lefebvre¹  Madjid Tagzirt³  Thavarak Ouk²  Sophie Gautier² 

[1] EA 2691 - Service de Neurologie et Pathologies Vasculaires, Institut de Médecine Prédictive et de Recherche Thérapeutique, 1 place de Verdun, Lille cedex F-59037, France;EA 1046 - Département de Pharmacologie médicale, Université de Lille 2 - Faculté de Médecine, 1 place de Verdun, Lille cedex F-59037, France;EA2693 - Laboratoire d’Interface sang-vaisseaux et de réparation cardiovasculaire, Centre Hospitalier Universitaire, 1 place de Verdun, Lille cedex F-59037, France

关键词: Vascular endothelium;    Hemorrhage;    Neutrophil;    G-CSF;    tPA;    Stroke;   

Others  :  803942
DOI  :  10.1186/1742-2094-11-96

 received in 2013-12-31, accepted in 2014-05-13,  发布年份 2014

【 摘 要 】

Background

Granulocyte colony-stimulating factor (G-CSF) is a pharmacologic agent inducing neutrophil mobilization and a new candidate for neuroprotection and neuroregeneration in stroke. Its effects when used in combination with tissue plasminogen activator (tPA) were explored during the acute phase of ischemic stroke.

Methods

We used a middle cerebral artery occlusion (MCAO) model of cerebral ischemia, associated with treatment with tPA, in male spontaneously hypertensive rats (SHR). Granulocyte colony-stimulating factor (G-CSF; 60 μg/kg) was injected just before tPA. Neutrophil response in peripheral blood and in the infarct area was quantified in parallel to the infarct volume. Protease matrix metallopeptidase 9 (MMP-9) release from circulating neutrophils was analyzed by immunochemistry and zymography. Vascular reactivity and hemorrhagic volume in the infarct area was also assessed.

Results

Twenty four hours after ischemia and tPA, G-CSF administration induced a significant increase of neutrophils in peripheral blood (P <0.05). At 72 hours post-ischemia, G-CSF was significantly associated with an increased risk of hemorrhage in the infarct area (2.5 times more likely; P <0.05) and significant cerebral endothelium-dependent dysfunction. Ex vivo, an increased MMP-9 release from neutrophils after tPA administration correlated to the increased hemorrhagic risk (P <0.05). In parallel, G-CSF administration was associated with a decreased neutrophil infiltration in the infarct area (-50%; P <0.05), with a concomitant significant neuroprotective effect (infarct volume: -40%; P <0.05).

Conclusions

We demonstrate that G-CSF potentiates the risk of hemorrhage in experimental stroke when used in combination with tPA by inducing neutrophilia. This effect is concomitant to an increased MMP-9 release from peripheral neutrophils induced by the tPA treatment. These results highlight the potential hemorrhagic risk of associating G-CSF to thrombolysis during the acute phase of stroke.

【 授权许可】

   
2014 Gautier et al.; licensee BioMed Central Ltd.

【 图 表 】

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