Neutrophil Infiltration Increases Matrix Metalloproteinase-9 in the Ischemic Brain after Occlusion/Reperfusion of the Middle Cerebral Artery in Rats

Abstract

Summary:Matrix metalloproteinase-9 (MMP-9) activity increases in the brain during the first day after focal ischemia and might be involved in the pathogenesis of tissue damage. We previously showed MMP-9 in the extracellular space of brain parenchyma along with neutrophil recruitment after ischemia. In the present study, we tested whether neutrophils were a direct source of enhanced MMP-9 in the ischemic brain. Neutrophil infiltration was prevented either by injecting an antibody against ICAM-1, which abrogates neutrophil adhesion to the endothelial vessel wall, or by inducing neutropenia. Onehour intraluminal middle cerebral artery occlusion with reperfusion was induced, and studies were performed at 24 hours. Circulating neutrophils expressed 95-kDa MMP-9 and dimers, and infiltrated neutrophils stained positive for MMP-9. The expression of MMP-9 (mainly 95-kDa proform and dimers and, to a lesser extent, 88-kDa form) increased in brain after ischemia/reperfusion. Treatments preventing neutrophil infiltration failed to preclude the ischemia-induced increase in 88-kDa MMP-9 form and gelatinase activity in neurons and blood vessels. However, these treatments prevented the major increase in 95-kDa MMP-9 form and dimers. We conclude that neutrophil infiltration highly contributes to enhanced MMP-9 in the ischemic brain by releasing MMP-9 proform, which might participate in the tissular inflammatory reaction.

Early Release of HMGB-1 from Neurons after the Onset of Brain Ischemia

“…In this early phase, in vivo and in vitro evidence is consistent with the paradigm that the endothelium promotes inflammation and recruits circulating leukocytes through the upregulation of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1, E-selectin, and P-selectin (del Zoppo and Mabuchi, 2003). These recruited leukocytes then release metalloproteinases, which participate in the breakdown of the neurovascular matrix with consequent blood-brain barrier disruption, edema, and/or hemorrhage (Justicia et al, 2003;Kolev et al, 2003;Maier et al, 2004;Ponnampalam and Mayberg, 2004;Veldhuis et al, 2003;Wang and Lo, 2003). The importance of the inflammatory response in the pathophysiology of ischemic stroke is generally recognized.…”

Metformin ameliorates BSCB disruption by inhibiting neutrophil infiltration and MMP‐9 expression but not direct TJ proteins expression regulation

“…It is widely accepted that in CNS disease, the increased MMP‐9 primarily come from infiltrating neutrophils 15, 16, 17. Removing neutrophils from the circulation prior to SCI with an anti‐neutrophil serum significantly reduces MMP‐9 level, which indicates that the increase in MMP‐9 after SCI come from neutrophils 17.…”

In Vivo Near-Infrared Fluorescence Imaging of Matrix Metalloproteinase Activity after Cerebral Ischemia

“…Indeed, we found that the treatment effect of GM6001 was paralleled by significantly reduced TBRs. Pharmacological intervention of MMPs leads to a marked reduction in lesion size, which might also affect downstream pathophysiological processes that are only indirectly related to MMP activity (Asahi et al, 2000;Rivera et al, 2002;Justicia et al, 2003;Magnoni et al, 2004). Such downstream effects may alter the compartmental distribution of intravenously injected compounds, which complicates the use of genetic or pharmacological manipulation of MMPs as control for the specificity of imaging approaches (Klohs et al, 2008b).…”