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Loss of shear stress induces leukocyte-mediated cytokine release and blood–brain barrier failure in dynamic in vitro blood–brain barrier model

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  • This study was presented in part at the Gordon Research Conference, Tilton, NH, 2004.

Abstract

Brain ischemia is associated with an acute release of pro-inflammatory cytokines, notably TNF-α and IL-6 and failure of the blood–brain barrier. Shear stress, hypoxia-hypoglycemia, and blood leukocytes play a significant role in blood–brain barrier failure during transient or permanent ischemia. However, these mechanisms have not been studied as independent variables for in vitro ischemia. The present study, using a dynamic in vitro blood–brain barrier model, showed that flow cessation/reperfusion under normoxia–normoglycemia or hypoxia–hypoglycemia without blood leukocytes in the luminal perfusate had a modest, transient effect on cytokine release and blood–brain barrier permeability. By contrast, exposure to normoxic–normoglycemic flow cessation/reperfusion with blood leukocytes in the luminal perfusate led to a significant increase in TNF-α and IL-6, accompanied by biphasic blood–brain barrier opening. Enhanced permeability was partially prevented with an anti-TNF-α antibody. In leukocyte-free cartridges, the same levels of IL-6 had no effect, while TNF-α caused a moderate increase in blood–brain barrier permeability, suggesting that blood leukocytes are the prerequisite for cytokine release and blood–brain barrier failure during reduction or cessation of flow. These cells induce release of TNF-α early after ischemia/reperfusion; TNF-α triggers release of IL-6, since blockade of TNF-α prevents IL-6 release, whereas blockade of IL-6 induces TNF-α release. Pre-treatment of blood leukocytes with the cyclooxygenase (COX) inhibitor, ibuprofen, inhibited cytokine release and completely preserved blood–brain barrier permeability during the reperfusion period. In conclusion, loss of flow (flow cessation/reperfusion) independent of hypoxia–hypoglycemia plays a significant role in blood–brain barrier failure by stimulating leukocyte-mediated inflammatory mechanisms. © 2005 Wiley-Liss, Inc.

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