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Loss of flow induces leukocyte-mediated MMP/TIMP imbalance in dynamic in vitro blood-brain barrier model: role of pro-inflammatory cytokines.

Authors: Krizanac-Bengez, L  Hossain, M  Fazio, V  Mayberg, M  Janigro, D 
Citation: Krizanac-Bengez L, etal., Am J Physiol Cell Physiol. 2006 Oct;291(4):C740-9. Epub 2006 May 17.
Pubmed: (View Article at PubMed) PMID:16707552
DOI: Full-text: DOI:10.1152/ajpcell.00516.2005

There is substantial evidence linking blood-brain barrier (BBB) failure during cerebral ischemia to matrix metalloproteinases (MMP). BBB function may be affected by loss of shear stress under normoxia/normoglycemia, as during cardiopulmonary bypass procedures. The present study used an in vitro flow-perfused BBB model to analyze the individual contributions of flow, cytokine levels, and circulating blood leukocytes on the release/activity of MMP-9, MMP-2, and their endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs), TIMP-1, and TIMP-2. The presence of circulating blood leukocytes under normoxic/normoglycemic flow cessation/reperfusion significantly increased the luminal levels of MMP-9 and activity of MMP-2, accompanied by partial reduction of TIMP-1, complete reduction of TIMP-2 and increased BBB permeability. These changes were not observed during constant flow with circulating blood leukocytes, or after normoxic/normoglycemic or hypoxic/hypoglycemic flow cessation/reperfusion without circulating blood leukocytes. The addition of anti-IL-6 or anti-TNF-alpha antibody in the lumen before reperfusion suppressed the levels of MMP-9 and activity of MMP-2, had no effect on TIMP-1, and completely restored TIMP-2 and BBB integrity. Injection of TIMP-2 in the lumen before reperfusion prevented the activation of MMP-2 and BBB permeability. These data indicate that blood leukocytes and loss of flow are major factors in the activation of MMP-2, and that cytokine-mediated differential regulation of TIMP-1 and TIMP-2 may contribute significantly to BBB failure.


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Additional Information

CRRD Object Information
CRRD ID: 1598575
Created: 2006-12-05
Species: All species
Last Modified: 2006-12-05
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.