PMID- 16707552
OWN - NLM
STAT- MEDLINE
DCOM- 20061031
LR  - 20200930
IS  - 0363-6143 (Print)
IS  - 0363-6143 (Linking)
VI  - 291
IP  - 4
DP  - 2006 Oct
TI  - Loss of flow induces leukocyte-mediated MMP/TIMP imbalance in dynamic in vitro 
      blood-brain barrier model: role of pro-inflammatory cytokines.
PG  - C740-9
AB  - 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.
FAU - Krizanac-Bengez, Ljiljana
AU  - Krizanac-Bengez L
AD  - Cerebrovascular Research Center, Department of Neurosurgery, Cleveland Clinic 
      Foundation, Cleveland, Ohio 44195, USA. bengezl@ccf.org
FAU - Hossain, Mohammed
AU  - Hossain M
FAU - Fazio, Vince
AU  - Fazio V
FAU - Mayberg, Marc
AU  - Mayberg M
FAU - Janigro, Damir
AU  - Janigro D
LA  - eng
GR  - HL-51614/HL/NHLBI NIH HHS/United States
GR  - NS-38195/NS/NINDS NIH HHS/United States
GR  - NS-43284/NS/NINDS NIH HHS/United States
GR  - NS-46513/NS/NINDS NIH HHS/United States
GR  - NS-49514/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060517
PL  - United States
TA  - Am J Physiol Cell Physiol
JT  - American journal of physiology. Cell physiology
JID - 100901225
RN  - 0 (Inflammation Mediators)
RN  - 0 (Tissue Inhibitor of Metalloproteinase-1)
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - 127497-59-0 (Tissue Inhibitor of Metalloproteinase-2)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
SB  - IM
MH  - Animals
MH  - *Blood Physiological Phenomena
MH  - Blood-Brain Barrier/drug effects/*metabolism
MH  - Capillary Permeability/drug effects
MH  - Cells, Cultured
MH  - Enzyme Activation/drug effects
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Inflammation Mediators/*physiology
MH  - Injections
MH  - Leukocytes/*physiology
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Matrix Metalloproteinases/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Stress, Mechanical
MH  - Tissue Inhibitor of Metalloproteinase-1/metabolism
MH  - Tissue Inhibitor of Metalloproteinase-2/administration & 
      dosage/metabolism/pharmacology
MH  - Tissue Inhibitor of Metalloproteinases/*metabolism
EDAT- 2006/05/19 09:00
MHDA- 2006/11/01 09:00
CRDT- 2006/05/19 09:00
PHST- 2006/05/19 09:00 [pubmed]
PHST- 2006/11/01 09:00 [medline]
PHST- 2006/05/19 09:00 [entrez]
AID - 00516.2005 [pii]
AID - 10.1152/ajpcell.00516.2005 [doi]
PST - ppublish
SO  - Am J Physiol Cell Physiol. 2006 Oct;291(4):C740-9. doi: 
      10.1152/ajpcell.00516.2005. Epub 2006 May 17.