Changes in tissue factor and the effects of tissue factor pathway inhibitor on transient focal cerebral ischemia in rats.
BACKGROUND
To determine the contribution of tissue factor (TF) to focal cerebral ischemia/reperfusion injury, we investigated the changes in TF in rat brains with transient focal cerebral ischemia and also assessed the effect of TF pathway inhibitor (TFPI).


METHODS
Spontaneous hypertensive rats were subjected to 90-min of middle cerebral artery occlusion (MCAO) and then were reperfused for up to 24 h. Immediately after MCAO, recombinant human TFPI (rhTFPI) (50 or 20 microg/kg/min) was administered by means of a continuous intravenous injection for 4.5 h.


CONCLUSIONS
TF immunoreactivity decreased or scattered in the ischemic area after reperfusion, however, an increased TF expression was observed in the microvasculature with the surrounding brain parenchyma and it peaked at 3 to 6 h, which coincided with the start of fibrin formation. On the other hand, total TF protein in ischemic area continued to exist and did not remarkably change until 24 h after reperfusion. At 24 h after reperfusion, the total infarct volume in the group treated with 50 microg/kg/min rhTFPI was significantly smaller than that in the controls (saline). Western blotting and immunohistochemical studies showed that rhTFPI treatment resulted in a decrease of fibrin in the ischemic brains and microvasculature. TF-mediated microvascular thrombosis is thus considered to contribute to focal cerebral ischemia/reperfusion injury. The continuous infusion of rhTFPI until a peak of TF-mediated microvascular thrombosis therefore attenuates the infarct volume by reducing fibrin deposition in the cerebral microcirculation.
Niiro
Masaki
M
Department of Neurosurgery, Graduate School of Medicine and Dental Sciences, University of Kagoshima, 8-35-1, Sakuragaoka, Kagoshima, 890-8520, Japan. niiromsk@m2.kufm.kagoshima-u.ac.jp
Nagayama
Tetsuya
T
Yunoue
Shunji
S
Obara
Soichi
S
Hirano
Hirofumi
H
D000818:Animals; D001921:Brain / Q000473:pathology; D005337:Fibrin / Q000737:chemistry; D007150:Immunohistochemistry / Q000379:methods; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000378:metabolism; D008074:Lipoproteins / Q000737:chemistry*; D008297:Male; D008954:Models, Biological; D010477:Perfusion; D051381:Rats; D011918:Rats, Inbred SHR; D011994:Recombinant Proteins / Q000737:chemistry; D015427:Reperfusion Injury; D013925:Thromboplastin / Q000737:chemistry*; D013997:Time Factors
D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; D005337:Fibrin; D013925:Thromboplastin