Lipopolysaccharide attenuates thrombolysis in batroxobin-induced lung vasculature fibrin deposition but not in ferrous chloride-induced carotid artery thrombus in rats: role of endogenous PAI-1.
In this study, we investigated if elevation of endogenous plasminogen activator inhibitor type 1 (PAI-1) by lipopolysaccharide (LPS) can retard thrombolysis in both a rat model of lung vasculature fibrin deposition and a platelet-rich thrombus model induced by endothelial injury. By 3 h following an intravenous bolus injection of 0.5 mg/kg LPS, the plasma PAI-1 level had increased to approximately 8 ng/ml. 125I-labeled fibrinogen was injected intravenously followed by an injection of batroxobin. Batroxobin converts fibrinogen into insoluble fibrin, which was then deposited in the lungs within 5 min, followed by spontaneous fibrinolysis that completely cleared fibrin deposition in the lungs by 30 min. In rats pre-treated with LPS, spontaneous fibrinolysis was significantly retarded. In the endothelial injury model, topical application of FeCl2 on the carotid artery induced an occlusive platelet-rich thrombus, which was not sensitive to endogenous thrombolysis. Exogenous tissue-type plasminogen activator (tPA) was required to recanalize the occlusive thrombus in a dose-dependent manner. Pre-treatment with LPS did not alter the dose-response curve of exogenous tPA-induced thrombolysis. These data indicate that batroxobin-induced lung vasculature fibrin deposition in rats, unlike the FeCl2 model, is sensitive to the impact of endogenous PAI-1 on fibrinolysis.
Wang
Yi Xin
YX
Department of Pharmacology, Berlex Biosciences, Richmond, CA 94804-0099, USA. jim_wang@berlex.com
Dong
Ningzheng
N
Wu
Chengliang
C
Martin-McNulty
Baby
B
Fitch
Richard M
RM
da Cunha
Valdeci
V
Vicelette
Jon
J
Tran
Katherine
K
Vergona
Ronald
R
Sullivan
Mark E
ME
Morser
John
J
Wu
Qingyu
Q
D000818:Animals; D012103:Batroxobin; D002339:Carotid Arteries / Q000473:pathology; D002341:Carotid Artery Thrombosis / Q000209:etiology*; D005296:Ferrous Compounds; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008171:Lung Diseases / Q000209:etiology*; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology
D005296:Ferrous Compounds; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D005337:Fibrin; D012103:Batroxobin; D010959:Tissue Plasminogen Activator; C029451:ferrous chloride