title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology, Berlex Biosciences, Richmond, CA 94804-0099, USA. jim_wang@berlex.com
authors.forename: Yi Xin
authors.initials: YX
authors.lastname: Wang
authors.forename: Ningzheng
authors.initials: N
authors.lastname: Dong
authors.forename: Chengliang
authors.initials: C
authors.lastname: Wu
authors.forename: Baby
authors.initials: B
authors.lastname: Martin-McNulty
authors.forename: Richard M
authors.initials: RM
authors.lastname: Fitch
authors.forename: Valdeci
authors.initials: V
authors.lastname: da Cunha
authors.forename: Jon
authors.initials: J
authors.lastname: Vicelette
authors.forename: Katherine
authors.initials: K
authors.lastname: Tran
authors.forename: Ronald
authors.initials: R
authors.lastname: Vergona
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sullivan
authors.forename: John
authors.initials: J
authors.lastname: Morser
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Wu
mesh_terms: 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
chemical_list: D005296:Ferrous Compounds; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D005337:Fibrin; D012103:Batroxobin; D010959:Tissue Plasminogen Activator; C029451:ferrous chloride