Interleukin-8 Administration Enhances Venous Thrombosis Resolution in a Rat Model

• Published in: The Journal of surgical research 2001-07, Vol.99 (1), p.84-91
• Main Authors: Henke, Peter K., Wakefield, Thomas W., Kadell, Amy M., Linn, Marisa J., Varma, Manu R., Sarkar, Minaski, Hawley, Angela, Fowlkes, J.Brian, Strieter, Robert M.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; chemokine; Chemokines - metabolism; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Growth Factors - metabolism; Fibrosis; Hypertension - etiology; Hypertension - physiopathology; inflammation; Interleukin-8 - pharmacokinetics; Interleukin-8 - therapeutic use; Leukocyte Count; Lymphokines - metabolism; Male; Medical sciences; Miscellaneous; neovascularization; Neovascularization, Physiologic - drug effects; neutrophil; Neutrophils - drug effects; Neutrophils - pathology; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Regional Blood Flow - drug effects; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Venous Pressure - drug effects; venous thrombosis; Venous Thrombosis - drug therapy; Venous Thrombosis - physiopathology
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.2001.6122

Background. Therapy for deep vein thrombosis (DVT) resolution in those patients in whom a complication or contraindication to anticoagulation occurs is limited. As prior work suggests that thrombus maturation involves early influx of neutrophils (PMN) and neovascularization, we hypothesized that administering the proinflammatory/proangiogenic chemokine interleukin (IL)-8 might accelerate thrombus resolution. Materials and methods. An established rodent model of DVT (inferior vena cava [IVC] ligation) was used whereby daily intravenous recombinant human IL-8 (1 μg) or vehicle control was administered, with sacrifice at 4 and 8 days. Prior to sacrifice and at harvest, duplex ultrasound of the DVT and femoral venous pressure measurements were performed. Thrombi were analyzed by immunohistochemical techniques for PMN, monocytes, and neovascularization; for chemokines, by enzyme-linked immunoassay; and fibrosis, by hydroxyproline assay and trichrome staining. Results. IL-8 accelerated thrombus dissolution 4 days after IVC ligation, with 6-fold increased thrombus blood flow by duplex ultrasound and a 23% increased absolute femoral venous pressure compared with controls (both P < 0.05). These findings may be partially explained by the fact that animals receiving IL-8, as compared with controls, had 2.5-fold greater thrombus neovascularization (with a trend continuing to 8 days) and increased PMN at 4 days. Thrombus vascular endothelial growth factor was significantly reduced at 8 days postligation, while monocyte chemotactic protein-1 and macrophage inflammatory protein-1α were not altered by IL-8 administration. At 8 days post-IVC-ligation, fibrosis was 12-fold greater with IL-8 treatment compared with controls. Conclusions. A proinflammatory/proangiogenic thrombus milieu, as conferred by IL-8, enhances thrombus resolution and underscores the important relationship between neovascularity and inflammation.