geoscience.net logo
+ Resolve Article
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter

+ Translate
+ Subscribe to Site Feed
GeoScience Most Shared ContentMost Shared Content

Monocyte urokinase-type plasminogen activator up-regulation reduces thrombus size in a model of venous thrombosis


, : Monocyte urokinase-type plasminogen activator up-regulation reduces thrombus size in a model of venous thrombosis. Journal of Vascular Surgery 50(5): 1127-1134

Our previous studies showed that the direct injection of an adenovirus construct expressing urokinase-type plasminogen activator (uPA) into experimental venous thrombi significantly reduces thrombus weight. The systemic use of adenovirus vectors is limited by inherent hepatic tropism and inflammatory response. As macrophages are recruited into venous thrombi, it is reasonable to speculate that these cells could be used to target the adenovirus uPA (ad-uPA) gene construct to the thrombus. The aims of this study were to determine whether macrophages transduced with ad-uPA have increased fibrinolytic activity and whether systemic injection of transduced cells could be used to target uPA expression to the thrombus and reduce its size. The effect of up-regulating uPA was examined in an immortalized macrophage cell line (MM6) and macrophages differentiated from human blood monocyte-derived macrophages (HBMMs). Cells were infected with ad-uPA or blank control virus (ad-blank). Fibrinolytic mediator expression, cell viability, and cytokine expression were measured by activity assays and enzyme-linked immunosorbent assays. Monocyte migration was measured using a modified Boyden chamber assay. A model of venous thrombosis was developed and characterized in mice with severe combined immunodeficiency (SCID). This model was used to study whether systemically administered macrophages over-expressing uPA reduced thrombus size. Uptake of HBMMs into the thrombus induced in these mice was confirmed by a combination of PKH2-labeled cell tracking and colocalization with human leukocyte antigen (HLA) by immunohistology. Compared with ad-blank, treated HBMMs transduction with ad-uPA increased uPA production by >1000-fold (P = .003), uPA activity by 150-fold (P = .0001), and soluble uPA receptor (uPAR) by almost twofold (P = .043). Expression of plasminogen activator inhibitor (PAI-1) and PAI-2 was decreased by about twofold (P = .011) and threefold (P = .005), respectively. Up-regulation of uPA had no effect on cell viability or inflammatory cytokine production compared with ad-blank or untreated cells. Ad-uPA transduction increased the migration rate of HBMMs (about 20%, P = .03) and MM6 cells (>twofold, P = .005) compared with ad-blank treated controls. Human macrophage recruitment into the mouse thrombus was confirmed by the colocalization of HLA with the PKH2-marked cells. Systemic injection of uPA-up-regulated HBMMs reduced thrombus weight by approximately 20% compared with ad-blank (P = .038) or sham-treated controls (P = .0028). Transduction of HBBM with ad-uPA increases their fibrinolytic activity. Systemic administration of uPA up-regulated HBBMs reduced thrombus size in an experimental model of venous thrombosis. Alternative methods of delivering fibrinolytic agents are worth exploring.

US$19.90

PMID: 19703758

DOI: 10.1016/j.jvs.2009.06.047


Other references

Koyama, Hiromasa, 1998: Seed heteromorphism and timing of germination-their mechanisms and adaptive significance. Seedling emergence usually occurs asynchronously, spread over several weeks or months. In some species, two or more discrete cohorts emerge in different seasons of the year (e. g. in autumn and spring). Such phenological patterns may result from s...

Cusano, A.; Iadicicco, A.; Paladino, D.; Campopiano, S.; Cutolo, A., 2008: Photonic band-gap engineering in UV fiber gratings by the arc discharge technique. Localized heat treatments combined with local non-adiabatic tapering is proposed as suitable tool for the engineering of photonic band-gaps in UV-written fiber Bragg gratings (FBGs). In particular, here, we propose the use of the electric arc disc...

Hernández, A.; Pluske, J.R.; D'Souza, D.N.; Mullan, B.P., 2008: Levels of copper and zinc in diets for growing and finishing pigs can be reduced without detrimental effects on production and mineral status. One hundred and sixty pigs were used to evaluate dietary copper (Cu) and zinc (Zn) supplementation on performance, fecal mineral levels, body mineral status and carcass and meat quality. Diets differed in mineral form (MF) (Cu and Zn in the form o...

Todd, P.; Garioch, J.J.; Humphreys, S.; Seywright, M.; Thomson, J.; D.V.vier, A.W.P., 1996: Evaluation of the 2-mm punch biopsy in dermatological diagnosis. This prospective study was undertaken to determine whether the 2-mm punch biopsy technique yields specimens of sufficient size and quality to allow a reliable histological diagnosis to be made. A histopathological comparison was made between tissu...

Johnson D.L., 1993: Dynamic denudation; a process model that explains many subsurface and out-of-context human artifacts and cultural materials. Agronomy Abstracts 85: 299

Gourley, D.R., 1974: Effects of opioid narcotic drugs on energy reserves of skeletal muscle. I. Glycogen. Biochemical Pharmacology 23(3): 489-501

Keller, C., 1897: Ueber einen neuen Fund von Bison prisons. MtLuzern: 181-184

Makkouk, K.M.; Kumari, S.G.; Leur, J.A.G. van, 2002: Screening and selection of faba bean (Vicia faba L.) germplasm resistant to Bean leafroll virus. Three hundred and fifty-eight faba bean accessions, originating from 28 countries in 5 continents, were evaluated for their reaction to a Syrian isolate (SV64-95) of bean leafroll virus (BLRV, family Luteoviridae). Selection for resistance was bas...

Teixeira, A.R.; Bueno, J.R.; do Lago, G.P., 1968: Uptake of serotonin (5-hydroxytryptamine) and N-N-dimethyl tryptamine (DMT) by dog's blood cells in vitro influence of chlorpromazine. Jornal Brasileiro de Psiquiatria 17(1): 53-57

Doyon, D.; Markovits, P.; Aaron, C.; Simon, J.; Richard, J.; Gasquet, V.; Paugam, B., 1967: Radio-anatomic study of the external carotid. Journal de Radiologie, D'electrologie, et de Medecine Nucleaire 48(5): 301-306