Polymorphonuclear leucocytes mediate endogenous thrombus lysis via a u‐PA‐dependent mechanism

Abstract

Summary. Many human thrombi lyse spontaneously without the administration of lytic drugs and cause no clinical symptoms. The mechanisms by which this occurs are incompletely understood. We found that model thrombi prepared from whole human blood in a Chandler loop also exhibited significant spontaneous lysis. Lysis was inhibited by chemical protease inhibitors, consistent with proteolysis resulting primarily from serine proteases, with a small contribution from matrix metalloproteinases. Whole blood was fractionated into platelet-rich plasma and cell populations. Significant spontaneous lysis was observed in plateletrich thrombi enriched with polymorphonuclear leucocytes (PMNs), whereas mononuclear cells (MCs) and erythrocytes did not contribute to lysis. Incorporation of antibodies to urokinase (u-PA) and its receptor u-PAR neutralized a large proportion of the activity. Incubation of plasma with PMNs generated free u-PA activity, which was also detectable in model thrombi and in vivo human thrombi. Purified neutrophils, free of eosinophils, generated activity identical to PMNs. Smaller contributions to lysis by tissue-type plasminogen activator (t-PA), elastase and cathepsin G were also identified. These findings suggest a major role for circulating PMNs in endogenous thrombus lysis.

The Transcriptional Activation Program of Human Neutrophils in Skin Lesions Supports Their Important Role in Wound Healing

“…This was somewhat surprising as uPA is not up-regulated by PMNs when activated in vitro by various stimuli (4,5,7). However, incubation of plasma with PMNs has been shown to generate thrombolytic uPA activity (24). Hence, activated PMNs in skin wounds might generate uPA resulting in plasminogen activation and subsequent breakdown of fibrin clots and extracellular matrix (25).…”

“…Additional up-regulated genes potentially involved in wound healing were laminin 5 ␤3 (LAMB3) (23), which promotes adhesion of keratinocytes to the dermal layer, and uPA (PLAU), which supports tissue remodelling by breakdown of fibrin clots and degradation of extracellular matrix (24,25). Other wound The table demonstrates the absence of lineage-specific transcripts for nongranulocytic cells in highly purified PMN preparations collected from pb-PMNs (n ϭ 4) and sl-PMNs (n ϭ 4) as detected by microarray analysis (Affymetrix; present/absent call).…”

Polymorphonuclear proteolytic activity and milk composition change

“…The epithelial barrier permeability could be responsible for an increase in plasminogen activator concentrations in milk (both tissular or t-PA and urokinase or the u-PA type) since these components are present in very high levels in the blood because of their involvement in blood clot dissolution [20]. Moreover, PMN synthesize plasminogen activators, mainly t-PA [49,57]. Other components with a main action other than plasminogen activation do have an effect on plasminogen conversion into plasmin.…”

“…These cells have the capacity of promoting plasminogen activity such as u-PA and less markedly t-PA [49]. In addition, the level of expression of plasminogen activators by PMN is intimately linked to the cell stage of maturity (Moussaoui et al, personnal communication).…”

Proteolysis in Milk During Experimental Escherichia coli Mastitis

“…During mastitis, the serine protease activator concentration, including plasmin and plasminogen in blood and also in milk, increases sharply according to some researchers (Yamagata et al, 2001;Le Roux et al, 2003;). Polymorphonuclear neutrophils have a pool of plasminogen activators, such as urokinase type (u-PA) and, to a lesser extent, tissue (t-PA), according to Moir et al (2001). Escherichia coli is reported to have both plasmin and plasminogen receptors on its surface, and these enhance enzyme activation and express plasminogen activators.…”