Urokinase-Type Plasminogen Activator Potentiates Lipopolysaccharide-Induced Neutrophil Activation

Abraham, Edward; Gyetko, Margaret R.; Kuhn, Katherine; Arcaroli, John J.; Strassheim, Derek; Park, Jong Sung; Shetty, Sreerama; Idell, Steven

doi:10.4049/jimmunol.170.11.5644

Cited by 99 publications

(95 citation statements)

References 55 publications

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“…Expression of u-PAR and PAI-1 by stromal and cellular tumour components are substantially increased by proinflammatory cytokines in vitro and sepsis significantly increases serum PAI-1 levels (Robbie et al, 2000;Abraham et al, 2003). Thus, although this study focused on u-PA and its inhibition, other elements of this cascade are also possibly involved and warrant further investigation.…”

Section: Discussionmentioning

confidence: 96%

“…One such effector mechanism subverted by the neoplastic process is the urokinase plasminogen activator system, which directly and indirectly promotes tumour cell invasion and metastasis through multiple mechanisms including plasminmediated pericellular proteolysis, enhanced vitronectin adhesion and activation of pro-metastatic intracellular pathways such as src and ERF 1 and 2 (Ahmed et al, 2003;Sidenius and Blasi, 2003). Furthermore u-PA is potently upregulated by the proinflammatory cytokines TNF-a and IL-6 in a variety of human cancer cell lines in vitro and the u-PA system is significantly activated by infection and sepsis in vivo as evidenced by increased circulating levels of u-PA (Robbie et al, 2000;Abraham et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of urokinase plasminogen activator with a novel enzyme inhibitor, wxc-340, ameliorates endotoxin and surgery-accelerated growth of murine metastases

et al. 2007

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The urokinase plasminogen activator (u-PA) is intimately associated with tumour invasion and metastases. Surgery facilitates accelerated metastatic tumour growth in murine models, a phenomenon related to elevated perioperative bacterial lipopolysaccaride (LPS) and inflammatory cytokine levels. The objectives of the study were to examine the role of u-PA in cytokine-enhanced tumour cell invasion in vitro and surgery-induced accelerated metastatic tumour growth in vivo and to assess the potential benefit of a novel selective u-PA inhibitor WXC-340 in this setting. CT-26 murine colorectal carcinoma cells were stimulated with LPS, tumour necrosis factor a (TNF-a) and interleukin 6 (IL-6). Cell supernatant u-PA expression and activity were determined using a colorimetric assay and Western blot analysis, respectively. Baseline and cytokine-stimulated in vitro invasion were assessed using ECmatrix invasion chambers. Two established murine models of accelerated metastatic tumour growth were used to investigate the consequences of u-PA inhibition on postoperative metastatic tumour burden. The effect of u-PA inhibition in vitro and in vivo was examined using the novel selective u-PA inhibitor, WXC-340. Proinflammatory cytokine stimulation significantly enhanced in vitro u-PA expression, activity and extracellular matrix invasion by approximately 50% compared to controls (Po0.05). This was abrogated by WXC-340. In vivo WXC-340 almost completely ameliorated both LPS-and surgery-induced, metastatic tumour growth compared to controls (P40.05). In conclusion, u-PA cascade is actively involved in cytokine-mediated enhanced tumour cell invasion and LPS and surgeryinduced metastatic tumour growth. Perioperative u-PA inhibition with WXC-340 may represent a novel therapeutic paradigm.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Inhibition of urokinase plasminogen activator with a novel enzyme inhibitor, wxc-340, ameliorates endotoxin and surgery-accelerated growth of murine metastases

et al. 2007

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“…The activation of NMDA-Rs by glutamate in isolated rat lungs was reported to trigger pulmonary edema (22), and uPA 2/2 mice are protected against LPS-induced pulmonary edema (18). Therefore, we investigated whether the binding of uPA to NMDA-R1 also increases lung permeability.…”

Section: Effects Of Upa and Nmdars On Pulmonary Vascular Permeabilitymentioning

confidence: 99%

“…The observation that uPA-deficient mice (uPA 2/2 ) are protected against the pulmonary edema induced by LPS (18) suggests that uPA may also affect vascular tone and permeability within the lung. We previously reported that uPA regulates the vascular contractility of isolated aortic rings (16,19), and that uPA 2/2 mice exhibit significantly lower mean arterial blood pressure than do wild-type mice, indicating a predominant procontractile effect of uPA in the systemic arterial circulation under physiological conditions (16).…”

mentioning

confidence: 99%

Urokinase Plasminogen Activator Regulates Pulmonary Arterial Contractility and Vascular Permeability in Mice

Nassar

Yarovoi

Fanne

et al. 2011

Am J Respir Cell Mol Biol

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The concentration of urokinase plasminogen activator (uPA) is elevated in pathological settings such as acute lung injury, where pulmonary arterial contractility and permeability are disrupted. uPA limits the accretion of fibrin after injury. Here we investigated whether uPA also regulates pulmonary arterial contractility and permeability. Contractility was measured using isolated pulmonary arterial rings. Pulmonary blood flow was measured in vivo by Doppler and pulmonary vascular permeability, according to the extravasation of Evans blue. Our data show that uPA regulates the in vitro pulmonary arterial contractility induced by phenylephrine in a dose-dependent manner through two receptor-dependent pathways, and regulates vascular contractility and permeability in vivo. Physiological concentrations of uPA (<1 nM) stimulate the contractility of pulmonary arterial rings induced by phenylephrine through the low-density lipoprotein receptor-related protein receptor. The procontractile effect of uPA is independent of its catalytic activity. At pathophysiological concentrations, uPA (20 nM) inhibits contractility and increases vascular permeability. The inhibition of vascular contractility and increase of vascular permeability is mediated through a two-step process that involves docking to N-methyl-Daspartate receptor-1 (NMDA-R1) on pulmonary vascular smooth muscle cells, and requires catalytic activity. Peptides that specifically inhibit the docking of uPA to NMDA-R, or the uPA variant with a mutated receptor docking site, abolished both the effects of uPA on vascular contractility and permeability, without affecting its catalytic activity. These data show that uPA, at concentrations found under pathological conditions, reduces pulmonary arterial contractility and increases permeability though the activation of NMDA-R1. The selective inhibition of NMDAR-1 activation by uPA can be accomplished without a loss of fibrinolytic activity.

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“…These dual properties enable the uPA/uPAR system to control pericellular fibrinolytic and proteolytic activities as well as cell adhesion, migration, proliferation, and differentiation (1). The uPA/uPAR system modulates Ag processing and presentation (2), lymphocyte activation (3), generation of pro-and anti-inflammatory signals (4), activation of intracellular signaling pathways (5), and cytotoxicity (6), all of which are critical steps in cell-mediated immune responses. Involvement of the uPA/uPAR system in derangements of immune responses in HIV disease via an IFN-like mechanism has also been demonstrated (7,8).…”

mentioning

confidence: 99%

The Urokinase/Urokinase Receptor System Mediates the IgG Immune Complex-Induced Inflammation in Lung

Shushakova

Eden

Dangers

et al. 2005

The Journal of Immunology

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Immune complex (IC) deposition induces an acute inflammatory response with tissue injury. IC-induced inflammation is mediated by inflammatory cell infiltration, a process highly regulated by the cell surface-specific receptor (uPAR), a binding partner for the urokinase-type plasminogen activator (uPA). We assessed the role of the uPA/uPAR system in IC-induced inflammation using the pulmonary reverse passive Arthus reaction in mice lacking uPA and uPAR compared with their corresponding wild-type controls. Both uPA-deficient C57BL/6J (uPA−/−) and uPAR-deficient mice on a mixed C57BL/6J (75%) × 129 (25%) background (uPAR−/−) demonstrated a marked reduction of the inflammatory response due to decreased production of proinflammatory mediators TNF-α and Glu-Leu-Arg (ELR)-CXC chemokine MIP-2. In uPAR−/− animals, the reduction of inflammatory response was more pronounced because of decreased migratory capacity of polymorphonuclear leukocytes. We show that the uPA/uPAR system is activated in lung of wild-type mice, particularly in resident alveolar macrophages (AM), early in IC-induced alveolitis. This activation is necessary for an adequate C5a anaphylatoxin receptor signaling on AM that, in turn, modulates the functional balance of the activating/inhibitory IgG FcγRs responsible for proinflammatory mediator release. These data provide the first evidence that the uPA/uPAR plays an important immunoregulatory role in the initiation of the reverse passive Arthus reaction in the lung by setting the threshold for C5a anaphylatoxin receptor/FcγR activation on AM. The findings indicate an important link between the uPA/uPAR system and the two main components involved in the IC inflammation, namely, complement and FcγRs.

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Urokinase-Type Plasminogen Activator Potentiates Lipopolysaccharide-Induced Neutrophil Activation

Cited by 99 publications

References 55 publications

Inhibition of urokinase plasminogen activator with a novel enzyme inhibitor, wxc-340, ameliorates endotoxin and surgery-accelerated growth of murine metastases

Inhibition of urokinase plasminogen activator with a novel enzyme inhibitor, wxc-340, ameliorates endotoxin and surgery-accelerated growth of murine metastases

Urokinase Plasminogen Activator Regulates Pulmonary Arterial Contractility and Vascular Permeability in Mice

The Urokinase/Urokinase Receptor System Mediates the IgG Immune Complex-Induced Inflammation in Lung

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