Increased secretion of urokinase-type plasminogen activator by human lung microvascular endothelial cells

Takahashi, Kimiko; Uwabe, Yasuhide; Sawasaki, Yoshio; Kiguchi, Toshio; Nakamura, Hiroyuki; Kashiwabara, Kosuke; Yagyu, Hisanaga; Matsuoka, Takeshi

doi:10.1152/ajplung.1998.275.1.l47

Cited by 30 publications

(32 citation statements)

References 30 publications

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“…No significant difference was observed between HUVEC and HPMEC after stimulation with LPS and TNF-␣. Previous studies concerning the secretion of urokinase-type plasminogen activator have already indicated differences between the human lung microvascular endothelium and HUVEC (38). In the bovine lung, TNF-␣ caused different effects on microvascular vs. macrovascular endothelial cell monolayers of the lung (29).…”

Section: Discussionmentioning

confidence: 99%

GM-CSF expression by human lung microvascular endothelial cells: in vitro and in vivo findings

Burg

Krump‐Konvalinkova

Bittinger

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Recently, many findings indicate that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the pathogenesis of acute and chronic lung diseases. In the present paper, the production of this cytokine in human pulmonary microvascular endothelial cells (HPMEC) is investigated. In an in vitro study, quiescent HPMEC did not express GM-CSF, either at the transcriptional or at the protein level. After activation for 4 h with tumor necrosis factor (TNF)-α (30/300 U/ml), lipopolysaccharide (LPS; 0.1/1 μg/ml), or interleukin (IL)-1β (100 U/ml), a significant release of GM-CSF was measured by enzyme-linked immunosorbent assay, with a time-dependent increase over 72 h. IL-8 (4, 16, or 64 ng/ml) or IL-1β at a concentration of 10 U/ml did not induce the release of GM-CSF. Human umbilical vein endothelial cells (HUVEC) and the angiosarcoma cell line HAEND served as reference cell lines. GM-CSF release in HPMEC was significantly ( P < 0.025–0.05) less inducible by IL-1β than in HUVEC. A constitutive expression of GM-CSF by HAEND was observed. Additionally, GM-CSF expression in vivo by the lung microvasculature was confirmed by immunohistochemistry in lung tissue. To our knowledge, this is the first report of the ability of human pulmonary endothelial cells to synthesize and release GM-CSF. These results support the hypothesis that the lung microvasculature via the production of GM-CSF is a potential contributor to the cytokine network in lung diseases. This could be of particular importance in the pathogenesis of the acute respiratory distress syndrome in which endothelial dysfunction plays a central pathogenetic role.

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Section: Discussionmentioning

confidence: 99%

GM-CSF expression by human lung microvascular endothelial cells: in vitro and in vivo findings

Burg

Krump‐Konvalinkova

Bittinger

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A substantial fraction of total plasminogen activator activity in the lungs is generated within the alveolar space (38,46). The pulmonary vasculature also expresses plasminogen activators (28,49). Thus the lungs seem to be well equipped to function as blood filters that trap and dissolve emboli (12).…”

Section: Discussionmentioning

confidence: 99%

Platelets inhibit the lysis of pulmonary microemboli

Murciano

Harshaw

Neschis

et al. 2002

American Journal of Physiology-Lung Cellular and Molecular Phys

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Using tracings of 125 I-labeled fibrin(ogen) in rodents, we examined the hypothesis that platelets impede the lysis of pulmonary emboli.125 I-Microemboli (ME, 3-10 micron diameter) lodged homogeneously throughout the lungs after intravenous injection in both rats and mice (60% of injected dose), caused no lethality, and underwent spontaneous dissolution (50 and 100% within 1 and 5 h, respectively). Although lung homogenates displayed the most intense fibrinolytic activity of all the major organs, dissolution of ME was much slower in isolated perfused lungs (IPL) than was observed in vivo. Addition of rat plasma to the perfusate facilitated ME dissolution in IPL to a greater extent than did addition of tissue-type plasminogen activator alone, suggesting that permeation of the clot by plasminogen is the rate-limited step in lysis. Platelet-containing ME injected in rats lysed much more slowly than did ME formed from fibrin alone.125 I-Thrombi, formed in the pulmonary vasculature of mice in response to intravascular activation of platelets by injection of collagen and epinephrine, were essentially resistant to spontaneous dissolution. Moreover, injection of the antiplatelet glycoprotein IIb/IIIa antibody 7E3 F(abЈ) 2 facilitated spontaneous dissolution of pulmonary ME and augmented fibrinolysis by a marginally effective dose of Retavase (10 g/kg) in rats. These studies show that platelets suppress pulmonary fibrinolysis. The mechanism(s) by which platelets stabilize ME and utility of platelet inhibitors to facilitate their dissolution deserves further study. pulmonary embolism; plasminogen activators; platelets; fibrinolysis; animal model; glycoprotein IIb/IIIa THE LUNG SERVES as a natural filter for thromboemboli of diverse sizes (12). Thrombotic occlusion of the main or lobar pulmonary arteries by large clots (massive pulmonary embolism, PE) is a common cause of morbidity and mortality (15,20). In contrast, pulmonary deposition of microemboli (ME) often does not cause acute symptoms (silent ME). Nevertheless, pulmonary ME is a relatively common accompaniment to acute lung injury (adult respiratory distress syndrome), hyperoxia, bleomycin toxicity, sepsis, trauma, surgery on the lower extremities, and angioplasty (2,21,30,33,36,39,40,44,52,53). Microembolism may lead to inflammation and edema acutely and contribute to the development of pulmonary fibrosis and hypertension over time (4,9,22,27,31).The treatment of PE, as with other venous thromboembolic conditions, is typically restricted to agents such as heparin that retard fibrin clot formation, with a relatively limited use of agents that promote fibrinolysis. Despite the effectiveness of such therapy, PE remains a common cause of mortality and morbidity. Thus there is a continuing need for more effective means to prevent and treat both PE and ME, based on a more thorough understanding of the mechanisms that regulate clot dissolution in the lung.For example, the role of platelets in PE and ME has received relatively little study. Recently, it has been shown tha...

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“…Bacterial products, such as endotoxin, as well as proinflammatory cytokines, including IL-1␤ and TNF-␣, whose release is increased in the setting of severe infection, induce uPA expression and secretion (5,6,15,23). Cleavage of cell-bound plasminogen to plasmin by uPA, in addition to promoting fibrinolysis, can enhance release of proinflammatory mediators, including cytokines such as IL-1␤ or matrix metalloproteinases, by facilitating conversion of the pro-form to the biologically active molecules, thereby potentiating acute inflammatory reactions (15,24).…”

Section: U Rokinase Plasminogen Activator (Upa)mentioning

confidence: 99%

Urokinase-Type Plasminogen Activator Potentiates Lipopolysaccharide-Induced Neutrophil Activation

Abraham

Gyetko

Kuhn

et al. 2003

The Journal of Immunology

100

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Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. Although increased circulating levels of uPA are present in endotoxemia and sepsis, conditions in which activated neutrophils contribute to the development of acute organ dysfunction, the ability of uPA to participate directly in LPS-induced neutrophil activation has not been examined. In the present experiments, we show that uPA can enhance activation of neutrophils exposed to submaximal stimulatory doses of LPS. In particular, uPA increased LPS-induced activation of intracellular signaling pathways, including Akt and c-Jun N-terminal kinase, nuclear translocation of the transcriptional regulatory factor NF-κB, and expression of proinflammatory cytokines, including IL-1β, macrophage-inflammatory protein-2, and TNF-α. There was no effect of uPA on LPS-induced activation of p38 mitogen-activated protein kinase in neutrophils. Transgenic mice unable to produce uPA (uPA−/−) were protected from endotoxemia-induced lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, lung IL-1β, macrophage-inflammatory protein-2, and TNF-α cytokine levels. These results demonstrate that uPA can potentiate LPS-induced neutrophil responses and also suggest that such effects are sufficiently important in vivo to play a major contributory role in neutrophil-mediated inflammatory responses, such as the development of acute lung injury.

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Increased secretion of urokinase-type plasminogen activator by human lung microvascular endothelial cells

Cited by 30 publications

References 30 publications

GM-CSF expression by human lung microvascular endothelial cells: in vitro and in vivo findings

GM-CSF expression by human lung microvascular endothelial cells: in vitro and in vivo findings

Platelets inhibit the lysis of pulmonary microemboli

Urokinase-Type Plasminogen Activator Potentiates Lipopolysaccharide-Induced Neutrophil Activation

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