Urokinase induces its own expression in Beas2B lung epithelial cells

Shetty, Sreerama; Pendurthi, Usha R.; Halady, Prathap Kumar Shetty; Azghani, Ali; Idell, Steven

doi:10.1152/ajplung.00395.2001

Cited by 25 publications

(43 citation statements)

References 45 publications

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“…BEAS-2B cells, a commonly studied lung epithelial model system (29,35), express both uPAR (receptor for uPA) and LRP (␣ 2 -M receptor; see Fig. 6).…”

Section: Resultsmentioning

confidence: 99%

“…6). uPA interacts with uPAR (35) in these cells while complexes between proteinases and ␣ 2 -M normally bind to LRP (25).…”

Section: Resultsmentioning

confidence: 99%

“…Since ␣ 2 -M:uPA complexes found in lungs of patients with ARDS were located in the epithelial layer, we used BEAS-2B cell line, a commonly studied model of lung epithelial system (29,35), in subsequent experiments. Data presented in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…It should be noted that BEAS-2B cells are widely used to study functions of epithelial cells in relation to lung inflammation/injury (12,28,29,35) as these cells display many of the phenotypic characteristics of primary cells when proper culture conditions are applied (ATCC). However, BEAS-2B cells lack several epithelial differentiation markers and do not form tight epithelial barriers (37).…”

Section: Discussionmentioning

confidence: 99%

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Novel aspects of urokinase function in the injured lung: role of α₂-macroglobulin

Komissarov

Stankowska

Krupa

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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(uPA) is decreased in lung fluids of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) whereas ␣2-macroglobulin (␣2-M), a plasma proteinase inhibitor, is a major component of these fluids. Since there have been reports describing the ability of ␣2-M to form complexes with uPA in vitro, we hypothesized that ␣2-M may interact with uPA in the lung to modulate its biological activity. Pulmonary edema fluids and lung tissues from patients with ALI/ARDS were evaluated for the presence of uPA associated with ␣2-M. Complexes between ␣2-M and uPA were detected in alveolar edema fluids as well as in lungs of patients with ALI/ARDS where they were located mainly in close proximity to epithelial cells. While uPA bound to ␣2-M retains its amidolytic activity towards low-molecularweight substrates, it is not inhibited by its main physiological inhibitor, plasminogen activator inhibitor 1. We also investigated the functional consequences of formation of complexes between uPA and ␣2-M in vitro. We found that when ␣2-M:uPA complexes were added to cultures of human bronchial epithelial cells (BEAS-2B), activation of nuclear factor-B as well as production of interleukin-6 and -8 was substantially suppressed compared with the addition of uPA alone. Our findings indicate for the first time that the function of uPA in patients with ALI/ARDS may be modulated by ␣2-M and that the effects may include the regulation of the fibrinolytic and signaling activities of uPA. epithelial cells; lung; inflammation; ␣ 2-macroglobulin; urokinase ␣ 2 -MACROGLOBULIN (␣ 2 -M), a high-molecular-weight (HMW; Ͼ700 kDa) plasma glycoprotein, forms a tetramer composed of identical subunits, linked in pairs by disulfide bonds. The major source of plasma ␣ 2 -M is the hepatocyte; however, other cells including monocytes and macrophages synthesize and secrete this protein. ␣ 2 -M is a "slow acting" proteinase inhibitor that binds proteinases from all major classes. The mechanism by which ␣ 2 -M inhibits proteinases is unique. When proteinases hydrolyze the specific peptide bond localized in the so called "bait" region of ␣ 2 -M, the resulting conformational change irreversibly traps the enzyme within the ␣ 2 -M molecule. One or two molecules of proteinase are bound per molecule of ␣ 2 -M depending on the association rate constant and possibly on the size of the proteinase. Further, among proteinase inhibitors, only ␣ 2 -M-entrapped enzymes can still interact with low-molecular-weight (LMW) substrates and inhibitors, which are able to reach the active site of the enzyme located in a "molecular cage" type complex with ␣ 2 -M.Conformational change of the ␣ 2 -M, which occurs upon reaction with proteinases, exposes binding sites for the ␣ 2 -M receptor/low-density lipoprotein receptor-related protein (LRP). LRP is present on the surfaces of many different cell types, including hepatocytes, macrophages, and dendritic cells. ␣ 2 -M in its native form does not bind LRP whereas ␣ 2 -M-proteinase complexes rapidly undergo endocytosis (6,18,...

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“…BEAS-2B cells, a commonly studied lung epithelial model system (29,35), express both uPAR (receptor for uPA) and LRP (␣ 2 -M receptor; see Fig. 6).…”

Section: Resultsmentioning

confidence: 99%

“…6). uPA interacts with uPAR (35) in these cells while complexes between proteinases and ␣ 2 -M normally bind to LRP (25).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Novel aspects of urokinase function in the injured lung: role of α₂-macroglobulin

Komissarov

Stankowska

Krupa

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Previous studies have shown that induction of uPA, uPA receptor (uPAR), and PAI-1 may occur in lung ECs through a uPA-mediated feedback pathway (6)(7)(8). Given the findings that uPA, PAI-1, and TF are all elevated in lung ECs during lung injury (9), we suspected that alveolar and airway ECs that were exposed to increased levels of uPA would demonstrate a concomitant increase in TF expression.…”

mentioning

confidence: 97%

Induction of Tissue Factor by Urokinase in Lung Epithelial Cells and in the Lungs

Shetty¹,

Bhandary²,

Shetty³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Urokinase-type plasminogen activator (uPA) regulates extracellular proteolysis in lung injury and repair. Although alveolar expression of uPA increases, procoagulant activity predominates. Objectives: This study was designed to investigate whether uPA alters the expression of tissue factor (TF), the major initiator of the coagulation cascade, in lung epithelial cells (ECs). Methods: Bronchial, primary airway ECs and C57B6 wild-type, uPAdeficient (uPA 2/2 ) mice were exposed to phosphate-buffered saline, uPA, or LPS. Immunohistochemistry, protein, cellular, and molecular techniques were used to assess TF expression and activity. Measurements and Main Results: uPA enhanced TF mRNA and protein expression, and TF-dependent coagulation in lung ECs. uPA-induced expression of TF involves both increased synthesis and enhanced stabilization of TF mRNA. uPA catalytic activity had little effect on induction of TF. By contrast, deletion of the uPA receptor binding growth factor domain from uPA markedly attenuated the induction of TF, suggesting that uPA receptor binding is sufficient for TF induction. Lung tissues of uPA-deficient mice expressed less TF protein and mRNA compared with wild-type mice. In addition, intratracheal instillation of mouse uPA increased TF mRNA and protein expression and accelerated coagulation in lung tissues. uPA 2/2 mice exposed to LPS failed to induce TF. Conclusions: uPA increased TF expression and TF-dependent coagulation in the lungs of mice. We hypothesize that uPA-mediated induction of TF occurs in lung ECs to promote increased fibrin deposition in the airways during acute lung injury.

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Clinical significance of urokinase‐type plasminogen activator receptor (uPAR) expression in cancer

Bock

Wang

2003

Medicinal Research Reviews

135

103

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The involvement of the urokinase-type plasminogen activator (uPA) system in particular has been extensively studied in the pathogenesis of cancer. The molecular role of the uPA receptor (uPAR) is well characterized with its participation in cell migration and extracellular matrix (ECM) degradation. Over-expression of uPAR in cancer has been demonstrated in many studies and is considered an attractive target for anticancer agents. We and others have down-regulated uPAR expression in an attempt to inhibit cancer metastasis based on its molecular role. Uniquely, uPAR which is a glycosyl phosphatidylinositol anchored protein is not only bound to the cell surface but also has a soluble form, suPAR. There is now accumulated clinical and experimental evidence supporting the significant role of uPAR and its soluble counterpart in a number of solid cancers. The expression of uPAR can be associated with tumor cells or stromal cells or both. Differences observed in the expression of uPAR using immunohistochemistry (IHC) are likely explained by the use of different antibodies and techniques rather than true cellular differences and are reviewed here. This review summarizes the clinical relevance of uPAR and its soluble form in the prognosis and diagnosis of different cancers.

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Urokinase induces its own expression in Beas2B lung epithelial cells

Cited by 25 publications

References 45 publications

Novel aspects of urokinase function in the injured lung: role of α₂-macroglobulin

Novel aspects of urokinase function in the injured lung: role of α₂-macroglobulin

Induction of Tissue Factor by Urokinase in Lung Epithelial Cells and in the Lungs

Clinical significance of urokinase‐type plasminogen activator receptor (uPAR) expression in cancer

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Urokinase induces its own expression in Beas2B lung epithelial cells

Cited by 25 publications

References 45 publications

Novel aspects of urokinase function in the injured lung: role of α2-macroglobulin

Novel aspects of urokinase function in the injured lung: role of α2-macroglobulin

Induction of Tissue Factor by Urokinase in Lung Epithelial Cells and in the Lungs

Clinical significance of urokinase‐type plasminogen activator receptor (uPAR) expression in cancer

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Novel aspects of urokinase function in the injured lung: role of α₂-macroglobulin

Novel aspects of urokinase function in the injured lung: role of α₂-macroglobulin