Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibrin deposition is prominent in the course of several forms of pulmonary fibrosis. To elucidate the role of fibrin deposition and fibrinolysis in the process of pulmonary fibrosis, we studied bleomycin-induced fibrosis and the effect of urokinase on it. Beagle dogs were injected intramuscularly 20 times with bleomycin in doses of 2 and 6 mg/kg body weight every other day. Intravenous urokinase treatment was subsequently performed with 3,000 units daily for 40 days and 9,000 units twice daily for 70 days. Histopathologic examination of the lungs of dogs receiving bleomycin alone revealed fibrosis. The lungs of bleomycin-treated dogs which received urokinase had less severe fibrosis and this was confirmed by morphometry with planimetry and the point counting method. Urokinase treatment also diminished the increase of hydroxyproline content of the lung of bleomycin-treated dogs. Decrease of lung tissue fibrinolytic activity assayed by fibrin plate method in bleomycin-treated dogs was also prevented by urokinase. Intravenous urokinase, 24,000 units per day in divided doses, was administered daily in cancer patients with bleomycin treatment. Incidence of pulmonary fibrosis was decreased by urokinase. These data indicate that fibrin deposition and fibrinolysis may have an important influence on the fibrotic process in the lung.
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PMID:[Fibrin deposition and fibrinolysis in the pathogenesis of pulmonary fibrosis]. 279 52

Pulmonary fibrosis was induced in male Sprague-Dawley rats by intratracheal instillation of bleomycin. By 30 d post-bleomycin, the lungs exhibited elevated interstitial collagen levels. Thirty d after exposure to bleomycin, animals were further treated by intratracheal administration of phosphate-buffered saline (PBS) or 12,500 units of recombinant human urokinase (rh-UK). Three days later, the animals were sacrificed and the lungs fixed, sectioned, and assessed for fibrosis. The presence of interstitial collagen was quantitated using a BioQuant Image Analysis System (R and M Biometrics, Inc., Nashville, TN). Urokinase treatment of animals with established pulmonary fibrosis induced by exposure to 0.5 units of bleomycin was found to diminish the collagen content of lungs to near control levels by 3 d post-UK treatment. By 36 d post-UK treatment (66 d post-bleomycin), values for interstitial collagen were again partially elevated, indicating that UK treatment interfered with established fibrosis but did not stop the bleomycin-mediated process. However, the extent of fibrosis was less than that observed in lungs from non-UK treated animals 66 d post-bleomycin. UK treatment initiated 63 d post-bleomycin exposure again revealed a decline in the extent of fibrosis, but the values did not return to baseline levels. A repeat of the short-term experiment with a higher dose of bleomycin (0.85 units) again revealed that UK treatment was effective in diminishing the extent of fibrosis from 22% to 12% collagen. These results indicate that exogenous UK may be an effective therapeutic modality in the treatment of pulmonary fibrosis induced by some stimuli or developing in association with diseases such as scleroderma.
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PMID:Partial reversal of established bleomycin-induced pulmonary fibrosis by rh-urokinase in a rat model. 751 75

Bleomycin-induced lung injury is an established murine model of human pulmonary fibrosis. Although procoagulant molecules (e.g., tissue factor [TF]) and fibrinolytic components (e.g., urokinase [u-PA] and type 1 plasminogen activator inhibitor [PAI-1]) have been detected in alveolar fluid from injured lungs, the origin of these molecules remains unknown. We therefore examined the expression of procoagulant and fibrinolytic components in relation to the distribution of parenchymal fibrin in bleomycin-injured lungs. Extravascular fibrin localized to the alveolar and extracellular matrix in injured lung tissue. Injured lung tissue extracts contained elevated levels of PAI-1 activity and decreased levels of u-PA activity. Whole lung PAI-1 and TF mRNAs were dramatically induced by lung injury. In situ hybridization of injured lungs revealed that PAI-1, u-PA, and TF mRNAs were induced within the fibrin-rich fibroproliferative lesions, primarily in fibroblast-like and macrophagelike cells, respectively, while TF mRNA was also induced in perilesional alveolar cells. Taken together, these observations suggest that the induction of PAI-1 and TF gene expression plays and important role in the formation and persistence of extracellular fibrin in bleomycin injured murine lungs.
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PMID:Changes in procoagulant and fibrinolytic gene expression during bleomycin-induced lung injury in the mouse. 754 11

Extensive tissue remodeling occurs in survivors of acute lung injury, leading to nearly normal histology and physiology in the majority of individuals, whereas others suffer significant impairment due to the development of pulmonary fibrosis. Alveolar epithelial cells play a central role in the repair process. They are strategically located to directly participate in the solubilization of intraalveolar fibrin deposits, and have the capacity to promote fibrinolysis. We have previously reported that interleukin-1 beta (IL-1 beta), an important inflammatory mediator in acute lung injury, upregulates urokinase-type plasminogen activator expression by human A549 cells (1). In this work, we show that IL-1 beta increases cell-surface plasmin generation, mediated in part by increased expression of urokinase receptor (u-PAR). Northern blot analyses demonstrated that IL-1 beta rapidly induces accumulation of u-PAR messenger RNA (mRNA) in a dose-dependent fashion, and that this effect is blocked by actinomycin. The IL-1 beta-mediated increase in u-PAR mRNA is inhibited by: (1) the relatively specific protein kinase C (PKC) inhibitors 1-(5-isoquinoline sulfonyl)-2-methylpiperazine (H7) and calphostin C; and (2) prolonged pretreatment of cells with phorbol myristate acetate (PMA), suggesting that PKC is an important component of the signaling pathway. Okadaic acid, an inhibitor of serine/threonine phosphatases, markedly potentiates the effect of IL-1 beta on u-PAR mRNA levels. In contrast, dexamethasone, in concentrations as low as 10(-8) M, completely blocks the IL-1 beta-mediated increase in u-PAR mRNA. Half-life experiments show that dexamethasone has no effect on u-PAR mRNA stability. Aldosterone, at concentrations in which it binds primarily to the mineralocorticoid receptor, has no effect on u-PAR expression, suggesting that the glucocorticoid effect is due to a transrepressive mechanism. In summary, IL-1 beta increases cell-surface plasmin generation in A549 cells by coordinately upregulating urokinase and u-PAR expression. Transcriptional activation of the u-PAR gene involves PKC-dependent mechanisms, and glucocorticoid suppression is probably due to interactions between the glucocorticoid receptor and another transcriptional activating system such as activator protein-1 (AP-1) and/or nuclear factor-kB (NF-kB).
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PMID:Induction of urokinase-type plasminogen activator receptor by IL-1 beta. 919 70

Impaired fibrinolytic activity within the lungs is a common manifestation of acute and chronic inflammatory lung diseases. Our previous work using transgenic mice showed that upregulation of fibrinolysis reduced pulmonary fibrosis following bleomycin-induced inflammatory lung injury. As a strategy to accelerate fibrinolysis, we generated recombinant adenoviruses containing human and mouse urokinase-type plasminogen activator (uPA) cDNAs. Both vectors induced the expression of functional uPA in human lung-derived epithelial A549 cells. A single intratracheal instillation of these uPA-containing adenoviruses into mouse lungs resulted in increased plasminogen activator activity in bronchoalveolar lavage fluid for at least 2 weeks. Plasma-derived fibrin-rich matrices overlaid on A549 cells infected with these uPA vectors were lysed efficiently in a dose-dependent fashion. Similarly, fibrin matrices formed within intact lungs that had been infected with these uPA-containing adenoviruses were also lysed more rapidly compared with noninfected and control virus-infected lungs. These results indicate that adenovirus-mediated transduction of uPA successfully upregulates fibrinolysis in vitro and in vivo. These uPA vectors can be readily used for testing the role of the fibrinolytic system in animal models of lung fibrosis, with particular attention to their therapeutic potential.
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PMID:Upregulation of fibrinolysis by adenovirus-mediated transfer of urokinase-type plasminogen activator genes to lung cells in vitro and in vivo. 1002 46

Exposure to chromium(VI) increases the incidence of cancer, respiratory distress, and pulmonary fibrosis. The latter is a pathological disorder characterized by decreased urokinase-type plasminogen activator (uPA) activity and fibrinolysis. In this study, treatment of alveolar type II cells (A549) with 1 to 5 microM chromium(VI) for 4 and 12 h decreased both the specific activity and the amount of uPA protein. Chromium reduced uPA protein levels by inhibiting protein synthesis and had no effect on uPA mRNA levels or the rate of uPA protein degradation. In contrast, both mRNA and protein levels for the uPA receptor (uPAR) were increased by treatment with concentrations of chromium(VI) that did not completely inhibit protein synthesis. The chromium-induced increase in uPAR resulted from increased message stability. These data indicate that chromium has differential effects on expression of the proteins in the pulmonary fibrinolytic cascade. The net loss of uPA activity may promote fibrosis following inhalation of chromium(VI).
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PMID:Inhibition of protein synthesis by chromium(VI) differentially affects expression of urokinase and its receptor in human type II pneumocytes. 1043 62

During acute and chronic inflammatory lung diseases, the normal fibrinolytic activity in the alveolar space is inhibited by increased levels of plasminogen activator inhibitor 1 (PAI-1). Transgenic mice having increased fibrinolytic activity due to genetic deficiency of PAI-1 develop less fibrosis after bleomycin-induced lung inflammation. These observations led us to hypothesize that pulmonary fibrosis could be limited through enhancement of alveolar fibrinolytic activity by adenovirus-mediated transfer of the urokinase-type plasminogen activator (uPA) gene to the lung. To investigate this hypothesis, 0.075 U of bleomycin was introduced intratracheally into mice. Twenty-one days later, the mice were treated intratracheally with phosphate-buffered saline (PBS), a control adenovirus, or adenoviruses containing murine or human uPA cDNAs. On day 28, the mice were sacrificed, and lung fibrosis was quantitated by measuring hydroxyproline content. As expected, bleomycin caused a doubling in lung hydroxyproline to 345.6+/-28.2 microg/lung (SEM) compared with mice receiving PBS (170.2+/-4.0 microg/lung). Treatment of the bleomycin-injured mice with the control adenovirus on day 21 had no impact on lung fibrosis (338.4+/-17.2 microg/lung). Importantly, the human uPA adenovirus significantly reduced (p<0.05) lung hydroxyproline (281.2+/-22.8 microg/lung), thus attenuating by 38% the bleomycin-induced increase in lung collagen. The improvement in bleomycin-induced lung fibrosis resulting from treatment with the human uPA adenovirus further supports the importance of the fibrinolytic system during inflammatory lung injury and repair.
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PMID:Treatment of bleomycin-induced pulmonary fibrosis by transfer of urokinase-type plasminogen activator genes. 1051 51

Acute and chronic pulmonary diseases are characterized by impaired fibrinolytic activity within the lung. To determine the role of the fibrinolytic system in regulating the pathologies associated with lung injury, we examined the effect of bleomycin, an agent that induces the development of pulmonary fibrosis, in mice deficient for plasminogen (Pg(-)(/-)), urokinase (u-PA(-)(/-)), urokinase receptor (u-PAR(-)(/-)), or tissue plasminogen activator (t-PA(-)(/-)), and in control wild-type (WT) mice. Pg(-)(/-) and t-PA(-)(/-) mice demonstrated an enhanced increase in lung collagen content relative to that observed in WT mice. Levels in u-PA(-)(/-) and u-PAR(-)(/-) mice were similar to those in WT mice. Histological analysis 14 days after lung injury confirmed enhanced interstitial fibrosis in Pg(-)(/-), u-PA(-)(/-), and t-PA(-)(/-) mice relative to WT and u-PAR(-)(/-) mice. Areas of pulmonary hemorrhage were observed in bleomycin-treated WT mice and not in Pg(-)(/-), u-PA(-)(/-), and u-PAR(-)(/-) mice or saline controls. Instead, extensive areas of fibrosis were present throughout the lungs of bleomycin-treated Pg(-)(/-) and u-PA(-)(/-) mice. A mixed phenotype (hemorrhage and fibrosis) was observed in t-PA(-)(/-) and Pg(+/-) mice. Hemosiderin-laden macrophages were abundant in the lungs of mice exhibiting hemorrhage and these mice were prone to an early death. Enhanced macrophage levels in the lungs and activation of matrix metalloelastase (MMP-12) were found in mice with a hemorrhage phenotype. The results of these studies indicate a role for the fibrinolytic system in acute lung injury and suggests that intra-alveolar hemorrhage is the result of basement membrane degradation through cell-mediated u-PA activation of Pg with possible involvement of matrix metalloproteinases. Absence of these two components of the fibrinolytic system, either urokinase or plasminogen, results in accelerated fibrosis.
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PMID:The development of bleomycin-induced pulmonary fibrosis in mice deficient for components of the fibrinolytic system. 1088 Mar 88

One cause of debilitating pulmonary fibrosis is inhalation of insoluble metals. Human epidemiological and animal studies have associated inhalation of nickel dusts with increased incidence of pulmonary fibrosis. However, specific mechanisms for nickel-induced pulmonary fibrosis have yet to be elucidated. The current studies examine the hypothesis that particulate nickel promotes pulmonary fibrosis by inhibiting the fibrinolytic cascade. Since the urokinase-type plasminogen activator (uPA) initiates this cascade, this hypothesis was tested by investigating the effects of noncytotoxic levels of nickel subsulfide on the balance of uPA expression relative to expression of its inhibitor, PAI-1, in cultured human bronchial epithelial cells (BEAS-2B). Exposure to the metal decreased secreted uPA protein levels and activity without affecting uPA mRNA levels. In contrast, these same exposures stimulated transcription of PAI-1, causing prolonged increases in both mRNA and protein levels. Despite partial recovery of uPA protein levels, uPA activity remained depressed for more than 48 h after exposure to nickel due to the continued increase in PAI-1 expression. These data indicate that particulate nickel inhibits the fibrinolytic cascade by increasing the ratio of plasminogen inhibitor to activator. Sustained loss of uPA activity may contribute to nickel-induced pulmonary fibrosis in exposed populations.
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PMID:Nickel-induced plasminogen activator inhibitor-1 expression inhibits the fibrinolytic activity of human airway epithelial cells. 1100 99

Human epidemiological and animal studies have associated inhalation of nickel dusts with an increased incidence of pulmonary fibrosis. At the cellular level, particulate nickel subsulfide inhibits fibrinolysis by transcriptionally inducing expression of plasminogen activator inhibitor (PAI)-1, an inhibitor of the urokinase-type plasminogen activator. Because nickel is known to mimic hypoxia, the present study examined whether nickel transcriptionally activates PAI-1 through the hypoxia-inducible factor (HIF)-1 alpha signaling pathway. The involvement of the NADPH oxidase complex, reactive oxygen species, and kinases in mediating nickel-induced HIF-1 alpha signaling was also investigated. Addition of nickel to BEAS-2B human airway epithelial cells increased HIF-1 alpha protein levels and elevated PAI-1 mRNA levels. Pretreatment of cells with the extracellular signal-regulated kinase inhibitor U-0126 partially blocked HIF-1 alpha protein and PAI-1 mRNA levels induced by nickel, whereas antioxidants and NADPH oxidase inhibitors had no effect. Pretreating cells with antisense, but not sense, oligonucleotides to HIF-1 alpha mRNA abolished nickel-stimulated increases in PAI-1 mRNA. These data indicate that signaling through extracellular signal-regulated kinase and HIF-1 alpha is required for nickel-induced transcriptional activation of PAI-1.
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PMID:Nickel requires hypoxia-inducible factor-1 alpha, not redox signaling, to induce plasminogen activator inhibitor-1. 1150 87


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