Prevention of Bleomycin-induced Lung Fibrosis by Aerosolization of Heparin or Urokinase in Rabbits

Günther, Andreas; Lübke, Norbert; Ermert, Monika; Schermuly, Ralph Theo; Weißmann, Norbert; Breithecker, Andreas; Markart, Philipp; Ruppert, Clemens; Quanz, Karin; Ermert, Leander; Grimminger, Friedrich; Seeger, Werner

doi:10.1164/rccm.2201082

Cited by 153 publications

(110 citation statements)

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“…In our experiments, we administered 500 IU of uPA (20,000 IU/kg) to each mouse, which was approximately fourfold higher per body weight than the dose of uPA used in a previously reported rabbit lung fibrosis study (9). However, in the rabbit model treatment was administrated with a tightfitting mask.…”

Section: Discussionmentioning

confidence: 99%

“…For example, wild-type mice administered uPA and mice transgenically deficient in PAI-1 are both resistant to pulmonary fibrosis after lung injury (7,9). Although the mechanism by which increased uPA/plasmin limits fibrogenesis is unclear, this system regulates the activity of hepatocyte growth factor (HGF) by cleaving latent HGF and by releasing it from its ECM reservoir.…”

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confidence: 99%

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Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model

Kuramoto¹,

Nishiuma²,

Kobayashi³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model. Am J Physiol Lung Cell Mol Physiol 296: L337-L346, 2009. First published December 19, 2008 doi:10.1152/ajplung.90434.2008.-The airway remodeling that occurs in asthma is characterized by an excess of extracellular matrix deposition in the submucosa, hyperplasia/hypertrophy of smooth muscle, goblet cell metaplasia, and accumulation of fibroblasts/myofibroblasts. The urokinase-type plasminogen activator (uPA)/plasmin system participates in pericellular proteolysis and is capable of directly degrading matrix components, activating latent proteinases, and activating growth factors. In a mouse ovalbumin (OVA) asthma model, we increased plasminogen activator activity in the lung by administering exogenous uPA or by using mice genetically deficient in the uPA inhibitor plasminogen activator inhibitor-1 (PAI-1) to assess the role of this system in asthma pathogenesis. After intraperitoneal OVA sensitization, mice inhaled OVA plus uPA (500 IU/ mouse) or saline by ultrasonic nebulization for 3 wk. When studied 24 h after the final exposure, the groups with upregulated plasmin activity had significantly reduced subepithelial fibrosis within the airway walls and had decreased airway hyperresponsiveness (AHR) to methacholine. Morphometric analysis showed that subepithelial wall thickening of the bronchi (subepithelial area ratio) was also reduced, as were collagen and ␣-smooth muscle actin. Upregulation of plasmin activity also increased the level of hepatocyte growth factor activity in bronchoalveolar lavage fluid, whereas the release of transforming growth factor-␤ was decreased. The administration of uPA 1 wk after the last OVA inhalation also significantly reduced lung hydroxyproline content and AHR. These results show that enhancing uPA/ plasmin activity lessens the airway remodeling in a murine asthma model.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model

Kuramoto¹,

Nishiuma²,

Kobayashi³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The experimental approaches used to increase plasminogen activation in the lung have included use of PAI-1 Ϫ/Ϫ mice (8), delivery of uPA protein directly to the lung (14,43), delivery of uPA genes using adenoviral vectors (9), and use of a transgenic mouse with doxycycline-inducible uPA activity expressed exclusively within the lung (11). In each situation, the lungs were relatively protected from bleomycininduced fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix

Matsuoka

Sisson

Nishiuma

et al. 2006

Am J Respir Cell Mol Biol

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Interventions that enhance plasminogen activation within the lung consistently limit the fibrosis that follows alveolar injury. However, this protective effect cannot be attributed solely to accelerated clearance of fibrin that forms as a provisional matrix after lung injury. To explore other mechanisms, we considered interactions between the plasminogen activation system and hepatocyte growth factor (HGF). HGF is known to have antifibrotic activity, but to do so, it must be both released from its sites of sequestration within extracellular matrix (ECM) and activated by proteolytic cleavage. A recent study using bleomycin-exposed mice showed that manipulations of the plasminogen activation system influenced the amount of free HGF within bronchoalveolar lavage fluid without affecting total lung HGF mRNA or protein. To elucidate the mechanisms, we studied the role of plasminogen activation in fibroblastmediated HGF release and activation. We found that NIH3T3 and mouse lung fibroblasts release ECM-bound HGF in a plasminogendependent fashion. The plasminogen effect was lost when lung fibroblasts from urokinase-type plasminogen activator (uPA)-deficient mice were used, and was increased by fibroblasts from plasminogen activator inhibitor (PAI)-1-deficient mice. Plasminogen addition to NIH3T3 or mouse lung fibroblasts increased conversion of pro-HGF to its active form. The plasminogen effect on activation was lost when uPA-deficient fibroblasts were used and accentuated by PAI-1-deficient fibroblasts. In conjunction with the previous in vivo study, these results suggest that plasminogen activation can protect the lung against fibrosis by increasing the availability of active HGF.

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“…), Angiotensin receptor blockers (Losartan (Fang, Zhu, Hu, & Liu, 2002;Marshall et al, 2004;Yao, Zhu, Zhao, & Lu, 2006), Candesartan (Otsuka, Takahashi, Shiratori, Chiba, & Abe, 2004), Valsartan (F. Liu, Xu, & Ye, 2005;Mancini & Khalil, 2005) etc. ), Anticoagulants (TFPI = tissue factor pathway inhibitor (Kijiyama et al, 2006), Urokinase (Hart, Whidden, Green, Henkin, & Woods, 1994;Hattori et al, 2004;Howell et al, 2001;Howell, Laurent, & Chambers, 2002;Ikeda, Hirose, Koto, Hirano, & Shigematsu, 1989), Heparin (Gunther et al, 2003;Piguet, Van, & Guo, 1996), APC = anticoagulant protein C (S. Shimizu et al, 2003;H. Yasui et al, 2001), Thromboxane synthetase inhibitor (Sato et al, 2004) etc.…”

Section: Drug Intervention Studies In the Bleomycin Modelmentioning

confidence: 99%

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

Moeller

Ask

Warburton

et al. 2008

The International Journal of Biochemistry & Cell Biology

841

724

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Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 246 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. In 221 of the studies we found enough details about the timing of drug application to allow inter-study comparison. 211 of those used a preventive regimen (drug given ≤ day 7 after last bleomycin application), only 10 were therapeutic trials (> 7 days after last bleomycin application). It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted.

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Prevention of Bleomycin-induced Lung Fibrosis by Aerosolization of Heparin or Urokinase in Rabbits

Cited by 153 publications

References 53 publications

Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model

Inhalation of urokinase-type plasminogen activator reduces airway remodeling in a murine asthma model

Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

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