The Plasminogen Activation System Reduces Fibrosis in the Lung by a Hepatocyte Growth Factor-Dependent Mechanism

Hattori, Noboru; Mizuno, Shinya; Yoshida, Yuka; Chin, Kazuo; Mishima, Michiaki; Sisson, Thomas H.; Simon, Richard H.; Nakamura, Toshikazu; Miyake, Masayuki

doi:10.1016/s0002-9440(10)63196-3

Cited by 76 publications

(75 citation statements)

References 55 publications

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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

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Warburton

et al. 2008

The International Journal of Biochemistry & Cell Biology

825

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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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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

825

724

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“…In particular, mice genetically deficient in PAI-1 (PAI-1 Ϫ/Ϫ ) released more HGF into BAL fluid after bleomycin exposure than did wild-type (WT) mice (14). Total lung HGF mRNA and protein, on the other hand, were not different in the two groups.…”

mentioning

confidence: 99%

“…However, the finding that pulmonary fibrosis occurred after bleomycin administration in mice genetically deficient in fibrinogen indicates that fibrin deposition is not required (12,13). Although a number of mechanisms may be involved in the plasminogen activation system's effect on lung repair, recent experimental results have led us to consider how this system affects HGF within the lung (14).…”

mentioning

confidence: 99%

“…In human diseases and experimental animals, HGF levels are found to be increased in blood and BAL fluid during lung injury/repair (19)(20)(21). These increases are significant because inhibition of HGF activity in the lung in animal models worsens lung fibrosis (14). Conversely, interventions designed to increase HGF reduce scarring (22)(23)(24).…”

mentioning

confidence: 99%

“…Total lung HGF mRNA and protein, on the other hand, were not different in the two groups. An inhibitor of plasminogen activation and plasmin activity, tranexamic acid, blocked HGF release (14) and worsened lung fibrosis (12). Administration of uPA to WT mice after bleomycin also increased HGF in BAL fluid and reduced the development of fibrosis (14).…”

mentioning

confidence: 99%

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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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Matrix Proteases in Health and Disease

Ellis

2012

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The Plasminogen Activation System Reduces Fibrosis in the Lung by a Hepatocyte Growth Factor-Dependent Mechanism

Cited by 76 publications

References 55 publications

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

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

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

Matrix Proteases in Health and Disease

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