Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice

Brewer, George J.; Ullenbruch, Matthew; Dick, Robert; Olivarez, Leovigildo; Phan, Sem H.

doi:10.1067/mlc.2003.20

Cited by 66 publications

(66 citation statements)

References 18 publications

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“…3). It is interesting that inhibition of TGF-␤ expression has been reported to be associated with the inhibitory effect of both lung and liver fibrosis by copper-lowering therapy with tetrathiomolybdate (Brewer et al, 2003Askari et al, 2004). Tetrathiomolybdate was also found to suppress nuclear factor B, which in turn controls transcription of many angiogenic cytokines (Brewer, 2005), and to inhibit long-term inflammation (Omoto et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Molecular Changes Evoked by Triethylenetetramine Treatment in the Extracellular Matrix of the Heart and Aorta in Diabetic Rats

Gong¹,

Lu²,

Chen³

et al. 2006

Mol Pharmacol

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Most patients with diabetes die from cardiac or arterial disease, for which there are limited therapeutic options. Free Cu 2ϩ ions are strongly pro-oxidant, and chelatable-Cu II is increased in the diabetic heart. We reported previously that treatment by Cu IIselective chelation with triethylenetetramine (TETA) evokes elevated urinary Cu II in diabetic rats and humans in whom it also improved hallmarks of established left ventricular (LV) disease. Here, we treated diabetic rats with TETA and evaluated its ability to ameliorate Cu 2ϩ -mediated LV and arterial damage by modifying the expression of molecular targets that included transforming growth factor (TGF)-␤1, Smad4, extracellular matrix (ECM) proteins, extracellular superoxide dismutase (EC-SOD), and heparan sulfate (HS). Eight-weeks of TETA treatment significantly improved cardiac diastolic function but not [glucose] plasma in diabetic animals. LV and aortic mRNAs corresponding to TGF-␤1, Smad4, collagen types I, III, and IV, and fibronectin-1, and plasminogen activator inhibitor-1, were elevated in untreated diabetic animals and normalized after TETA treatment. EC-SOD mRNA and protein, and [HS] tissue were significantly decreased in diabetes and restored by drug treatment. Candidate molecular mechanisms by which TETA could ameliorate diabetic cardiac and arteriovascular disease include the suppression of an activated TGF-␤/Smad signaling pathway that mediates increased ECM gene expression and restoration of normal EC-SOD and HS regulation. These findings are relevant to the restoration toward normal by TETA treatment of cardiac and arterial structure and function in diabetes.

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Section: Discussionmentioning

confidence: 99%

Molecular Changes Evoked by Triethylenetetramine Treatment in the Extracellular Matrix of the Heart and Aorta in Diabetic Rats

Gong¹,

Lu²,

Chen³

et al. 2006

Mol Pharmacol

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“…Compound Name Application Reference 1 Pirfenidone analogues early (Ammar et al, 2006) (Azuma et al, 1998) 8 14-MRMLs early (Azuma et al, 2001) 9 IFN-beta early (Azuma, Li et al, 2005) 10 Taurine and Niacin early (Blaisdell & Giri, 1995) 11 EC-SOD early (Bowler, Nicks, Warnick, & Crapo, 2002) 12 Erdosteine early (Boyaci et al, 2006) 13 CME early (Breuer et al, 1995) 14 Tetrathiomolybdate early (Brewer, Ullenbruch, Dick, Olivarez, & Phan, 2003) …”

Section: Idmentioning

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

787

697

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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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“…TM therapy is able to almost completely abrogate these bleomycin induced injuries [72,73]. Fibrosis is measured by an increase in hydroxyproline, a major amino acid constituent of collagen, in the lung.…”

Section: Cytokine or Factor Referencesmentioning

confidence: 99%

“…TM completely protected against bleomycin induced weight loss. TM could be started after the inflammatory peak, and still protect against much of the fibrosis, indicating it is probably inhibiting both fibrotic and inflammatory responses [72,73].…”

Section: Cytokine or Factor Referencesmentioning

confidence: 99%

Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammation

Brewer

2003

J Cellular Molecular Medi

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The need for agents to lower body copper in Wilson's disease, a disease which results from copper toxicity has been the driving force for the development of the effective anticopper drugs penicillamine, trientine, zinc, and now tetrathiomolybdate (TM). Because of its rapid action, potency, and safety, TM is proving to be a very effective drug for initial treatment of acutely ill Wilson's disease patients. Beyond this, TM has antiangiogenic effects, because many proangiogenic cytokines require normal levels of copper. This has led to use of TM in cancer, where it is generally effective in animal tumor models, and has shown efficacy in preliminary clinical studies. Most recently, it has been found that TM has antifibrotic and antiinflammatory effects through inhibition of profibrotic and proinflammatory cytokines.

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Tetrathiomolybdate therapy protects against bleomycin-induced pulmonary fibrosis in mice

Cited by 66 publications

References 18 publications

Molecular Changes Evoked by Triethylenetetramine Treatment in the Extracellular Matrix of the Heart and Aorta in Diabetic Rats

Molecular Changes Evoked by Triethylenetetramine Treatment in the Extracellular Matrix of the Heart and Aorta in Diabetic Rats

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

Tetrathiomolybdate anticopper therapy for Wilson's disease inhibits angiogenesis, fibrosis and inflammation

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