Inconsistent hepatic antifibrotic effects with the iron chelator deferasirox

Sobbe, Amy, Bridle, Kim R., Jaskowski, Lesley, de Guzman, C. Erika, Santrampurwala, Nishreen, Clouston, Andrew D., Campbell, Catherine M., Subramaniam, V. Nathan and Crawford, Darrell H. G. (2015) Inconsistent hepatic antifibrotic effects with the iron chelator deferasirox. Journal of Gastroenterology and Hepatology, 30 3: 638-645. doi:10.1111/jgh.12720


Author Sobbe, Amy
Bridle, Kim R.
Jaskowski, Lesley
de Guzman, C. Erika
Santrampurwala, Nishreen
Clouston, Andrew D.
Campbell, Catherine M.
Subramaniam, V. Nathan
Crawford, Darrell H. G.
Title Inconsistent hepatic antifibrotic effects with the iron chelator deferasirox
Journal name Journal of Gastroenterology and Hepatology   Check publisher's open access policy
ISSN 1440-1746
0815-9319
Publication date 2015-03-01
Year available 2015
Sub-type Article (original research)
DOI 10.1111/jgh.12720
Volume 30
Issue 3
Start page 638
End page 645
Total pages 8
Place of publication Richmond, VIC Australia
Publisher Wiley-Blackwell Publishing Asia
Collection year 2016
Language eng
Formatted abstract
Background and Aim
Development of effective antifibrotic treatments that can be translated to clinical practice is an important challenge in contemporary hepatology. A recent report on β-thalassemia patients demonstrated that deferasirox treatment reversed or stabilized liver fibrosis independent of its iron-chelating properties. In this study, we investigated deferasirox in cell and animal models to better understand its potential antifibrotic effects.

Methods
The LX-2 stellate cell line was treated with 5 μM or 50 μM deferasirox (Exjade, Novartis Pharmaceuticals Australia, North Ryde, NSW, Australia) for up to 120 h. Three-week-old multidrug resistance 2 null (Mdr2–/–) mice received oral deferasirox or vehicle for 4 weeks (30 mg/kg/day). Cells and liver tissue were collected for assessment of fibrosis and fibrogenic gene expression.

Results
In LX-2 cells treated with 50 μM deferasirox for 12 h, α1(I)procollagen expression was decreased by 25%, with maximal reductions (10-fold) seen following 24–120 h of treatment. Similarly, α-smooth muscle actin (αSMA) expression was significantly lower. Alterations in matrix remodeling genes, specifically decreased expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2, were observed. There was no significant difference in hepatic hydroxyproline content in Mdr2–/– mice following deferasirox administration (vehicle: 395 ± 27 μg/g vs deferasirox: 421 ± 33 μg/g). Similarly, no changes in the expression of fibrogenic genes were observed.

Conclusion
Despite reductions in α1(I)procollagen and αSMA expression and alterations in matrix degradation genes in LX-2 cells, deferasirox did not exhibit antifibrotic activity in Mdr2–/– mice. Given the positive outcomes seen in human trials, it may be appropriate to study deferasirox in other animal models of fibrosis and/or for a longer duration of therapy.
Keyword Animal models
Iron-chelating agents
Liver fibrosis
Stellate cells
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
School of Medicine Publications
 
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