Systems biology identifies a fibrosis target

HIV-associated nephropathy (HIVAN) includes kidney inflammation and fibrosis. Transgenic mice (Tg26 mice) develop both tubulointerstitial fibrosis and glomerulosclerosis.

TRANSFAC, ChEA, and a protein-DNA interaction array were used to identify 18 transcription factors (TFs) differentially activated in kidneys of Tg26 mice. Using Genes2Networks, a network of proteins interacted with 18 transcription factors was generated. HIPK2 is one of the most highly ranked kinases in the network.

The authors went on to show:
1. HIPK2 was expressed in kidney, in humans and mice, and regulated by HIV;
2. SIAH1 is an upstream regulator of HIPK2;
3. HIPK2 mediates apoptosis and EMT;
4. Downstream signals include profibrotic TGF-β–Smad3, Wnt, p53 and NF-κB pathways;

5. Importantly, knockout of HIPK2 prevents kidney injury, and attenuates kidney fibrosis in Tg26 mice;
6. HIPK2 knockout prevents tubulointerstitial fibrosis in a second kidney fibrosis model (the UUO model).

While this is very exciting with the hope that blocking HIPK2 with inhibitors may be an attractive approach for renal fibrotic diseases, further studies are needed to show:
a. HIPK2 and related signaling in human disease cells in much more details; what kind of cells; possible interacting cells;
b. More importantly, cell type specific knockout to dissect the role of HIPK2 in either epithelial cells or fibroblasts.


References
Jin, Y. et al. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat. Med. doi:10.1038/nm.2685
http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.2685.html

Jin Y, et al. A systems approach identifies HIPK2 as a key regulator of kidney fibrosis. Nat Med. 2012 Mar 11. doi: 10.1038/nm.2685. [Epub ahead of print] PubMed PMID: 22406746.

 

Octreotide for IPF

Somatostatin receptor sst2A  is highly expressed in fibrotic lung tissue in IPF patients. Uptake of a somatostatin analogue octreotide is elevated in the lungs of IPF patients.

Octreotide has been widely used for the treatment of neuroendocrine tumours.

A team of French scientists initiated a study that evaluated the safety and efficacy of intramuscular long-actingoctreotide as a therapy for IPF.  This was an open-label, proof-of-concept, non-randomised, non-controlled, multicentre phase II study on 25 patients over 48 weeks performed in France between October 2006 and April 2008.

The study concluded that long-acting octreotide is well tolerated and provide a proof of concept that octreotide treatment slows down the progression of lung fibrosis. A larger placebo-controlled study is needed to confirm the efficacy.

Reference
Crestani B, et al. Octreotide treatment of idiopathic pulmonary fibrosis: a proof-of-concept study. Eur Respir J. 2012 Mar;39(3):772-5. PubMed PMID: 22379151.

miR-29 and Bleomycin-induced Lung Fibrosis in Mice.

A recent study suggested that miR-29 was a downstream target gene of Smad3 and negatively regulated by TGF-β/Smad signaling in fibrosis. This was evidenced by the findings that mice or pulmonary fibroblasts null for Smad3 were protected against bleomycin or TGF-β1-induced loss of miR-29 along with fibrosis in vivo and in vitro. Interestingly, overexpression of miR-29 could in turn negatively regulated TGF-β and connective tissue growth factor (CTGF) expression and Smad3 signaling. Therefore, Sleeping Beauty (SB)-mediated miR-29 gene transfer into normal and diseased lung tissues was capable of preventing and treating pulmonary fibrosis including inflammatory macrophage infiltration induced by bleomycin in mice. In conclusion, miR-29 is negatively regulated by TGF-β/Smad3 and has a therapeutic potential for pulmonary fibrosis. SB-mediated miR-29 gene therapy is a non-invasive therapeutic strategy for lung disease associated with fibrosis.


Reference
1. Xiao J, et al.  miR-29 Inhibits Bleomycin-induced Pulmonary Fibrosis in Mice. Mol Ther. 2012 Mar  6. doi: 10.1038/mt.2012.36. [Epub ahead of print] PubMed PMID: 22395530.]

Inhaled IFNgamma for IPF

Three years ago, a trial showed that inteferon-gamma 1b did not improve survival for patients with idiopathic pulmonary fibrosis [ref1]. A recent study evaluated safety and delivery of aerosol IFN-γ (100 μg 3 times/week) in 10 IPF patients using the I-neb. Although PFTs showed minimal change in FVC, and 6MW was unchanged, the slope of (pre-therapy) decline in TLC and DLCO reversed after beginning therapy.


This eliminates the systemic effect of the drug. Further large study is needed to prove the efficacy of inhaled IFN-gamma for IPF.



References:
1. King TE Jr, Albera C, Bradford WZ, Costabel U, Hormel P, Lancaster L, Noble PW, Sahn SA, Szwarcberg J, Thomeer M, Valeyre D, du Bois RM; INSPIRE Study Group. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet. 2009 Jul 18;374(9685):222-8. Epub 2009 Jun 29. PubMed PMID: 19570573.

2.  Diaz KT, Skaria S, Harris K, Solomita M, Lau S, Bauer K, Smaldone GC, Condos R. Delivery and Safety of Inhaled Interferon-γ in Idiopathic Pulmonary Fibrosis. J Aerosol Med Pulm Drug Deliv. 2012 Feb 23. [Epub ahead of print] PubMed PMID:22360317.