Research ArticleFibrosis

A Peptide Derived from Endostatin Ameliorates Organ Fibrosis

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Science Translational Medicine  30 May 2012:
Vol. 4, Issue 136, pp. 136ra71
DOI: 10.1126/scitranslmed.3003421

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Putting an End to Fibrotic Organ Failure with Endostatin?

Organ fibrosis or “scarring” has the dubious distinction of accounting for nearly half of all deaths in the developed world, taking its toll in disorders ranging from liver cirrhosis to cardiovascular disease. There are no effective treatments for fibrosis, an out-of-control wound-healing process in which excess extracellular matrix components such as collagen and fibronectin replace normal tissue, ultimately resulting in organ failure.

Endostatin, a naturally occurring proteolytic fragment of one form of collagen, is elevated in patients with different forms of fibrosis. Previously, endostatin was shown to inhibit the growth of new blood vessels, an effect attributed to its N-terminal region. Because signaling molecules involved in blood vessel formation are also present in fibrotic tissues, Yamaguchi et al. investigated whether endostatin might inhibit fibrosis as well. Indeed, they found that a recombinant form did inhibit dermal fibrosis, in this case induced by the profibrotic factor transforming growth factor–β (TGF-β) in an ex vivo human skin model. So, too, could a smaller peptide, termed E4, which was derived from the C terminus of endostatin. In addition, E4 prevented TGF-β–induced dermal fibrosis in a mouse model—as well as dermal and lung fibrosis induced by a different trigger, bleomycin. E4 also reduced bleomycin-induced cell death in the mouse lung. Furthermore, Yamaguchi et al. found that E4 could reverse ongoing fibrosis, in addition to preventing its initiation, in these models. Finally, the researchers showed that E4 reduced the expression of two key proteins: lysyl oxidase, an enzyme that cross-links collagen and thereby contributes to fibrosis, and the transcription factor Egr-1, which is a central fibrosis regulator.

Because E4 can inhibit both skin and lung fibrosis, it may well be able to inhibit fibrosis in other tissues as well. Further research is needed to explore the therapeutic potential of this peptide for preventing or reversing organ fibrosis.

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