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EMBO Mol Med. 2015 Sep;7(9):1211-28. doi: 10.15252/emmm.201505061.

Losartan ameliorates dystrophic epidermolysis bullosa and uncovers new disease mechanisms.

Author information

1
Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
2
Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany ZBSA Center for Biological Systems Analysis, Freiburg, Germany FRIAS Freiburg Institute for Advanced Studies, Freiburg, Germany.
3
Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany ZBSA Center for Biological Systems Analysis, Freiburg, Germany FRIAS Freiburg Institute for Advanced Studies, Freiburg, Germany BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
4
Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany FRIAS Freiburg Institute for Advanced Studies, Freiburg, Germany bruckner-tuderman@uniklinik-freiburg.de.

Abstract

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB)-a severe skin fragility disorder associated with lifelong blistering and disabling progressive soft tissue fibrosis. Causative therapies for this complex disorder face major hurdles, and clinical implementation remains elusive. Here, we report an alternative evidence-based approach to ameliorate fibrosis and relieve symptoms in RDEB. Based on the findings that TGF-β activity is elevated in injured RDEB skin, we targeted TGF-β activity with losartan in a preclinical setting. Long-term treatment of RDEB mice efficiently reduced TGF-β signaling in chronically injured forepaws and halted fibrosis and subsequent fusion of the digits. In addition, proteomics analysis of losartan- vs. vehicle-treated RDEB skin uncovered changes in multiple proteins related to tissue inflammation. In line with this, losartan reduced inflammation and diminished TNF-α and IL-6 expression in injured forepaws. Collectively, the data argue that RDEB fibrosis is a consequence of a cascade encompassing tissue damage, TGF-β-mediated inflammation, and matrix remodeling. Inhibition of TGF-β activity limits these unwanted outcomes and thereby substantially ameliorates long-term symptoms.

KEYWORDS:

TGF‐β; collagen VII; dystrophic epidermolysis bullosa; fibrosis; losartan

PMID:
26194911
PMCID:
PMC4568953
DOI:
10.15252/emmm.201505061
[Indexed for MEDLINE]
Free PMC Article

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