631 Oxidative stress imbalance as contributing factor in the establishment of fibrosis in recessive dystrophic epidermolysis bullosa

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare skin fragility disorder characterized by deficient dermo-epidermal adhesion, due to mutations in the gene encoding collagen VII. Patients with RDEB suffer chronic wounds and inflammation that ultimately trigger fibrosis and highly aggressive squamous cell carcinoma development. We previously reported a clinical case of two siblings carrying in homozygosis the same null mutation (c.6527insC) in the COL7A1 gene, but with marked phenotypic differences with respect to the extent of mucocutaneous involvement, skin fragility and fibrosis. Transcriptomic analysis (RNA-Seq) of primary fibroblasts revealed a significant downregulation in the gene encoding the antioxidant enzyme ALDH1A1 in all RDEB patients, but not in the sibling with mild phenotype (M-RDEB) whose expression levels remain at those found in fibroblasts from healthy volunteers. In this study, flow cytometry analysis showed higher levels of basal and induced reactive oxygen species (ROS) in RDEB fibroblasts, compared to healthy controls and M-RDEB, suggesting redox imbalance as a possible new disease-severity modulator. Thus, treatment of RDEB fibroblasts with N-acetylcysteine (NAC) as an antioxidant allowed a reduction of the fibrotic and activated phenotype, possibly through interaction with the TGF-β pathway. This study proposes a contributing role of oxidative stress in RDEB pathophysiology, opening new therapeutic opportunities to treat the fibrotic and pro-tumorigenic dermal stroma of these patients.