Protective effects of alpha-lipoic acid on bleomycin-induced skin fibrosis through the repression of NADPH Oxidase 4 and TGF-β1/Smad3 signaling pathways

Hum Exp Toxicol. 2022 Jan-Dec:41:9603271211065975. doi: 10.1177/09603271211065975.


The aim of this study was to determine the protective effects of alpha-lipoic acid (ALA), which is known as a powerful antioxidant, and the possible related molecular mechanisms that mediate its favorable action on skin fibrosis in the bleomycin (BLM)-induced scleroderma (SSc) model in mice. The experimental design was established with four groups of eight mice: Control, ALA (100 mg/kg), BLM (5 μg/kg), and BLM + ALA group. BLM was administered via subcutaneous (sc) once a day while ALA was injected intraperitoneally (ip) twice a week for 21 days. Histopathological and biochemical analyses showed that ALA significantly reduced BLM-induced dermal thickness, inflammation score, and mRNA expression of tumor necrosis factor-alpha (TNF-α) in the skin. Besides, the mRNA expressions of the subunits of NADPH oxidase, which are Nox4 and p22phox, were found to be significantly induced in the BLM group. However, ALA significantly reduced their mRNA expression, which were in parallel to its decreasing effect on serum total oxidant status (TOS) level. Moreover, it was found that ALA downregulated the mRNA expressions of alpha-smooth muscle actin (α-SMA), collagen type I and fibronectin in the skin tissue of the BLM group. Additionally, it was shown that ALA reduced significantly the TGF-β1 and p-Smad3 protein expressions in the BLM + ALA group. On the other hand, ALA did not exhibit any significant effect on the p38 mitogen-activated kinase (MAPK) activation induced by BLM. All these findings point out that ALA may be a promising treatment for the attenuation of skin fibrosis in SSc patients.

Keywords: alpha-lipoic acid; oxidative stress; scleroderma; skin fibrosis.

MeSH terms

  • Animals
  • Bleomycin / toxicity*
  • Disease Models, Animal
  • Fibrosis / chemically induced*
  • Fibrosis / prevention & control*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • NADPH Oxidase 4 / metabolism
  • Protective Agents / pharmacology
  • Signal Transduction / drug effects*
  • Skin / drug effects*
  • Smad3 Protein / metabolism*
  • Thioctic Acid / pharmacology*
  • Transforming Growth Factor beta1 / metabolism*


  • Protective Agents
  • Smad3 Protein
  • Transforming Growth Factor beta1
  • Bleomycin
  • Thioctic Acid
  • NADPH Oxidase 4