All Trans Retinoic Acid (ATRA) progresses alveolar epithelium regeneration by involving diverse signalling pathways in emphysematous rat

Biomed Pharmacother. 2020 Nov;131:110725. doi: 10.1016/j.biopha.2020.110725. Epub 2020 Sep 11.


Introduction: Pulmonary emphysema is characterized by destruction of alveoli leading to inadequate oxygenation, disability and frequently death. This destruction was understood so far as irreversible. Published data has shown that ATRA (All Trans Retinoic Acid) reverses elastase-induced emphysema in rats. However, the molecular mechanisms governing regeneration process are so far unknown.

Objective: To examine the therapeutic potential of ATRA on various molecular pathways and their coordination towards governance of alveolar epithelial regeneration in emphysematous rats.

Methods: Emphysema was induced by elastase versus saline in Sprague-Dawley rats. On days 26-37, rats received daily intraperitoneal injections with ATRA (500 μg/kg b.w.) versus olive-oil. Lungs were removed at day 38 for histopathology and investigation of relative mRNA and protein expressions.

Results: Histopathological analysis has shown that losses of alveoli were recovered in therapy (EA) group. Moreover, expressions of markers genes for alveolar cell proliferation, differentiation and EMT events at mRNA and protein levels were significantly increased in EA group than emphysema group (ES). Upon validation at genomics level, expressions of components of Notch, Hedgehog, Wnt, BMP and TGFβ pathways were significantly attenuated in EA group when compared with ES and were well comparable with the healthy group.

Conclusion: Therapeutic supplementation of ATRA rectifies the deregulated Notch, Hedgehog, Wnt, BMP and TGFβ pathways in emphysema condition, resulting in alveolar epithelium regeneration. Hence, ATRA may prove to be a potential drug in the treatment of emphysema. Nevertheless, elaborated studies are to be conducted.

Keywords: All Trans Retinoic Acid; Alveolar regeneration; Emphysema.

MeSH terms

  • Animals
  • Aquaporin 4 / genetics
  • Body Weight / drug effects
  • Bone Morphogenetic Proteins / physiology
  • Epithelium / physiology
  • Male
  • Pulmonary Alveoli / drug effects*
  • Pulmonary Alveoli / pathology
  • Pulmonary Alveoli / physiology
  • Pulmonary Emphysema / drug therapy*
  • Pulmonary Emphysema / pathology
  • Pulmonary Emphysema / physiopathology
  • Rats
  • Rats, Sprague-Dawley
  • Regeneration / drug effects*
  • Regeneration / physiology
  • Signal Transduction / physiology
  • Transforming Growth Factor beta / physiology
  • Tretinoin / pharmacology
  • Tretinoin / therapeutic use*
  • Vimentin / genetics


  • Aqp4 protein, rat
  • Aquaporin 4
  • Bone Morphogenetic Proteins
  • Transforming Growth Factor beta
  • Vimentin
  • Tretinoin