Madecassoside ameliorates bleomycin-induced pulmonary fibrosis in mice by downregulating collagen deposition.
This study aimed to explore the protective effects of madecassoside (Mad), a triterpenoid saponin isolated from Centella asiatica herbs, on experimental pulmonary fibrosis (PF) and underlying mechanisms. PF model was established in mice by endotracheal instillation with bleomycin (5 mg/kg). Mice were orally administered with Mad (10, 20, 40 mg/kg) and prednisone (5 mg/kg) for 7 or 21 days. Mad (20, 40 mg/kg) significantly improved lung pathological changes and reduced collagen deposition. In the aspect of collagen synthesis, Mad (20, 40 mg/kg) reduced the expressions of α-smooth muscle actin and transforming growth factor-β1 (TGF-β1), and inhibited the phosphorylations of Smad2 and Smad3 in the lung tissues. However, in vitro, Mad showed little effect on TGF-β1-induced phosphorylation of either Smad2 or Smad3 in primary mouse lung fibroblasts. Moreover, Mad (20, 40 mg/kg) attenuated oxidative damage and inflammation presented at the early stage of PF, evidenced by reduced total leukocytes in the bronchoalveolar lavage fluid, decreased myeloperoxidase activity and malondialdehyde level, and increased super-oxide dismutase activity and glutathione level in lung tissues. On the other hand, Mad (40 mg/kg) elevated the matrix metalloproteinase 1/tissue inhibitor of metalloproteinase 1 ratio in lung tissues of PF mice mainly by downregulating tissue inhibitor of metalloproteinase 1 expression. The present study demonstrated that Mad can ameliorate PF by preventing the deposition of extracellular matrix, which might be achieved mainly through attenuating inflammation and oxidative stress and consequent TGF-β1 overexpression.
State Key Laboratory of Natural Medicines, Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
Guo-Xun
GX
Lu
Di-Fei
DF
Bian
Yu
Y
Ji
Jiao-Mei
JM
Guo
Zhi-Feng
ZF
Wei
Si-De
SD
Jiang
Yu-Feng
YF
Xia
Yue
Y
Dai
D000199:Actins / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects; D003094:Collagen / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000473:pathology; D053509:Matrix Metalloproteinase 13 / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D011658:Pulmonary Fibrosis / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
C558396:Acta2 protein, mouse; D000199:Actins; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D053773:Transforming Growth Factor beta1; D014315:Triterpenes; D001761:Bleomycin; D003094:Collagen; C093443:madecassoside; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse
TGF-β1 overexpression; collagen deposition; extracellular matrix; madecassoside; pulmonary fibrosis