HIF-1α regulates EMT via the Snail and β-catenin pathways in paraquat poisoning-induced early pulmonary fibrosis

J Cell Mol Med. 2016 Apr;20(4):688-97. doi: 10.1111/jcmm.12769. Epub 2016 Jan 19.


Paraquat (PQ) poisoning-induced pulmonary fibrosis is one of the primary causes of death in patients with PQ poisoning. Hypoxia-inducible factor-1α (HIF-1α) and epithelial-mesenchymal transition (EMT) are involved in the progression of pulmonary fibrosis. Snail and β-catenin are two other factors involved in promoting EMT. However, the relationship among HIF-1α, Snail and β-catenin in PQ poisoning-induced pulmonary fibrosis is not clear. Our research aimed to determine whether the regulation of HIF-1α in EMT occurs via the Snail and β-catenin pathways in PQ poisoning-induced pulmonary fibrosis. Sixty-six Sprague-Dawley rats were randomly and evenly divided into a control group and a PQ group. The PQ group was treated with an intragastric infusion of a 20% PQ solution (50 mg/kg) for 2, 6, 12, 24, 48 and 72 hrs. A549 and RLE-6TN cell lines were transfected with HIF-1α siRNA for 48 hrs before being exposed to PQ. Western blotting, real-time quantitative PCR, immunofluorescence, immunohistochemistry and other assays were used in our research. In vivo, the protein levels of HIF-1α and α-SMA were increased at 2 hrs and the level of ZO-1 (Zonula Occluden-1) was reduced at 12 hrs. In vitro, the transient transfection of HIF-1α siRNA resulted in a decrease in the degree of EMT. The expression levels of Snail and β-catenin were significantly reduced when HIF-α was silenced. These data demonstrate that EMT may be involved in PQ poisoning-induced pulmonary fibrosis and regulated by HIF-1α via the Snail and β-catenin pathways. Hypoxia-inducible factor-1α may be a therapeutic target for the treatment of PQ poisoning-induced pulmonary fibrosis.

Keywords: epithelial-mesenchymal transition; hypoxia-inducible factor-1α; paraquat; pulmonary fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Cell Line
  • Disease Progression
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Expression Regulation
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Male
  • Paraquat
  • Pulmonary Alveoli / metabolism
  • Pulmonary Alveoli / pathology
  • Pulmonary Fibrosis / chemically induced
  • Pulmonary Fibrosis / genetics*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Snail Family Transcription Factors / genetics*
  • Snail Family Transcription Factors / metabolism
  • Zonula Occludens-1 Protein / genetics
  • Zonula Occludens-1 Protein / metabolism
  • beta Catenin / genetics*
  • beta Catenin / metabolism


  • Ctnnb1 protein, rat
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • RNA, Small Interfering
  • Snail Family Transcription Factors
  • Tjp1 protein, rat
  • Zonula Occludens-1 Protein
  • beta Catenin
  • snai1 protein, rat
  • Paraquat