The interaction between Toll-like receptor 4 signaling pathway and hypoxia-inducible factor 1α in lung ischemia-reperfusion injury

J Surg Res. 2014 May 1;188(1):290-7. doi: 10.1016/j.jss.2013.11.1086. Epub 2013 Nov 22.


Background: Lung ischemia-reperfusion injury (LIRI) is the life-threatening complication occurring after lung transplantation. Toll-like receptor 4 (TLR4) signaling pathway and hypoxia-inducible factor-1α (HIF-1α) are intimately involved in the development and progression of various inflammatory and hypoxia diseases; however, the relationship of them in LIRI in vivo is still far from clear.

Materials and methods: Forty-five Sprague-Dawley rats were randomly distributed in nine groups: (1) Sham group, (2) LIRI group, (3) LIRI + saline control group, (4) LIRI + dimethyl Sulfoxide control group, (5) LIRI + lipopolysaccharide group, (6) LIRI + TAK-242 group (TAK-242 is a TLR4 inhibitor, ethyl (6R)-6- [N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate), (7) LIRI + thioredoxin group (thioredoxin is an apoptosis signal-regulating kinase 1 (ASK1) inhibitor), (8) LIRI + SB203580 group (SB203580 is a p38 inhibitor), and (9) LIRI + chetomin group (chetomin is a HIF-1α inhibitor). The interaction between TLR4 signaling pathway (including TLR4, myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF), ASK1, and p38) and HIF-1α and the role of TLR4-dependent HIF-1α were analyzed.

Results: In LIRI, HIF-1α accumulation was induced in a TLR4-dependent fashion, and MyD88, but not TRIF, and activation of ASK1 and p38 were found to be critical for TLR4-mediated HIF-1α accumulation. HIF-1α protein played a critical role in TLR4-mediated lung injury of LIRI (including inflammation, cell apoptosis, and lung damage). HIF-1α protein upregulated TLR4 expression of LIRI in a positive feedback manner.

Conclusions: We identify that the TLR4-HIF-1 loop may be existed in LIRI. Therefore, we suggest that the interaction between them may represent a novel therapeutic target for the development of novel target-based therapies of LIRI.

Keywords: Hypoxia-inducible factor-1α; Lung ischemia–reperfusion injury; TLR4-HIF-1 loop; Toll-like receptor 4 signaling pathway.

MeSH terms

  • Acute Lung Injury / metabolism*
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Animals
  • Apoptosis
  • Feedback, Physiological
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Signaling System
  • Male
  • Myeloid Differentiation Factor 88 / metabolism
  • Random Allocation
  • Rats
  • Rats, Sprague-Dawley
  • Reperfusion Injury / metabolism*
  • Toll-Like Receptor 4 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Adaptor Proteins, Vesicular Transport
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Myd88 protein, rat
  • Myeloid Differentiation Factor 88
  • Ticam1 protein, rat
  • Tlr4 protein, rat
  • Toll-Like Receptor 4
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5