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


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.
Department of Pathology, Wuxi People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, China.
Zhiyi
Z
Zhou
Department of Thoracic Surgery, Wuxi People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, China.
Xingfeng
X
Zhu
Department of Thoracic Surgery, Wuxi People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, China.
Jingyu
J
Chen
Department of Pathology, Wuxi People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, China.
Shudong
S
Yang
Department of Pathology, Wuxi People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, China.
Rongchao
R
Sun
Department of Pathology, Wuxi People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, China. Electronic address: yanggywin2013@163.com.
Guoyi
G
Yang
D055371:Acute Lung Injury / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D025461:Feedback, Physiological; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; C523075:Ticam1 protein, rat; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5
Hypoxia-inducible factor-1α; Lung ischemia–reperfusion injury; TLR4-HIF-1 loop; Toll-like receptor 4 signaling pathway