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Endogenous danger signals trigger hepatic ischemia/reperfusion injury through toll-like receptor 4/nuclear factor-kappa B pathway.
Chin Med J (Engl). 2007 Mar 20; 120(6):509-14.CM

Abstract

BACKGROUND

Restoration of blood flow to the ischemic liver lobes may paradoxically exacerbate tissue injury, which is called hepatic ischemia/reperfusion injury (IRI). Toll-like receptor 4 (TLR4), expressed on several liver cell types, and the nuclear factor-kappa B (NF-kappaB) signaling pathway are crucial to mediating hepatic inflammatory response. Because IRI is essentially a kind of profound acute inflammatory reaction evoked by many kinds of danger signals, we investigated TLR4/NF-kappaB signaling pathway activation in a murine model of partial hepatic IRI.

METHODS

Wild-type mice (WT, C3H/HeN) or TLR4 mutant mice (C3H/HeJ) were subjected to 45 minutes of partial hepatic ischemia followed by 1 hour, 3 hours of reperfusion. Sham group accepted the same procedure without the obstruction of blood supply. At the end of reperfusion, the compromise of liver function and the histological change of liver sections were measured as the severity of liver injury. The level of endotoxin in the portal vein was measured by limulus assay. NF-kappaB activation was determined by electrophoretic mobility shift assay (EMSA). The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in systemic blood after hepatic IRI were assessed by enzyme-linked immunosorbent assay (ELISA).

RESULTS

The compromise of liver function and the morphological injuries in mutant mice were relieved more markedly than those in WT mice after partial hepatic IRI. NF-kappaB activation in WT mice was stronger than that in TLR4 mutant mice, and both were stronger than those in the sham operated mice (P < 0.01). Endotoxin in each group was undetectable. The levels of TNF-alpha and IL-1beta in systemic blood were elevated in both strains, but lower in the sham operated group. These mediators were significantly decreased in TLR4 mutant mice compared with those in WT mice (P < 0.01).

CONCLUSIONS

The TLR4/NF-kappaB signaling pathway may mediate hepatic IRI triggered by endogenous danger signals. Inhibition of the TLR4/NF-kappaB pathway may be a potential therapeutic target for attenuating ischemia/reperfusion-induced tissue damage in some clinical settings.

Authors+Show Affiliations

Department of Medical Biology, Tongji Medical College Affiliated to Huazhong University of Science and Technology, Wuhan 430030, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17439747

Citation

Wang, Hui, et al. "Endogenous Danger Signals Trigger Hepatic Ischemia/reperfusion Injury Through Toll-like Receptor 4/nuclear Factor-kappa B Pathway." Chinese Medical Journal, vol. 120, no. 6, 2007, pp. 509-14.
Wang H, Li ZY, Wu HS, et al. Endogenous danger signals trigger hepatic ischemia/reperfusion injury through toll-like receptor 4/nuclear factor-kappa B pathway. Chin Med J (Engl). 2007;120(6):509-14.
Wang, H., Li, Z. Y., Wu, H. S., Wang, Y., Jiang, C. F., Zheng, Q. C., & Zhang, J. X. (2007). Endogenous danger signals trigger hepatic ischemia/reperfusion injury through toll-like receptor 4/nuclear factor-kappa B pathway. Chinese Medical Journal, 120(6), 509-14.
Wang H, et al. Endogenous Danger Signals Trigger Hepatic Ischemia/reperfusion Injury Through Toll-like Receptor 4/nuclear Factor-kappa B Pathway. Chin Med J (Engl). 2007 Mar 20;120(6):509-14. PubMed PMID: 17439747.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Endogenous danger signals trigger hepatic ischemia/reperfusion injury through toll-like receptor 4/nuclear factor-kappa B pathway. AU - Wang,Hui, AU - Li,Zhuo-ya, AU - Wu,He-shui, AU - Wang,Yang, AU - Jiang,Chun-fang, AU - Zheng,Qi-chang, AU - Zhang,Jin-xiang, PY - 2007/4/19/pubmed PY - 2007/5/12/medline PY - 2007/4/19/entrez SP - 509 EP - 14 JF - Chinese medical journal JO - Chin Med J (Engl) VL - 120 IS - 6 N2 - BACKGROUND: Restoration of blood flow to the ischemic liver lobes may paradoxically exacerbate tissue injury, which is called hepatic ischemia/reperfusion injury (IRI). Toll-like receptor 4 (TLR4), expressed on several liver cell types, and the nuclear factor-kappa B (NF-kappaB) signaling pathway are crucial to mediating hepatic inflammatory response. Because IRI is essentially a kind of profound acute inflammatory reaction evoked by many kinds of danger signals, we investigated TLR4/NF-kappaB signaling pathway activation in a murine model of partial hepatic IRI. METHODS: Wild-type mice (WT, C3H/HeN) or TLR4 mutant mice (C3H/HeJ) were subjected to 45 minutes of partial hepatic ischemia followed by 1 hour, 3 hours of reperfusion. Sham group accepted the same procedure without the obstruction of blood supply. At the end of reperfusion, the compromise of liver function and the histological change of liver sections were measured as the severity of liver injury. The level of endotoxin in the portal vein was measured by limulus assay. NF-kappaB activation was determined by electrophoretic mobility shift assay (EMSA). The levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in systemic blood after hepatic IRI were assessed by enzyme-linked immunosorbent assay (ELISA). RESULTS: The compromise of liver function and the morphological injuries in mutant mice were relieved more markedly than those in WT mice after partial hepatic IRI. NF-kappaB activation in WT mice was stronger than that in TLR4 mutant mice, and both were stronger than those in the sham operated mice (P < 0.01). Endotoxin in each group was undetectable. The levels of TNF-alpha and IL-1beta in systemic blood were elevated in both strains, but lower in the sham operated group. These mediators were significantly decreased in TLR4 mutant mice compared with those in WT mice (P < 0.01). CONCLUSIONS: The TLR4/NF-kappaB signaling pathway may mediate hepatic IRI triggered by endogenous danger signals. Inhibition of the TLR4/NF-kappaB pathway may be a potential therapeutic target for attenuating ischemia/reperfusion-induced tissue damage in some clinical settings. SN - 0366-6999 UR - https://www.unboundmedicine.com/medline/citation/17439747/Endogenous_danger_signals_trigger_hepatic_ischemia/reperfusion_injury_through_toll_like_receptor_4/nuclear_factor_kappa_B_pathway_ DB - PRIME DP - Unbound Medicine ER -