TY - JOUR
T1 - Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure
AU - Fisher, James E.
AU - McKenzie, Travis J.
AU - Lillegard, Joseph B.
AU - Yu, Yue
AU - Juskewitch, Justin E.
AU - Nedredal, Geir I.
AU - Brunn, Gregory J.
AU - Yi, Eunhee S.
AU - Malhi, Harmeet
AU - Smyrk, Thomas C.
AU - Nyberg, Scott L.
N1 - Funding Information:
Funding for this work was provided by NIH - R01-DK56733 . J.F. and T.M. were supported by the Clinical Investigator Training Program–Mayo Foundation. J.L. was supported by the American Society of Transplant Surgery (ASTS)-National Kidney Foundation (NKF) Folkert Belzer, MD research fellowship. E5564 was gifted by Eisai Research Institute. No monetary support was received from Eisai Research Institute for completion of this study.
PY - 2013/3
Y1 - 2013/3
N2 - Background: Significant morbidity associated with acute liver failure (ALF) is from the systemic inflammatory response syndrome (SIRS). Toll-like receptor 4 (TLR4) has been shown to play an integral role in the modulation of SIRS. However, little is known about the mechanistic role of TLR4 in ALF. Also, no cell type has been identified as the key mediator of the TLR4 pathway in ALF. This study examines the role of TLR4 and Kupffer cells (KCs) in the development of the SIRS following acetaminophen (APAP)-induced ALF. Materials and methods: Five groups of mice were established: untreated wild-type, E5564-treated (a TLR4 antagonist), gadolinium chloride -treated (KC-depleted), clodronate-treated (KC-depleted), and TLR4-mutant. Following APAP administration, 72-h survival, biochemical and histologic liver injury, extent of lung injury and edema, and proinflammatory gene expression were studied. Additionally, TLR4 expression was determined in livers of wild-type and KC-depleted mice. Results: Following APAP administration, wild-type, TLR4-mutant, E5564-treated, and KC-depleted mice had significant liver injury. However, wild-type mice had markedly worse survival compared with the other four treatment groups. TLR4-mutant, E5564-treated, and KC-depleted mice had less lung inflammation and edema than wild-type mice. Selected proinflammatory gene expression (interleukin 1β, interleukin 6, tumor necrosis factor) in TLR4-mutant, E5564-treated, and KC-depleted mice was significantly lower compared with wild-type mice after acute liver injury. Conclusion: This study demonstrates that survival in APAP-induced ALF potentially correlates with the level of proinflammatory gene expression. This study points to a link between TLR4 and KCs in the APAP model of ALF and, more importantly, demonstrates benefits of TLR4 antagonism in ALF.
AB - Background: Significant morbidity associated with acute liver failure (ALF) is from the systemic inflammatory response syndrome (SIRS). Toll-like receptor 4 (TLR4) has been shown to play an integral role in the modulation of SIRS. However, little is known about the mechanistic role of TLR4 in ALF. Also, no cell type has been identified as the key mediator of the TLR4 pathway in ALF. This study examines the role of TLR4 and Kupffer cells (KCs) in the development of the SIRS following acetaminophen (APAP)-induced ALF. Materials and methods: Five groups of mice were established: untreated wild-type, E5564-treated (a TLR4 antagonist), gadolinium chloride -treated (KC-depleted), clodronate-treated (KC-depleted), and TLR4-mutant. Following APAP administration, 72-h survival, biochemical and histologic liver injury, extent of lung injury and edema, and proinflammatory gene expression were studied. Additionally, TLR4 expression was determined in livers of wild-type and KC-depleted mice. Results: Following APAP administration, wild-type, TLR4-mutant, E5564-treated, and KC-depleted mice had significant liver injury. However, wild-type mice had markedly worse survival compared with the other four treatment groups. TLR4-mutant, E5564-treated, and KC-depleted mice had less lung inflammation and edema than wild-type mice. Selected proinflammatory gene expression (interleukin 1β, interleukin 6, tumor necrosis factor) in TLR4-mutant, E5564-treated, and KC-depleted mice was significantly lower compared with wild-type mice after acute liver injury. Conclusion: This study demonstrates that survival in APAP-induced ALF potentially correlates with the level of proinflammatory gene expression. This study points to a link between TLR4 and KCs in the APAP model of ALF and, more importantly, demonstrates benefits of TLR4 antagonism in ALF.
KW - Acute liver failure
KW - E5564
KW - Mice
KW - Systemic inflammatory response syndrome
UR - http://www.scopus.com/inward/record.url?scp=84873735534&partnerID=8YFLogxK
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U2 - 10.1016/j.jss.2012.11.051
DO - 10.1016/j.jss.2012.11.051
M3 - Article
C2 - 23260383
AN - SCOPUS:84873735534
SN - 0022-4804
VL - 180
SP - 147
EP - 155
JO - Journal of Surgical Research
JF - Journal of Surgical Research
IS - 1
ER -