Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure

James E. Fisher, Travis J. McKenzie, Joseph B. Lillegard, Yue Yu, Justin E. Juskewitch, Geir I. Nedredal, Gregory J. Brunn, Eunhee S. Yi, Harmeet M Malhi, Thomas Christopher Smyrk, Scott Nyberg

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)147-155
Number of pages9
JournalJournal of Surgical Research
Volume180
Issue number1
DOIs
StatePublished - Mar 2013

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Toll-Like Receptor 4
Kupffer Cells
Acute Liver Failure
Acetaminophen
Systemic Inflammatory Response Syndrome
Liver
Gene Expression
Edema
Wounds and Injuries
Clodronic Acid
Lung Injury
Interleukin-1
Interleukin-6
Pneumonia
Tumor Necrosis Factor-alpha

Keywords

  • Acute liver failure
  • E5564
  • Mice
  • Systemic inflammatory response syndrome

ASJC Scopus subject areas

  • Surgery

Cite this

Fisher, J. E., McKenzie, T. J., Lillegard, J. B., Yu, Y., Juskewitch, J. E., Nedredal, G. I., ... Nyberg, S. (2013). Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure. Journal of Surgical Research, 180(1), 147-155. https://doi.org/10.1016/j.jss.2012.11.051

Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure. / Fisher, James E.; McKenzie, Travis J.; Lillegard, Joseph B.; Yu, Yue; Juskewitch, Justin E.; Nedredal, Geir I.; Brunn, Gregory J.; Yi, Eunhee S.; Malhi, Harmeet M; Smyrk, Thomas Christopher; Nyberg, Scott.

In: Journal of Surgical Research, Vol. 180, No. 1, 03.2013, p. 147-155.

Research output: Contribution to journalArticle

Fisher, JE, McKenzie, TJ, Lillegard, JB, Yu, Y, Juskewitch, JE, Nedredal, GI, Brunn, GJ, Yi, ES, Malhi, HM, Smyrk, TC & Nyberg, S 2013, 'Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure', Journal of Surgical Research, vol. 180, no. 1, pp. 147-155. https://doi.org/10.1016/j.jss.2012.11.051
Fisher JE, McKenzie TJ, Lillegard JB, Yu Y, Juskewitch JE, Nedredal GI et al. Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure. Journal of Surgical Research. 2013 Mar;180(1):147-155. https://doi.org/10.1016/j.jss.2012.11.051
Fisher, James E. ; McKenzie, Travis J. ; Lillegard, Joseph B. ; Yu, Yue ; Juskewitch, Justin E. ; Nedredal, Geir I. ; Brunn, Gregory J. ; Yi, Eunhee S. ; Malhi, Harmeet M ; Smyrk, Thomas Christopher ; Nyberg, Scott. / Role of Kupffer cells and toll-like receptor 4 in acetaminophen-induced acute liver failure. In: Journal of Surgical Research. 2013 ; Vol. 180, No. 1. pp. 147-155.
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abstract = "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.",
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AU - Yu, Yue

AU - Juskewitch, Justin E.

AU - Nedredal, Geir I.

AU - Brunn, Gregory J.

AU - Yi, Eunhee S.

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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.

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