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

Publication Type:

Journal Article

Source:

The Journal of surgical research, Volume 180, Issue 1, p.147-55 (2013)

Keywords:

Acetaminophendigestive disease, digestive deseases Analgesics, Non-Narcoticdigestive disease, digestive deseases Animalsdigestive disease, digestive deseases HEK293 Cellsdigestive disease, digestive deseases Humansdigestive disease, digestive deseases Kupffer Cellsdigestive disease, digestive deseases Lipopolysaccharidesdigestive disease, digestive deseases Liver Failure, Acutedigestive disease, digestive deseases Maledigestive disease, digestive deseases Micedigestive disease, digestive deseases Mice, Inbred C3Hdigestive disease, digestive deseases Systemic Inflammatory Response Syndromedigestive disease, digestive deseases Toll-Like Receptor 4

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.