Tài liệu Báo cáo khoa học: Role of Kupffer cells in pathogenesis of sepsis-induced drug metabolizing

Role of Kupffer cells in pathogenesis of sepsis-induced

drug metabolizing dysfunction

Tae-Hoon Kim*, Sang-Ho Lee* and Sun-Mee Lee

School of Pharmacy, Sungkyunkwan University, Suwon, South Korea

Introduction

Sepsis, severe sepsis and septic shock are worldwide

problems and continue to be the most common causes

of death in surgical intensive care units [1]. The patho￾genesis of sepsis has often been viewed to involve

excessive immune inflammation that can lead to lethal

multiple organ failure, suggesting that the downregula￾tion of immunity could be beneficial [2]. As a result of

its major implications in essential metabolic functions

and host defense, the liver plays an important role in

the development of multiple organ failure [3].

Patients who are diagnosed with sepsis receive vari￾ous therapeutic agents because of its complex patho￾physiology and varied symptoms; the main clinical

concern has been that patients on a stable drug regi￾men would have increased exposure to an incidence of

adverse drug events. The cytochrome P450 (CYP)

enzyme system constitutes one of the major aspects of

hepatocyte function and contributes to the metabolism

and elimination of exogenous and endogenous sub￾stances [4]. In various models and in clinical reports,

Keywords

CYP450; HMGB1; Kupffer cells; sepsis;

Toll-like receptor

Correspondence

S.-M. Lee, School of Pharmacy,

Sungkyunkwan University, 300 Cheoncheon￾dong, Jangan-gu, Suwon-si, Gyeonggi￾do 440-746, South Korea

Fax: +82 31 292 8800

Tel: +82 31 290 7712

E-mail: [email protected]

*These authors contributed equally to this

work

(Received 2 December 2010, revised 19

April 2011, accepted 28 April 2011)

doi:10.1111/j.1742-4658.2011.08148.x

The present study aimed to determine the role of Kupffer cells (KCs) in

cytochrome P450 (CYP) isozyme activity and the expression of its gene

during polymicrobial sepsis. For ablation of KCs, rats were pretreated with

gadolinium chloride (GdCl3) at 48 and 24 h before cecal ligation and punc￾ture (CLP). The depletion of KCs was confirmed by measuring the mRNA

level of the KC marker gene CD163. Serum aminotransferase levels and

lipid peroxidation showed an increase and hepatic glutathione content

showed a decrease at 24 h after CLP. These changes were prevented by

GdCl3 pretreatment. Catalytic activities of CYP1A1, 1A2 and 2E1 showed

a significant reduction at 24 h after CLP but were prevented by GdCl3.

A reduction in the levels of CYP2E1 protein and CYP2B1 and CYP2E1

mRNA expression was prevented by GdCl3. Phosphorylation of

CYP1A1 ⁄ 1A2 markedly increased 24 h after CLP, which was prevented by

GdCl3. The increased serum level of high mobility group box 1, hepatic

level of Toll-like receptors 2 and 4, and inducible nitric oxide synthase pro￾tein expression were prevented by GdCl3. In addition, elevated serum con￾centrations of tumor necrosis factor-a and interleukin-6, and increased

hepatic mRNA levels of tumor necrosis factor-a and interleukin-6 were

decreased by depletion of KCs. Our findings suggest that ablation of KCs

protects against hepatic drug-metabolizing dysfunction by modulation of

the inflammatory response.

Abbreviations

ALT, alanine aminotrasferase; AST, aspartate aminotrasferase; CLP, cecal ligation and puncture; CYP, cytochrome P450; GdCl3, gadolinium

chloride; GSH, glutathione; GSSG, glutathione disulfide; HMGB1, high mobility group box 1; IL, interleukin; iNOS, inducible nitric oxide

synthase; KCs, Kupffer cells; LPS, lipopolysaccharide; MDA, malondialdehyde; NO, nitric oxide; PAP, p-aminophenol;

RIPA, radioimmunoprecipitation assay; ROS, reactive oxygen species; TLR, Toll-like receptor; TNF, tumor necrosis factor.

FEBS Journal 278 (2011) 2307–2317 ª 2011 The Authors Journal compilation ª 2011 FEBS 2307