非特异性磷酸二酯酶抑制可减轻急性内毒素血症中的肝损伤。

Nonspecific phosphodiesterase inhibition attenuates liver injury in acute endotoxemia.

作者信息

Coimbra Raul, Porcides Rafael Dib, Melbostad Heidi, Loomis William, Tobar Maria, Hoyt David B, Wolf Paul

机构信息

Division of Trauma and Surgical Critical Care, Department of Surgery, University of California San Diego School of Medicine, San Diego, California 92103-8896, USA.

出版信息

Surg Infect (Larchmt). 2005 Spring;6(1):73-85. doi: 10.1089/sur.2005.6.73.

DOI:10.1089/sur.2005.6.73

PMID:15865553

Abstract

BACKGROUND

Endotoxemia is accompanied by pro-inflammatory cytokine production, generation of reactive oxygen species, and end-organ injury. Pentoxifylline (PTX), a methylxanthine derivative and phosphodiesterase inhibitor, is known for its anti-inflammatory properties, including down-regulation of interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha synthesis. Its effects on liver function and hepatic histology following acute endotoxemia have not been investigated fully. We hypothesized that PTX would preserve liver architecture and function after intravenous lipopolysaccharide (LPS) injection.

METHODS

Anesthetized Sprague-Dawley rats received an i.v. bolus injection of LPS (5 mg/kg), LPS + PTX (25 mg/kg), or saline (sham). Plasma concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNF-alpha, IL-6, and nitrite were measured at different time points after LPS injection. Liver injury was graded according to a scoring system in a blinded fashion from 0 (normal) to 4 (severe) for hepatocellular necrosis, hemorrhage, and parenchymal and sinusoidal inflammatory infiltrates. Neutrophil infiltration was measured by counting myeloperoxidase (MPO)-positive stained cells. Nuclear factor (NF)-kappaB p-65 was measured by counting positive stained nuclei of hepatocytes and Kupffer cells (KC). Inducible nitric oxide synthase (iNOS) was evaluated by positively stained KC. Data are presented as mean +/- SEM. Analysis of variance with p < 0.05 was considered statistically significant.

RESULTS

Animals treated with PTX showed a significant reduction in liver injury score and neutrophil infiltration. Treatment with PTX significantly decreased TNF-alpha, IL-6, and the concentrations of AST and ALT when compared to LPS alone. In addition, a significant decrease in NF-kappaB-positive staining in hepatocytes and KC, as well as in KC iNOS immunostaining was observed in PTX-treated animals compared to the LPS group.

CONCLUSIONS

Pentoxifylline downregulates the inflammatory response significantly and decreases liver injury in acute endotoxemia.

摘要

背景

内毒素血症伴有促炎细胞因子生成、活性氧产生及终末器官损伤。己酮可可碱（PTX）是一种甲基黄嘌呤衍生物和磷酸二酯酶抑制剂，以其抗炎特性而闻名，包括下调白细胞介素（IL）-6和肿瘤坏死因子（TNF）-α的合成。其对急性内毒素血症后肝功能和肝脏组织学的影响尚未得到充分研究。我们假设PTX在静脉注射脂多糖（LPS）后能保护肝脏结构和功能。

方法

将麻醉的Sprague-Dawley大鼠静脉推注LPS（5mg/kg）、LPS+PTX（25mg/kg）或生理盐水（假手术组）。在注射LPS后的不同时间点测量血浆丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、TNF-α、IL-6和亚硝酸盐的浓度。根据评分系统对肝损伤进行盲法分级，肝细胞坏死、出血以及实质和窦状隙炎症浸润从0（正常）到4（严重）。通过计数髓过氧化物酶（MPO）阳性染色细胞来测量中性粒细胞浸润。通过计数肝细胞和库普弗细胞（KC）的阳性染色细胞核来测量核因子（NF）-κB p-65。通过KC阳性染色评估诱导型一氧化氮合酶（iNOS）。数据以平均值±标准误表示。p<0.05的方差分析被认为具有统计学意义。