TNF-α 中和可改善大鼠实验性肝肺综合征。

TNF-α neutralization improves experimental hepatopulmonary syndrome in rats.

机构信息

Department of Medicine, Hebei Key Laboratory of Gastroenterology, Second Hospital of Hebei Medical University, Shijiazhuang, China.

出版信息

Liver Int. 2012 Jul;32(6):1018-26. doi: 10.1111/j.1478-3231.2012.02821.x.

DOI:10.1111/j.1478-3231.2012.02821.x

PMID:22672643

Abstract

BACKGROUND/AIM: TNF-α is increased in hepatopulmonary syndrome (HPS). Pentoxifylline (PTX) mitigated experimental HPS through the inhibition of TNF-α. However, PTX has pleiotropic effects besides the inhibition of TNF-α. This study is to neutralize TNF-α with specific monoclonal antibody to TNF-α (TNF-α McAb) to investigate the effect of TNF-α on HPS.

MATERIALS AND METHODS

Hepatopulmonary syndrome was induced by common bile duct ligation (CBDL); controls were sham operated. The endpoints were 1, 2, 3, 4 and 5 weeks after surgery. (99m) Technetium-macroaggregated albumin (Tc-MAA) was to evaluate intrapulmonary arteriovenous shunts; Portal venous pressure, cardiac output and mean blood pressure (MAP) were also measured. Serum was for Alanine transaminase (ALT), endotoxin, TNF-α and nitric oxide (NO) measurements, liver for histology, lung for histology and iNOS, PI3K/Akt expression assay.

RESULTS

Portal vein pressure was significantly elevated and MAP decreased in CBDL rats. Tc-MAA was mainly located in lung and very weak in brain in sham group and mainly in brain of CBDL rats. TNF-α McAb significantly decreased the radioactivity in the brain, reduced cardiac output, increased MAP and systemic vascular resistance (SVR) in CBDL animals. Serum ALT, endotoxin, TNF-α and NO were significantly increased. TNF-α McAb significantly decreased these serum indices in CBDL rats. TNF-α McAb significantly alleviated liver damage, decreased alveolar-arterial gradient and inhibited iNOS, PI3K/Akt and p-Akt expression in lung tissue. Furthermore, TNF-α McAb significantly attenuated the inflammatory response in lung.

CONCLUSION

TNF-α McAb improves HPS in cirrhotic rats; this effect is likely mediated through the inhibition of TNF-α PI3K/Akt-NO pathway.

摘要

背景/目的：肿瘤坏死因子-α（TNF-α）在肝肺综合征（HPS）中增加。己酮可可碱（PTX）通过抑制 TNF-α减轻了实验性 HPS。然而，PTX 除了抑制 TNF-α之外，还具有多种作用。本研究使用 TNF-α 特异性单克隆抗体（TNF-α McAb）中和 TNF-α，以研究 TNF-α 对 HPS 的影响。

材料和方法

通过胆总管结扎（CBDL）诱导 HPS；对照组进行假手术。术后 1、2、3、4 和 5 周为终点。（99m）锝-聚合白蛋白（Tc-MAA）用于评估肺内动静脉分流；门静脉压、心输出量和平均血压（MAP）也进行了测量。血清用于丙氨酸转氨酶（ALT）、内毒素、TNF-α 和一氧化氮（NO）的测量，肝脏用于组织学检查，肺用于组织学和 iNOS、PI3K/Akt 表达测定。

结果

CBDL 大鼠门静脉压明显升高，MAP 降低。Tc-MAA 在假手术组主要位于肺，在脑内很少，而在 CBDL 大鼠主要位于脑内。TNF-α McAb 显著降低了 CBDL 动物脑内的放射性，降低了心输出量，增加了 MAP 和全身血管阻力（SVR）。血清 ALT、内毒素、TNF-α 和 NO 明显升高。TNF-α McAb 显著降低了 CBDL 大鼠的这些血清指标。TNF-α McAb 显著减轻了肝损伤，降低了肺泡-动脉梯度，并抑制了肺组织中 iNOS、PI3K/Akt 和 p-Akt 的表达。此外，TNF-α McAb 显著减轻了肺组织中的炎症反应。