肿瘤坏死因子受体I介导全身注射脂多糖后肺内趋化因子的产生和中性粒细胞的聚集。

TNF receptor I mediates chemokine production and neutrophil accumulation in the lung following systemic lipopolysaccharide.

作者信息

Calkins C M, Heimbach J K, Bensard D D, Song Y, Raeburn C D, Meng X, McIntyre R C

机构信息

Department of Surgery, University of Colorado Health Sciences Center and the Veterans Affairs Hospital, Denver 80262, USA.

出版信息

J Surg Res. 2001 Dec;101(2):232-7. doi: 10.1006/jsre.2001.6274.

DOI:10.1006/jsre.2001.6274

PMID:11735280

Abstract

BACKGROUND

Tumor necrosis factor (TNF)-alpha is a critical effector of lipopolysaccharide (LPS)-induced acute lung injury, and its effects are mediated by two structurally related receptors, RI and RII. Cellular adhesion molecules and C-X-C chemokines (Keratinocyte chemoattractant (KC) and macrophage inflammatory protein [MIP]-2) regulate tissue neutrophil polymorphonuclear neutrophil (PMN) accumulation in a multitude of inflammatory states. We hypothesized that TNFRI signaling dictates PMN accumulation in the lung via regulation of chemokine molecule production. Therefore, the purposes of this study were to (1) delineate LPS-induced lung TNF-alpha production and (2) characterize the contribution of both TNF receptors to lung chemokine production and neutrophil influx following systemic LPS.

METHODS

Wild-type or TNFRI and TNFRII knockout (KO) mice were injected with vehicle (saline) or LPS (Escherichia coli 0.5 mg/kg intraperitoneally). After 2, 4, 6, or 24 h, lungs were analyzed for TNF-alpha and chemokine (KC and MIP-2) protein expression (enzyme-linked immunosorbent assay) and PMN accumulation (myeloperoxidase assay).

RESULTS

There was an increase in total lung TNF-alpha (vehicle, 5.0 +/- 1.2 pg/mg total protein vs LPS, 950 +/- 318; P < 0.05) after LPS. Lung chemokine production and PMN accumulation were also increased compared to vehicle-injected mice. Lung chemokine production and PMN accumulation were significantly lower in TNFRI KO, but not TNFRII KO, mice, despite no difference in TNF-alpha production (TNFRI KO, 925 +/- 301 vs TNFRII KO, 837 +/- 267, P = 0.82).

CONCLUSIONS

Acute lung injury following systemic LPS administration is characterized by increased lung (1) TNF-alpha production, (2) C-X-C chemokine production, and (3) neutrophil accumulation. The maximal effect of LPS-induced lung neutrophil accumulation appears to be dependent upon the TNFRI receptor but not the TNFRII receptor. .

摘要

背景

肿瘤坏死因子（TNF）-α是脂多糖（LPS）诱导的急性肺损伤的关键效应因子，其作用由两种结构相关的受体RI和RII介导。细胞黏附分子和C-X-C趋化因子（角质形成细胞趋化因子（KC）和巨噬细胞炎性蛋白[MIP]-2）在多种炎症状态下调节组织中中性粒细胞多形核中性粒细胞（PMN）的聚集。我们假设TNFRI信号通过调节趋化因子分子的产生来决定肺中PMN的聚集。因此，本研究的目的是（1）描述LPS诱导的肺TNF-α产生情况，以及（2）表征两种TNF受体对全身LPS后肺趋化因子产生和中性粒细胞流入的作用。

方法

给野生型或TNFRI和TNFRII基因敲除（KO）小鼠注射溶剂（生理盐水）或LPS（大肠杆菌0.5mg/kg腹腔注射）。2、4、6或24小时后，分析肺组织中TNF-α和趋化因子（KC和MIP-2）的蛋白表达（酶联免疫吸附测定）以及PMN的聚集情况（髓过氧化物酶测定）。

结果

LPS处理后，肺组织中总TNF-α含量增加（溶剂组，5.0±1.2pg/mg总蛋白；LPS组，950±318；P<0.05）。与注射溶剂的小鼠相比，肺趋化因子的产生和PMN的聚集也增加。尽管TNF-α的产生没有差异（TNFRI KO组，925±301；TNFRII KO组，837±267，P = 0.82），但TNFRI KO小鼠的肺趋化因子产生和PMN聚集明显低于TNFRII KO小鼠。