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Host defense system in the lung using pulmonary surfactant proteins and Toll-like reosptors

使用肺表面活性蛋白和 Toll 样重反应器的肺部宿主防御系统

基本信息

批准号：
18390241
负责人：
KUROKI Yoshio
金额：
$ 11.12万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390241/
关键词：
pulmonary surfactant collectin SP-A SP-D Toll-like receptor pulmonary inflammation endotoxin MD-2 TLR4

项目摘要

The purposes of this project were to investigate the mechanisms by which pulmonary collections, surfactant proteins A and D (SP-A and SP-D), and Toll-like receptor (TISO function against infection and inflammation, and to establish the molecular basis for the clinical application of these proteins. The research results are summarized below.1. We have found that SP-A and SP-D bind to TLR2, TLR4 and MD-2. SP-A inhibited the binding of smooth LPS on the cells expressing TLR4 and MD-2 and suppresses inflammation elicited by smooth LPS. The functional domain was the carbohydrate recognition domain (CRD) of SP-A, but the collagenase-resistant fragment of SP-A (CRF) in which the collagenous domain was removed bound to TLR4 very weakly and did not inhibit LPS-induced inflammation, indicating that the oligometric structure composed of SP-A octadecamers is important for expressing its function. Unlike SP-A SP-D inhibits inflammation elicited by different serotypes of LPS, rough LPS and smooth LPS. The experiments with SP-A/SP-D chimeric proteins revealed that the cruciform structure of SP-D composed of long collagenous domain was crucial for suppressing inflammation.2. We have also found that the amino-terminal region of TLR4, Glu24-Lys47, is a site for MD-2 binding. Recombinant soluble forms of the extracellular TLR4 domain and MD-2 were demonstrated to dampen endotoxin-induced pulmonary inflammation in mice.3. The experiments with TLR4 mutant, TLR4C88A, revealed that MD-2 possesses crucial abilities to express cell surface expression of TLR4 and its N-linked complex type glyoosylation.4. SP-A and SP-D bound to Mycobacterium avium and induced bacrerial aggregation. SP-D possesses a potent ability to aggregate M. avium compared with SP-A The ligand for SP-D on M. avium was lipoarabinomannan (LAM) and that for SP-Aexisted in the lipid fraction extracted M. avium.

本课题旨在探讨肺集合物、表面活性蛋白A和D （SP-A和SP-D）以及toll样受体（TISO）抗感染和炎症的作用机制，并为这些蛋白的临床应用奠定分子基础。研究结果总结如下：1。我们发现SP-A和SP-D与TLR2、TLR4和MD-2结合。SP-A抑制光滑LPS与表达TLR4和MD-2的细胞的结合，抑制光滑LPS引起的炎症。功能域是SP-A的碳水化合物识别域（CRD），但去除胶原结构域的SP-A抗胶原酶片段（CRF）与TLR4结合非常弱，对lps诱导的炎症没有抑制作用，表明SP-A十八聚体组成的寡聚结构对表达其功能很重要。与SP-A不同，SP-D抑制不同血清型LPS，粗糙型LPS和光滑型LPS引起的炎症。SP-A/SP-D嵌合蛋白实验表明，SP-D由长胶原结构域组成的十字形结构对抑制炎症至关重要。我们还发现TLR4的氨基末端区域Glu24-Lys47是MD-2结合的位点。细胞外TLR4结构域和MD-2的重组可溶性形式被证明可以抑制内毒素诱导的小鼠肺部炎症。对TLR4突变体TLR4C88A的实验表明，MD-2具有表达TLR4及其n -连接复合物型糖基化细胞表面表达的关键能力。SP-A和SP-D与鸟分枝杆菌结合并诱导细菌聚集。SP-D与SP-A相比具有较强的聚集鸟分枝杆菌的能力，SP-D在鸟分枝杆菌上的配体是脂质体阿拉伯甘露聚糖（LAM）， SP-A的配体存在于鸟分枝杆菌提取的脂质部分。