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Roles of HGF and SLPI on the pathophysiology in the inflammatory and neoplastic pulmonary lesions : Mechanisms of defense and regeneration and their aberration in these disease statuses.

HGF 和 SLPI 在炎症和肿瘤性肺部病变病理生理学中的作用：防御和再生机制及其在这些疾病状态中的畸变。

基本信息

批准号：
14207027
负责人：
NUKIWA Toshihiro
金额：
$ 31.95万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-14207027/
关键词：
HGF SLPI Bone marrow derived cells Tissue repair Tissue regeneration Defense system Knockout mouse Lung carcinogenesis LPS

项目摘要

The number of patients with lung cancer or pulmonary inflammatory diseases has been increasing recently. In these diseases, the basic mechanisms of defense or regeneration must have been flawed due to in part aging process, and related to the pathophysiology or intractability of the diseases. The aim of this investigation is to analyze these mechanisms in the direction of hepatocyte growth factor (HGF) or secretory leukoprotease inhibitor (SLPI) in which we have been studying. The summary of the research achievements in these 3 years is as follows :1)Antiprotease and non-antiprotease function of SLPI : phenatypic analyzes of the SLPI targeted mice :Although the antiprotease phenotypes of the SLPI for wound healing or protective effect of proepithelin against neutrophil elastase are well analyzed, we found that SLPI-/-mice are vulnerable to LPS with response of high IL-6 production or suppression of IkB-beta expression in SLPI-/-macrophages. These phenomena are likely based on the non-antiprotease functions. Interestingly, lung carcinogenesis by urethane (1mg/g body wt) was suppressed in SLPI-/-mice. These facts indicate a need to analyze SLPI binding proteins for clarify non-antiproease activity of SLPI.2)HGF suppresses the recruitment of bone marrow (BM) derived progenitor cells :4 weeks after the transplantation of BM cells from GFP mice following whole body irradiation (6-10 Gy), the mice were treated using bleomycin with or without gene transfer of HGF. While incorporation of BM cells in the inflammatory lesions is enhanced, HGF rather suppressed the recruitment of BM cells in the bleomycin-induced lung injury. In the context that fibrocytes derived from BM cells promotes lung fibrosis, the suppressive effect of HGF for BM cells could be a novel function.

近年来，肺癌或肺部炎性疾病患者的数量一直在增加。在这些疾病中，防御或再生的基本机制一定是有缺陷的，部分原因是衰老过程，并与疾病的病理生理学或顽固性有关。本研究的目的是从肝细胞生长因子（HGF）或分泌性白细胞蛋白酶抑制剂（SLPI）的方向分析这些机制。1）SLPI的抗蛋白酶和非抗蛋白酶功能：SLPI靶向小鼠的表型分析：虽然SLPI对伤口愈合的抗蛋白酶表型或前上皮素对中性粒细胞弹性蛋白酶的保护作用得到了很好的分析，但我们发现SLPI-/-小鼠对LPS敏感，其反应是SLPI-/-巨噬细胞产生高IL-6或抑制IkB-β表达。这些现象可能是基于非抗蛋白酶功能。有趣的是，在SLPI-/-小鼠中，乌拉坦（1 mg/g体重）的肺癌发生受到抑制。这些事实表明需要分析SLPI结合蛋白以澄清SLPI的非抗蛋白酶活性。2）HGF抑制骨髓（BM）衍生的祖细胞的募集：在全身照射（6-10戈伊）后移植来自GFP小鼠的BM细胞4周后，使用博来霉素处理小鼠，有或没有HGF的基因转移。虽然BM细胞在炎性病变中的掺入增强，但HGF反而抑制BM细胞在博来霉素诱导的肺损伤中的募集。在来源于BM细胞的纤维细胞促进肺纤维化的背景下，HGF对BM细胞的抑制作用可能是一种新的功能。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

AkiyamaK, et al.: "Targeting apoptotic tumor cells to FcgR provides efficient and versatile vaccination against tumors by denfritic cells"J. Immunol.. 170. 1641-1648 (2003)

AkiyamaK 等人：“将凋亡肿瘤细胞靶向 FcgR 可以通过树突状细胞提供针对肿瘤的高效且多功能的疫苗接种”J.

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Antitumor immune response by CX3CL1 fractalkine gene transfer depends on both NK and T cells

DOI：
10.1002/eji.200526042
发表时间：
2005-05
期刊：
European Journal of Immunology
影响因子：
5.4
作者：
H. Xin;T. Kikuchi;S. Andarini;S. Ohkouchi;Takuji Suzuki;T. Nukiwa;Huqun;K. Hagiwara;T. Honjo;Y. Saijo
通讯作者：
H. Xin;T. Kikuchi;S. Andarini;S. Ohkouchi;Takuji Suzuki;T. Nukiwa;Huqun;K. Hagiwara;T. Honjo;Y. Saijo

Targeting angiogenesis and HGF function using an adenoviral vector expressing the HGF antagonist NK4 for cancer therapy