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Functional analysis of lipid mediators in pulmonary fibrosis

脂质介质在肺纤维化中的功能分析

基本信息

批准号：
15590790
负责人：
TAZAWA Ryushi
金额：
$ 1.86万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

BACKGROUND : Pulmonary fibrosis is an interstitial disorder of the lung parenchyma, of which mechanism is poorly understood. Prostanoids are known to participate in the process of fibrogenesis and produced by various cells in the lung, such as macrophages, epithelial cells, endothelial cells, smooth muscle cells, and fibroblasts, which are involved in the pathogenesis of pulmonary fibrosis. We hypothesized that intratracheal gene transfer of a synthase of anti-fibrotic (prostaglandin I2 [PGI2]) or pro-fibrotic (thromboxane [TX]A2) prostaglandins (PGs) alters severity of lung fibrosis. METHODS : A 1.6-BamHI fragment containing human PGIS gene or a 1.8-kb BamHI fragment containing human TXAS gene was ligated into pCI-neo expression vector, and designated pCI-PGIS and pCI-TXAS, respectively. We injected HVJ-liposome complex including 20 mcg of pCI-PGIS or pCI-TXAS into tracheas of C57BL/6 mice at age of 6-8 weeks. The animals were administered with 60 mcg of bloemycin intratracheally 24 hours after gene transfer, observed daily, and sacrificed for histological study of right lungs and hydroxyproline assay of left lungs. RESULTS : The gene transfer of PGIS increased body weight (157%, day 21, vs null-vector control ; p<0.05), decreased hydroxyproline content in the lung (75%, day 14, vs null-vector control ; p<0.05) and decreased cell infiltration in the lung, whereas TXAS gene transfer tended to present opposite effects. CONCLUSION : These results suggest that a balance of antifibrotic and profibrotic PGs might be a determinant of severity of lung fibrosis. The anti-fibrotic or pro-fibrotic PGs might be molecular targets for new therapies to treat pulmonary fibrosis.

背景：肺纤维化是一种肺实质间质性疾病，其发病机制尚不清楚。已知前列腺素类参与纤维发生过程，并由肺中的各种细胞产生，如巨噬细胞、上皮细胞、内皮细胞、平滑肌细胞和成纤维细胞，其参与肺纤维化的发病机制。我们假设，肺内抗纤维化（前列腺素I2 [PGI 2]）或促纤维化（血栓烷[TX]A2）前列腺素（PGs）合酶的基因转移改变了肺纤维化的严重程度。方法：将含有人PGIS基因的1.6-BamHI片段或含有人TXAS基因的1.8-kb BamHI片段连接到pCI-neo表达载体中，分别命名为pCI-PGIS和pCI-TXAS。我们将含有20 mcg pCI-PGIS或pCI-TXAS的HVJ-脂质体复合物注射到6-8周龄的C57 BL/6小鼠的气管中。在基因转移后24小时，向动物体内施用60 mcg博莱霉素，每天观察，并处死动物进行右肺的组织学研究和左肺的羟脯氨酸测定。研究结果：PGIS的基因转移增加了体重（157%，第21天，相对于空载体对照; p<0.05），降低了肺中的羟脯氨酸含量（75%，第14天，相对于空载体对照; p<0.05），并降低了肺中的细胞浸润，而TXAS基因转移倾向于呈现相反的效果。结论：这些结果表明，抗纤维化和促纤维化PG的平衡可能是肺纤维化严重程度的决定因素。抗纤维化或促纤维化PG可能成为治疗肺纤维化新疗法的分子靶点。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Usui K, Saijo Y, Narumi K, Koyama S, Maemondo M, Kikuchi T, Tazawa R, et al.: "N-terminal deletion augments the cell-death-inducing activity of BAX in adenoviral gene delivery to nonsmall cell lung cancers"Oncogene. 22. 2255-2263 (2003)

Usui K、Saijo Y、Narumi K、Koyama S、Maemondo M、Kikuchi T、Tazawa R 等人：“N 末端缺失增强了 BAX 在腺病毒基因递送至非小细胞肺癌中的细胞死亡诱导活性”

DOI：
发表时间：
期刊：
影响因子：
0
作者：
通讯作者：

Granulocyte-macrophage colony-stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis

粒细胞-巨噬细胞集落刺激因子吸入治疗特发性肺泡蛋白沉积症

DOI：
发表时间：
2006
期刊：
Respirology 11
影响因子：
0
作者：
Tazawa R;et al.
通讯作者：
et al.

Vaccination of dendritic cells loaded with interleukin-12-secreting cancer cells augments in vivo antitumor immunity: characteristics of syngeneic and allogeneic antigen-presenting cell cancer hybrid cells.

DOI：
发表时间：
2005
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
0
作者：
Takuji Suzuki;T. Fukuhara;Masashi Tanaka;A. Nakamura;Kenichi Akiyama;Tomohiro Sakakibara;D. Koinuma;T. Kikuchi;R. Tazawa;M. Maemondo;K. Hagiwara;Y. Saijo;T. Nukiwa
通讯作者：
Takuji Suzuki;T. Fukuhara;Masashi Tanaka;A. Nakamura;Kenichi Akiyama;Tomohiro Sakakibara;D. Koinuma;T. Kikuchi;R. Tazawa;M. Maemondo;K. Hagiwara;Y. Saijo;T. Nukiwa

Tazawa R, Ishimoto O, Ohta H, Suznki T, Maemondo M, Ebina M, Hagiwara K, et al.: "Granulocyte-macrophage colony stimulating factor inhalation therapy as a treatment for pulmonary alveolar proteinosis"Eur.Resp.J.. 22. 377s-377s (2003)

Tazawa R、Ishimoto O、Ohta H、Suznki T、Maemondo M、Ebina M、Hagiwara K 等人：“粒细胞巨噬细胞集落刺激因子吸入疗法治疗肺泡蛋白沉积症”Eur.Resp.J.. 22