Study for roles of IL-18 in interstitial lung diseases and lung remodeling

IL-18在间质性肺疾病和肺重塑中的作用研究

• 批准号: 15390261
• 负责人: HOSHINO Tomoaki
• 金额: $ 8.19万
• 依托单位: Kurume University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390261/
• 关键词: Interstitial Lung Diseases; Cytokine; IL-18; Caspase-1; Mouse Model; thioredoxin

Rationale : Administration of several chemotherapeutic drugs such as bleomycin, busulfan, and gefitinib often induces lethal lung injury. IL-1β and IL-18, members of the IL-1 family, are produced from a biologically inactive precursor and secreted from macrophages after cleavage by caspase-1. We established a new mouse model for human interstitial lung diseases in which daily administration of IL-18 with IL-2 induced lethal lung injury. Recently, we reported an increased level of IL-18 and IL-18Rα expression in the lungs of patients with idiopathic pulmonary fibrosis. Objectives : The aim of our present study was to evaluate the roles of IL-1β and IL-18 in the pathogenesis of bleomycin-induced lung injury. Methods : We investigated whether IL-1R and IL-18 secretion induced by bleomycin causes lung injury in caspase-1 deficient (-/-), IL-18 (-/-), and IL-18Ra (-/-) mice, and in humans. Measurement and Main Results: Intravenous administration of bleomycin induced the expression of IL-1β, IL-18, and various cytokines and chemokines (e.g. MIP-2, IP-10, MCP-1, and TCA-3) in the serum and lungs of normal mice. Macrophages (Kupffer cells) isolated from wild-type mice, but not caspase-1 (-/-) mice, secreted IL-1βand IL-18 upon stimulation with bleomycin in vitro. Bleomycin-induced lung injury was prevented in caspase-1 (-/-), IL-18 (-/-), and IL-18Rα (-/-) mice, but not in control mice. Moreover, enhanced expression of IL-18 and IL-18Rα was observed in the lungs of patients with bleomycin-induced lung injury. Conclusions : Our results suggest IL-1β and IL-18 secretion in the lungs may cause severe lung injury as a consequence of treatment with some chemotherapeutic drugs.

基本原理：几种化疗药物如博来霉素、白消安和吉非替尼的给药经常诱导致死性肺损伤。IL-1β和IL-18是IL-1家族的成员，由生物学上无活性的前体产生，并在半胱天冬酶-1切割后由巨噬细胞分泌。我们建立了一种新的人间质性肺疾病小鼠模型，其中每天给予IL-18和IL-2诱导致死性肺损伤。最近，我们报道了特发性肺纤维化患者肺中IL-18和IL-18 R α表达水平升高。目的：探讨白细胞介素1β（IL-1β）和白细胞介素18（IL-18）在博莱霉素致肺损伤中的作用。研究方法：我们研究了博来霉素诱导的IL-1 R和IL-18分泌是否会导致caspase-1缺陷（-/-）、IL-18（-/-）和IL-18 Ra（-/-）小鼠以及人类的肺损伤。测量和主要结果：博来霉素静脉给药诱导正常小鼠血清和肺中IL-1β、IL-18和各种细胞因子和趋化因子（例如MIP-2、IP-10、MCP-1和TCA-3）的表达。从野生型小鼠中分离的巨噬细胞（库普弗细胞）在体外用博来霉素刺激后分泌IL-1β和IL-18，但胱天蛋白酶-1（-/-）小鼠除外。博来霉素诱导的肺损伤在caspase-1（-/-）、IL-18（-/-）和IL-18 R α（-/-）小鼠中得到预防，但在对照小鼠中没有。此外，在博莱霉素诱导的肺损伤患者的肺中观察到IL-18和IL-18 R α的表达增强。结论：我们的研究结果表明，IL-1β和IL-18在肺中的分泌可能会导致严重的肺损伤，作为治疗的结果与一些化疗药物。

项目成果

Enhanced expression of interleukin-18 and its receptor in idiopathic pulmonary fibrosis

• DOI: 10.1165/rcmb.2003-0306oc
• 发表时间: 2004-12-01
• 期刊: AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
• 影响因子: 6.4
• 作者: Kitasato, Y;Hoshino, T;Aizawa, H
• 通讯作者: Aizawa, H

Kawase, Y., Hoshino, T., Yokota, K., et al.: "Exacerbated and Prolonged Allergic and Non-Allergic Inflammatory Cutaneous Reaction in Mice with Targeted Interleukin-18 Expression in the Skin."J Invest Dermatol. 121. 502-509 (2003)

Kawase, Y.、Hoshino, T.、Yokota, K. 等人：“皮肤中靶向表达白细胞介素 18 导致小鼠的过敏性和非过敏性皮肤炎症反应加剧和延长。”J Invest Dermatol。

Molecular cloning, chromosomal location, and biological activity of porcine interleukin-21.

猪白细胞介素21的分子克隆、染色体定位和生物活性。

• 发表时间: 2004
• 期刊: J Vet Med Sci 66
• 作者: Muneta;Y.;Hoshino;T.;et al.
• 通讯作者: et al.

Limited Role for Interleukin-18 in the Host Protection Response to Pulmonary Infection with Pseudomonas aeruginosa in Mice

Interleukin-18 在小鼠铜绿假单胞菌肺部感染的宿主保护反应中的作用有限

• DOI: 10.1128/iai.72.10.6176-6180.2003
• 发表时间: 2004
• 期刊: Infection and Immunity
• 影响因子: 3.1
• 作者: C. Nakasone;K. Kawakami;T. Hoshino;Y. Kawase;K. Yokota;K. Yoshino;K. Takeda;S. Akira;A. Saito
• 通讯作者: A. Saito

Hoshino, T., Nakamura, H., Okamoto et al.: "Redox-active protein thioredoxin prevents proinflammatory cytokine- or bleomycin-induced lung injury."Am J Respir Crit Care Med. 168. 1075-1083 (2003)

Hoshino, T.、Nakamura, H.、Okamoto 等人：“氧化还原活性蛋白硫氧还蛋白可预防促炎细胞因子或博莱霉素诱导的肺损伤。”Am J Respir Crit Care Med。