Cell therapy by manipulation of biological function of prostaglandin as self-defense factor

通过操纵前列腺素作为自卫因子的生物功能进行细胞治疗

• 批准号: 16590204
• 负责人: HAYASHI Izumi
• 金额: $ 1.86万
• 依托单位: Nihon Pharmaceutical Univeristy (2005-2006)Kitasato University (2004)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590204/
• 关键词: prostaglandin; cell therapy; biological function; expression cell; pharmacology; pulmonary hypertension; connective tissue disease; prostaglandin D_2; 強皮症; プロスタグランジンD_2; レトロウイルス; 肺高血圧; エンドセリン

Hematopoietic prostaglandin D synthase (PGDS) is a key enzyme to produce prostaglandin (PG) D and J series. These PGs are involved in inflammation and immune system. While PGD_2 mediates sleep and allergic reaction in asthma, the non-enzymatic metabolite, 15-deoxy-Δ^<12,14>-PGJ_2, displays several anti-inflammatory effects. Since the PGs are structurally labile and instable in body, constitutive expression of the producing enzyme, PGDS would be expected to evaluate biological activities of PGD2 and PGJ series. To determine whether introduction of PGDS exerts proinflammatory or anti-inflammatory effect, human hematopoietic PGDS complementary DNA-expressing retrovirally transfected fibroblasts were introduced in vivo, and effects of the introduction on several inflammatory models were investigated. Introduction of PGDS-expressing fibroblasts effectively attenuated carrageenin-induced paw edema as an acute inflammatory model and formation of granuloma and angiogenesis in sponge-implanted … More model as a chronic inflammatory model, suggesting the introduction could be anti-inflammatory. Moreover, expression of PGDS decreased generation of chemokines followed by decreased infiltration of leukocytes in sodium urate monohydrate crystal-induced acute inflammation using air-pouch model in mice, and suppressed fibrosis with reduced expression of cytokines and growth factors in bleomycin-induced lung injury and bleomycin-induced skin sclerosis. Furthermore, elevated pressure in right atrium was attenuated by introducing PGDS-expressing fibroblasts in monocrotaline-induced pulmonary hypertension. Administration of 15-deoxy-Δ12,14_prostaglandin J2 also reduced deterioration of lunge fibrosis and skin sclerosis in the models. Therefore, a part of the preventive action of PGDS-expressing fibroblasts raise could be mediated via biological activities by 15-deoxy-Δ^<12,14>-prostaglandin J_2. These results suggest a potential cell therapy for such pathogenesis by PGDS-expressing cells and the possibility of therapeutic approaches targeting for PGD_2-derived metabolites. Less

造血前列腺素D合酶（PGD）是产生前列腺素（PG）D和J系列的关键酶。这些PG参与炎症和免疫系统。虽然PGD_2介导哮喘中的睡眠和过敏反应，但非酶代谢产物，15-脱氧-Δ^<12,14> -PGJ_2，显示出几种抗炎作用。由于PG在结构上标记并且在体内不稳定，因此产生酶的本构表达，PGD有望评估PGD2和PGJ系列的生物学活性。为了确定PGD的引入是否发挥促炎或抗炎作用，在体内引入了人类造血PGDS的完整性表达DNA倒流的成纤维细胞，并研究了引言对几种炎症模型的作用。在赞助者植入的急性炎症模型中，引入表达PGDS的成纤维细胞有效地减弱了Carrageenin诱导的PAW水肿作为急性炎症模型和肉芽肿和血管生成的形成，并且是慢性炎症模型的更多模型，这表明引言可能是抗炎的。此外，PGD的表达降低了趋化因子的产生，随后使用气袋在小鼠中使用空气袋抑制纤维化，并抑制细胞因子表达和生长因子的肺部诱导的肺诱导的肺诱导的肺损伤和生长因子，降低了尿酸钠单水合晶体晶体晶体浓度降低白细胞的浸润。此外，通过在单蛋白诱导的肺动脉高压中引入表达PGDS的成纤维细胞来减弱右心房的升高。在模型中，服用15-脱氧-Δ12,14_prostaglandinJ2还降低了爆发纤维化和皮肤硬化症的定义。因此，表达PGDS的成纤维细胞升高的预防作用的一部分可以通过15-脱氧-ud-δ^<12,14> -prostaglandin J_2介导。这些结果表明，通过表达PGDS的细胞对这种发病机理进行了潜在的细胞疗法，以及针对PGD_2衍生代谢物的治疗方法的可能性。较少的

项目成果

Nitric oxide generated by iNOS reduces deformability of Lewis Jung carcinoma cells.

iNOS 产生的一氧化氮可降低 Lewis Jung 癌细胞的变形能力。

• 发表时间: 2004
• 期刊: Cancer Science 95(4)
• 作者: Hashimoto;Terumasa;H.Ohata;K.Momose.;Igawa S et al.
• 通讯作者: Igawa S et al.

Angiotensin type la receptor signaling-dependent induction of vascular endothelial growth factor in stroma is relevant to tumor-associated angiogenesis and tumor growth.

基质中血管紧张素1a型受体信号传导依赖性血管内皮生长因子的诱导与肿瘤相关的血管生成和肿瘤生长相关。

• 发表时间: 2005
• 期刊: Carcinogenesis 26
• 作者: Fujita M;Hayashi I;Yamashina S;Fukamizu A;Itoman M;Majima M
• 通讯作者: Majima M

Calcitonin gene-related peptide released by capsaicin suppresses myoelectrical activity of gastric smooth muscle.

辣椒素释放的降钙素基因相关肽抑制胃平滑肌的肌电活动。

• 发表时间: 2005
• 期刊: J.Gastroenterol.Hepatol. 20
• 作者: Mizuguchi S;Ohno T;Hattori Y;Kamata K;Arai K;Saeki T;Saigenji K;Hayashi I;Kuribayashi Y;Majima M
• 通讯作者: Majima M

The effects of cholesterol-3-sulfate(CH-3S) on the phosphorylation of human C3a(hC3a) in vitro and on the ability of hC3a to induce vascular permeability in Rats

3-硫酸胆固醇(CH-3S)对体外人C3a(hC3a)磷酸化及hC3a诱导大鼠血管通透性的影响

• 发表时间: 2004
• 期刊: Biological & Pharmaceutical Bulletin 27(3)
• 作者: Hashimoto;Terumasa et al.;Kawakami F et al.
• 通讯作者: Kawakami F et al.

Inhibition of skin sclerosis by 15deoxy Delta 12,14-prostaglandin J2 and retrovirally transfected prostaglandin D synthase in a mouse model of bleomycin-induced scleroderma.

在博莱霉素诱导的硬皮病小鼠模型中，15-脱氧 Delta 12,14-前列腺素 J2 和逆转录病毒转染的前列腺素 D 合酶对皮肤硬化的抑制作用。

• 发表时间: 2006
• 期刊: Biomed Pharmacother. 60・1
• 作者: Kohno S;Endo H;Hashimoto A;Hayashi I;Murakami Y;Kitasato H;Kojima F;Kawai S;Kondo H.
• 通讯作者: Kondo H.