PULMONARY FIBROSIS INDUCED BY ANTICANCER DRUGS-ITS MECHANISM AND PROPHYLAXIS

抗癌药物所致肺纤维化的机制及预防

• 批准号: 07672049
• 负责人: YONEDA Kazunori
• 金额: $ 1.54万
• 依托单位: Kochi Medical School
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1997
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07672049/
• 关键词: peplomycin; Azeptin; pulmonary fibrosis; cytokine; NF-kappaB; superoxide; signal transduction; alpha-smooth muscle actin; iNOS; redok; redox; アセプチン

To prevent pulmonary fibrosis (PF) in cancer chemotherapy, we examined the mechanism of peplomycin (PLM)-induced PF and obtained following results.1. Both in and ex vivo, PLM enhanced cytokine generation by lymphocytes, macrophages, neutrophils and fibroblasts (Fb).2. In and ex vivo PLM enhanced proliferation and collagen synthesis of Fb.3. In Fb, lymphocytes and neutrophils, PLM enhanced phosphorylation of inositols protein and tyrosine residues and activated^<ras> p21 and MAPK,inducing activation of NF-kappaB with c-myc expression.4. PLM activated p47^<phox> and p67^<phox> (components of NADPH) and increased reactive oxygen generation by neutrophils and macrophages.5. Azelastine hydrochloride (Azeptin, an anti-allergic drug) inhibited these PLM activities and suppressed PLM-induced pulmonary fibrosis in mice.6. PLM-induced fibrosis begun in the periphery of the lung and advanced to the central region, especially around the bronchi. Immunohistochemically and electromicroscopically. Fb in the lung with fibrosis expressed vimentin, desmin and alpha-smooth muscle (alpha-SM) actin. The change of Fb to myofibroblasts was ascertained by in situ hybridization of alpha-SM and blotting for alpha-SM-mRNA and its protein.These results indicate that PLM-induced fibrosis is resulted from enhanced signal transduction which induces cytokine and reactive oxygen generation, that Azeptin is expected to prohibit pulmonary fibrosis in cancer therapy and that with advance of fibrosis, Fb, become myofibroblasts expressing alpha-SM.Therefore, it is important to investigate the intracellular signals associated with the expression of alpha-SM.

为了预防肿瘤化疗中肺纤维化的发生，我们研究了培普霉素(PLM)诱导肺纤维化的机制，并获得了以下结果。在体内和体外，PLM促进淋巴细胞、巨噬细胞、中性粒细胞和成纤维细胞产生细胞因子(FB)。体内和体外PLM促进Fb.3细胞的增殖和胶原合成。在FB、淋巴细胞和中性粒细胞中，PLM促进肌醇蛋白和酪氨酸残基的磷酸化，并激活p21和MAPK，诱导核因子-kappaB的活化和c-myc的表达。PLM激活p47；lt；Phox&gt；和p67；Phox&gt；(NADPH的组成部分)，并增加中性粒细胞和巨噬细胞产生的活性氧。抗过敏药物盐酸氮卓斯汀抑制上述PLM活性，抑制PLM诱导的小鼠肺纤维化。PLM诱导的纤维化开始于肺的外围，并进展到中央区域，特别是支气管周围。免疫组织化学和电子显微镜检查。纤维化肺组织中FB表达波形蛋白、结蛋白和α-平滑肌肌动蛋白。通过α-SM的原位杂交和α-SM-mRNA及其蛋白的印迹杂交，确定Fb向肌成纤维细胞的转化。这些结果表明，PLM诱导的纤维化是细胞因子和活性氧产生的信号转导增强的结果，阿齐普汀有望在癌症治疗中抑制肺纤维化，随着纤维化的推进，Fb成为表达α-SM的肌成纤维细胞。因此，研究与α-SM表达相关的细胞内信号是重要的。

项目成果

Kazunori Yoneda: "Suppression by azelastine hydrochloride of NF-_KB activation involved in generation of cytokines and nitric oxide" Japanese Journal of Pharmacology. 73 : 2. 145-153 (1997)

Kazunori Yoneda：“盐酸氮卓斯汀对参与细胞因子和一氧化氮生成的 NF-_KB 激活的抑制”《日本药理学杂志》。

Eisaku Ueta: "Upregulation of respiratory burst of polymorphonuclear leukocytes by a bleomycin derivative.peplomycin" Free Radical Research. 22. 533-544 (1995)

Eisaku Ueta：“博莱霉素衍生物.peplomycin 对多形核白细胞呼吸爆发的上调”自由基研究。

Kazunori Yoneda: "Suppression by azelastine hydrochloride of NF-kB activation involved in generation of cytokines and nitric oxide" Japanese Journal of Pharmacology. 73. 145-153 (1997)

Kazunori Yoneda：“盐酸氮卓斯汀对参与细胞因子和一氧化氮生成的 NF-kB 激活的抑制”《日本药理学杂志》。

Eisaku Ueta: "Upregulation of respiratory burst of polymorphonuclear leukocytes by a bleomycin derivative, peplomycin" Free Radical Research. 22 : 6. 533-544 (1995)

Eisaku Ueta：“博来霉素衍生物佩普霉素对多形核白细胞呼吸爆发的上调”自由基研究。

Kazunori Yoneda: "Suppression by azelastine hydrochloride of NF-κB activation involved in generation of cytokines and nitric oxide" Japanese Journal of Pharmacology. 73. 145-153 (1997)

Kazunori Yoneda：“盐酸氮卓斯汀对参与细胞因子和一氧化氮生成的 NF-κB 活化的抑制”，《日本药理学杂志》73. 145-153 (1997)。