PULMONARY FIBROSIS INDUCED BY ANTICANCER DRUGS-ITS MECHANISM AND PROPHYLAXIS

为了预防肿瘤化疗中肺纤维化的发生，我们研究了培洛霉素（PLM）诱导肺纤维化的机制，并获得以下结果.无论是在体内还是体外，PLM都能增强淋巴细胞、巨噬细胞、中性粒细胞和成纤维细胞（Fb）的细胞因子生成。在和离体PLM增强Fb.3的增殖和胶原合成。在Fb、淋巴细胞和中性粒细胞中，PLM增强肌醇蛋白和酪氨酸残基的磷酸化，激活<ras>p21和MAPK，诱导NF-κ B的激活和c-myc的表达. PLM激活p47^<phox>和p67^<phox>（NADPH的组分）并增加中性粒细胞和巨噬细胞的活性氧产生。盐酸氮卓斯汀（Azeptin，一种抗过敏药物）抑制这些PLM活性，并抑制PLM诱导的小鼠肺纤维化. PLM诱导的纤维化开始于肺的外周并进展到中心区域，特别是支气管周围。免疫组织化学和电镜检查。纤维化肺组织Fb表达波形蛋白、结蛋白和α-平滑肌肌动蛋白。结果表明，PLM诱导的肺纤维化是由于细胞因子和活性氧产生的信号转导增强所致，Azeptin有望在肿瘤治疗中抑制肺纤维化，随着纤维化的进展，Fb向表达α-SM的肌成纤维细胞转化。研究与α-SM表达相关的细胞内信号是重要的。

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.