The efficacy of HSP-47 antisense therapy for pulmonary fibrosis

HSP-47反义疗法治疗肺纤维化的疗效

• 批准号: 15590816
• 负责人: FUJII Takashi
• 金额: $ 1.79万
• 依托单位: The University of Tokyo
• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590816/
• 关键词: HSP-47; Idiopathic Pulmonary Fibrosis; Bleomycin-induced Pulmonary Fibrosis; Collagen; Lung Fibroblast; Bronchilal epithelial cells; Antisense Therapy; 突発性肺線維症

Heat shock protein (HSP) 47, a collagen-specific molecular chaperone, is involved in the processing and/or secretion of procollagen. We investigated whether treatment with the antifibrotic drug pirfenidone attenuates the bleomycin (BL)-induced overexpression of HSP47 in the lungs. Male ICR mice were intravenously injected with BL or saline (SA). Pirfenidone or control drug (CD) was administered 14 days after commencement of BL or SA, and continued throughout the course of the experiment. The mice were randomly divided into three experimental groups : 1)SA-treated with CD (SA group) ; 2)BL-treated with CD (BL group) ; and 3)BL-treated with pirfenidone (pirfenidone group). Lungs of the pirfenidone group showed a marked reduction of fibrotic lesions compared with the corresponding BL group. Immunohistochemical studies showed that BL treatment significantly increased the number of macrophages, myofibroblasts, HSP47-positive type II pneumocytes and HSP47-positive interstitial spindle-shaped cells. Treatment with pirfenidone significantly reduced the number of these cells compared with the corresponding BL group. Furthermore, treatment with pirfenidone significantly suppressed the BL-induced increase of the positive ratio of HSP47 and alpha-smooth muscle actin to interstitial spindle-shaped cells. This study results showed that pirfenidone inhibited heat shock protein 47-positive cells and myofibroblasts, the principal cells responsible for the accumulation and deposition of extracellular matrix seen in pulmonary fibrosis.

热休克蛋白（HSP）47是一种胶原特异性分子伴侣，参与前胶原的加工和/或分泌。我们研究了用抗纤维化药物吡非尼酮治疗是否减弱博莱霉素（BL）诱导的肺中HSP 47的过表达。雄性ICR小鼠静脉注射BL或盐水（SA）。在BL或SA开始后14天施用吡非尼酮或对照药物（CD），并在整个实验过程中持续施用。将小鼠随机分为三个实验组：1）用CD治疗的SA（SA组）; 2）用CD治疗的BL（BL组）;和3）用吡非尼酮治疗的BL（吡非尼酮组）。与相应的BL组相比，吡非尼酮组的肺显示纤维化病变显著减少。免疫组织化学研究表明，BL治疗显着增加的数量巨噬细胞，肌成纤维细胞，HSP 47阳性的II型肺细胞和HSP 47阳性的间质梭形细胞。与相应的BL组相比，吡非尼酮治疗显著减少了这些细胞的数量。此外，吡非尼酮治疗显著抑制BL诱导的HSP 47和α-平滑肌肌动蛋白与间质梭形细胞的阳性比率增加。该研究结果表明，吡非尼酮抑制热休克蛋白47阳性细胞和肌成纤维细胞，这些细胞是负责肺纤维化中细胞外基质积累和沉积的主要细胞。

项目成果

Kakugawa T, Mukae H, Fujii T, et al.: "Pirfenidone Attenuates Expression of HSP47 in Murine Bleomycin-Induced Pulmonary Fibrosis"European Respiratory Journal. (In press).

Kakukawa T、Mukae H、Fujii T 等人：“吡非尼酮减弱小鼠博莱霉素诱导的肺纤维化中 HSP47 的表达”欧洲呼吸杂志。

High-BAL fluid concentrations of RANTES in nonspecific interstitial pneumonia compared with usual interstitial pneumonia

• DOI: 10.1016/j.rmed.2004.03.008
• 发表时间: 2004-10-01
• 期刊: RESPIRATORY MEDICINE
• 影响因子: 4.3
• 作者: Yoshioka, S;Mukae, H;Kohno, S
• 通讯作者: Kohno, S

Differential effects of a-and b-defensin on cytokine production by cultured human bronchial epithelial cells

a-和b-防御素对培养的人支气管上皮细胞产生细胞因子的不同影响

• 发表时间: 2005
• 期刊: Am J Physiol Lung Cell Mol Physiol 288
• 作者: Sakamoto N;Mukae H;et al.;Sakamoto N
• 通讯作者: Sakamoto N

肺線維症進展のメカニズム-heat shock protein 47との関連

肺纤维化进展机制——与热休克蛋白47的关系

• 发表时间: 2004
• 期刊: 医学のあゆみ
• 作者: 角川智之;迎 寛;門田淳一
• 通讯作者: 門田淳一

High concentrations of a-defensins in plasma and bronchoalveolar lavage fluid of patients with acute distress syndrome

急性窘迫综合征患者血浆和支气管肺泡灌洗液中高浓度的α-防御素

• 发表时间: 2004
• 期刊: Life Sci 75
• 作者: 角川智之;迎 寛;門田淳一;Yoshioka S;Kakugawa T;Ashitani J
• 通讯作者: Ashitani J