The efficacy of HSP-47 antisense therapy for pulmonary fibrosis

热休克蛋白(HSP)47是一种胶原特异的分子伴侣，参与了前胶原的加工和/或分泌。我们研究了抗纤维化药物吡非尼酮的治疗是否减轻了博莱霉素(BL)诱导的HSP47在肺中的过度表达。雄性ICR小鼠静脉注射布洛芬或生理盐水(SA)。在BL或SA开始后14天给予吡非尼酮或对照药物(CD)，并持续整个实验过程。将小鼠随机分为3组：1)SA+CD组(SA组)；2)BL+CD组(BL组)；3)BL+吡非尼酮组(Pirfenidone组)。与相应的BL组相比，吡非尼酮组的肺纤维化病变明显减少。免疫组织化学研究显示，灯盏细辛处理组大鼠巨噬细胞、肌成纤维细胞、HSP47阳性的II型肺泡细胞和HSP47阳性的间质梭形细胞数量显著增加。与相应的BL组相比，吡非尼酮处理组显著减少了这些细胞的数量。此外，吡非尼酮可显著抑制BL诱导的间质梭形细胞HSP47和α-平滑肌肌动蛋白阳性细胞比率的增加。这项研究结果表明，吡非尼酮抑制热休克蛋白47阳性细胞和肌成纤维细胞，这两种细胞是肺纤维化中细胞外基质积累和沉积的主要细胞。

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.