Ruigrok Mitchel J R, El Amasi Khaled E M, Leeming Diana J, Sand Jannie M B, Frijlink Henderik W, Hinrichs Wouter L J, Olinga Peter
Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands.
Nordic Bioscience, Herlev, Denmark.
Front Med (Lausanne). 2021 Feb 15;8:607962. doi: 10.3389/fmed.2021.607962. eCollection 2021.
Idiopathic pulmonary fibrosis (IPF) is a chronic disease that is characterized by the excessive deposition of scar tissue in the lungs. As currently available treatments are unable to restore lung function in patients, there is an urgent medical need for more effective drugs. Developing such drugs, however, is challenging because IPF has a complex pathogenesis. Emerging evidence indicates that heat shock protein 47 (HSP47), which is encoded by the gene , may be a suitable therapeutic target as it is required for collagen synthesis. Pharmacological inhibition or knockdown of HSP47 could therefore be a promising approach to treat fibrosis. The objective of this study was to assess the therapeutic potential of -targeting small interfering RNA (siRNA) in fibrogenic precision-cut lung slices prepared from murine tissue. To enhance fibrogenesis, slices were cultured for up to 144 h with transforming growth factor β1. Self-deliverable siRNA was used to knockdown mRNA and protein expression, without affecting the viability and morphology of slices. After silencing HSP47, only the secretion of fibronectin was reduced while other aspects of fibrogenesis remained unaffected (e.g., myofibroblast differentiation as well as collagen secretion and deposition). These observations are surprising as others have shown that -targeting siRNA suppressed collagen deposition in animals. Further studies are therefore warranted to elucidate downstream effects on fibrosis upon silencing HSP47.
特发性肺纤维化（IPF）是一种慢性疾病，其特征是肺部瘢痕组织过度沉积。由于目前可用的治疗方法无法恢复患者的肺功能，因此迫切需要更有效的药物。然而，开发此类药物具有挑战性，因为IPF的发病机制复杂。新出现的证据表明，由该基因编码的热休克蛋白47（HSP47）可能是一个合适的治疗靶点，因为它是胶原蛋白合成所必需的。因此，对HSP47进行药理学抑制或敲低可能是治疗纤维化的一种有前景的方法。本研究的目的是评估靶向的小干扰RNA（siRNA）在从小鼠组织制备的纤维化精密切割肺切片中的治疗潜力。为了增强纤维化，将切片用转化生长因子β1培养长达144小时。使用可自我递送的siRNA来敲低mRNA和蛋白质表达，而不影响切片的活力和形态。沉默HSP47后，仅纤连蛋白的分泌减少，而纤维化的其他方面仍未受影响（例如，肌成纤维细胞分化以及胶原蛋白的分泌和沉积）。这些观察结果令人惊讶，因为其他人已经表明靶向的siRNA可抑制动物体内的胶原蛋白沉积。因此，有必要进行进一步的研究以阐明沉默HSP47后对纤维化的下游影响。
