Department of Rheumatology, Faculty of Medicine, Firat University, Elazig, Turkey.
Inflammation. 2012 Jun;35(3):810-7. doi: 10.1007/s10753-011-9380-y.
Scleroderma is a chronic fibrotic disorder. Bortezomib, a proteasome inhibitor, is reported to attenuate experimentally induced renal and cardiac fibrosis. This study aimed to evaluate the preventive and therapeutic efficacies of bortezomib on a bleomycin (BLM)-induced scleroderma model. Dermal fibrosis was induced in Balb/c mice by subcutaneous BLM (100 μg/day) injections. Bortezomib (1.6 mg/kg twice/week) was applied intraperitoneally to BLM-injected mice during the first 3 weeks for preventive interventions and in the second 3 weeks for therapeutic interventions. IL-4 and TGF-β1 serum levels, dermal thicknesses, dermal inflammatory cell counts, and α-SMA-positive fibroblastic cell counts were determined, and type-I collagen, NF-κBp65, I-κBα, and JNK1 expressions were assessed. BLM applications increased serum IL-4 level, dermal inflammatory cell counts, α-SMA-positive cell counts, expression of type-I collagen, NF-κB, and JNK1, and dermal thickness in early stage of fibrosis, but serum IL-4 level and dermal inflammatory cell counts showed no increases in later stages. As a preventive intervention, bortezomib decreased dermal thickness, inflammatory cell infiltrations, fibroblastic activity, and expression of type-I collagen, NF-κB, and JNK1, but did not decrease fibroblastic activity and dermal thickness at later stages of fibrosis. Inflammatory status is prominent in the early stage of dermal fibrosis, but declines at later stages. In BLM-induced dermal fibrosis, bortezomib has a preventive anti-fibrotic and anti-inflammatory efficacy, but has no therapeutic anti-fibrotic efficacy in preexisting tissue fibrosis. These findings suggest that the effect of proteasome inhibition in early stages of dermal fibrosis may be related to its anti-inflammatory effects.
硬皮病是一种慢性纤维化疾病。硼替佐米是一种蛋白酶体抑制剂，据报道可减轻实验性诱导的肾脏和心脏纤维化。本研究旨在评估硼替佐米对博莱霉素（BLM）诱导的硬皮病模型的预防和治疗效果。通过皮下 BLM（100μg/天）注射在 Balb/c 小鼠中诱导皮肤纤维化。硼替佐米（1.6mg/kg，每周两次）在第 1 至 3 周内通过腹腔内应用于 BLM 注射的小鼠中进行预防干预，在第 2 至 3 周内进行治疗干预。测定了血清白细胞介素 4（IL-4）和转化生长因子-β1（TGF-β1）水平、皮肤厚度、皮肤炎性细胞计数和α-SMA 阳性成纤维细胞计数，并评估了 I 型胶原、NF-κBp65、I-κBα 和 JNK1 的表达。BLM 应用增加了早期纤维化阶段的血清 IL-4 水平、皮肤炎性细胞计数、α-SMA 阳性细胞计数、I 型胶原、NF-κB 和 JNK1 的表达以及皮肤厚度，但在后期阶段血清 IL-4 水平和皮肤炎性细胞计数没有增加。作为预防干预，硼替佐米降低了皮肤厚度、炎性细胞浸润、成纤维细胞活性以及 I 型胶原、NF-κB 和 JNK1 的表达，但在纤维化后期阶段并未降低成纤维细胞活性和皮肤厚度。在皮肤纤维化的早期阶段，炎症状态明显，但在后期阶段下降。在 BLM 诱导的皮肤纤维化中，硼替佐米具有预防抗纤维化和抗炎作用，但在已有组织纤维化中无治疗抗纤维化作用。这些发现表明，蛋白酶体抑制在皮肤纤维化早期阶段的作用可能与其抗炎作用有关。
