Cardiopulmonary Research Group, Transplantation Laboratory, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
J Heart Lung Transplant. 2012 Feb;31(2):194-203. doi: 10.1016/j.healun.2011.11.008.
Obliterative bronchiolitis after lung transplantation is characterized by airway inflammation leading to obliteration of small airways. Statins are known to have lipid-independent immunomodulatory properties. We investigated the effect of simvastatin treatment on innate and adaptive immune responses and the development of obliterative airway disease (OAD).
In fully MHC-mismatched rat tracheal allograft recipients, we used simvastatin at different doses (0.1 to 20 mg/kg/day orally) to assess its effect on OAD development. No immunosuppressive treatment was administered. Histologic, immunohistochemical and real-time RT-PCR analyses were performed 3, 10 and 30 days after transplantation.
Simvastatin treatment with doses ranging from 0.5 to 20 mg/kg/day significantly enhanced early epithelial recovery and reduced the development of OAD. No dose response was observed. Simvastatin treatment markedly reduced IL-23 mRNA and lymphocyte chemokine CCL20 production, and the infiltration of CD4(+) and CD8(+) T cells into allografts already at 3 days. At 10 days, simvastatin significantly attenuated the production of pro-inflammatory cytokines, IL-1β, TNF-α, MCP-1 and IP-10, and Th17-polarizing cytokines, IL-6 and IL-17e, and inhibited allograft infiltration by inflammatory cells. The protective effects of simvastatin on inflammation and OAD were partially mediated through nitric oxide synthase.
Simvastatin treatment inhibited adaptive T-cell alloimmune activation as depicted by reduced expression of lymphocyte chemokine and pro-inflammatory cytokine mRNA and reduced allograft infiltration by inflammatory cells. Importantly, simvastatin inhibits the development of OAD and this effect is partially mediated by increased nitric oxide activity. These results suggest a role for simvastatin in the prevention of obliterative bronchiolitis.
肺移植后闭塞性细支气管炎的特征是气道炎症导致小气道闭塞。他汀类药物具有独立于脂质的免疫调节特性。我们研究了辛伐他汀治疗对固有和适应性免疫反应以及闭塞性气道疾病（OAD）发展的影响。
在完全 MHC 错配的大鼠气管同种异体移植受者中，我们使用不同剂量（0.1 至 20 mg/kg/天口服）的辛伐他汀来评估其对 OAD 发展的影响。未给予免疫抑制治疗。移植后 3、10 和 30 天进行组织学、免疫组织化学和实时 RT-PCR 分析。
0.5 至 20 mg/kg/天剂量的辛伐他汀治疗显著增强了早期上皮恢复并减少了 OAD 的发展。未观察到剂量反应。辛伐他汀治疗可显著降低 IL-23 mRNA 和淋巴细胞趋化因子 CCL20 的产生，并在 3 天时减少 CD4+和 CD8+T 细胞向同种异体移植物的浸润。在 10 天时，辛伐他汀显著抑制促炎细胞因子、IL-1β、TNF-α、MCP-1 和 IP-10 的产生以及 Th17 极化细胞因子 IL-6 和 IL-17e 的产生，并抑制炎症细胞对同种异体移植物的浸润。辛伐他汀对炎症和 OAD 的保护作用部分是通过一氧化氮合酶介导的。
辛伐他汀治疗抑制了适应性 T 细胞同种免疫激活，表现为淋巴细胞趋化因子和促炎细胞因子 mRNA 的表达减少，以及炎症细胞对同种异体移植物的浸润减少。重要的是，辛伐他汀抑制了 OAD 的发展，这种作用部分是通过增加一氧化氮活性介导的。这些结果表明辛伐他汀在预防闭塞性细支气管炎方面具有作用。
