Division of Respiratory Medicine, Department of Medicine, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA.
Transplantation. 2012 Jul 27;94(2):114-22. doi: 10.1097/TP.0b013e3182584879.
Pirfenidone (PFD) is an antifibrotic agent with beneficial effects on proinflammatory disorders. In this study, we further investigated PFD and long-acting form, "deuterated PFD," immune-modulating properties by evaluating their effects on mouse dendritic cells (DCs).
The effects of PFD on DCs were examined in vivo using an orthotopic mouse lung transplant model and in vitro using isolated bone marrow-derived DCs in response to lipopolysaccharide and allogeneic stimulation.
In mouse lung transplants, PFD and deuterated PFD treatment improved allograft lung function based on peak airway pressure, less infiltrates/consolidation on micro-computed tomography scan imaging, and reduced lung rejection/injury. DC activation from lung allografts was suppressed with PFD, and there seemed to be a greater effect of PFD on CD11c(+)CD11b(-)CD103(+) lung DCs. In addition, PFD reduced the expression of several proinflammatory cytokines/chemokines from lung allografts. In vitro, DCs treated with PFD showed decreased expression of major histocompatibility complex class II and costimulatory molecules and the capacity of these DCs to stimulate T-cell activation was impaired, although antigen uptake was preserved. PFD directly inhibited the release of inflammatory cytokines from isolated DCs, was associated with a reduction of stress protein kinases, and attenuated lipopolysaccharide-dependent mitogen-activated protein kinase p38 phosphorylation.
PFD has lung allograft protective properties, and in addition to its known effects on T-cell biology, PFD immune-modulating activities encompass inhibitory effects on DC activation and function.
吡非尼酮（PFD）是一种抗纤维化药物，对促炎疾病有有益作用。在这项研究中，我们通过评估其对小鼠树突状细胞（DC）的影响，进一步研究了 PFD 和长效形式“氘代 PFD”的免疫调节特性。
使用原位小鼠肺移植模型和分离的骨髓源性 DC 对脂多糖和同种异体刺激的反应，在体内和体外研究 PFD 对 DC 的作用。
在小鼠肺移植中，PFD 和氘代 PFD 治疗可改善同种异体肺功能（基于气道峰压）、减少微计算机断层扫描成像上的浸润/实变，并减少肺排斥/损伤。PFD 抑制了来自肺移植物的 DC 活化，并且 PFD 对 CD11c（+）CD11b（-）CD103（+）肺 DC 的作用似乎更大。此外，PFD 降低了来自肺移植物的几种促炎细胞因子/趋化因子的表达。在体外，用 PFD 处理的 DC 显示主要组织相容性复合物 II 和共刺激分子的表达降低，并且这些 DC 刺激 T 细胞活化的能力受损，尽管抗原摄取得到保留。PFD 直接抑制分离的 DC 释放炎症细胞因子，与应激蛋白激酶减少以及减弱脂多糖依赖性丝裂原激活蛋白激酶 p38 磷酸化有关。
PFD 具有肺移植保护特性，除了对 T 细胞生物学的已知作用外，PFD 的免疫调节活性还包括抑制 DC 活化和功能。
