Pioglitazone prevents acute and chronic cardiac allograft rejection
Pioglitazone prevents acute and chronic cardiac allograft rejection
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DOI：
10.1161/circulationaha.105.594101
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发表时间：
2006-06-06
期刊：
影响因子：
37.8
通讯作者：
Isobe, Mitsuaki
中科院分区：
文献类型：
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作者：
Kosuge, Hisanori;Haraguchi, Go;Isobe, Mitsuaki
背景-过氧化物酶体增殖物激活受体-γ在调节炎症中起重要作用。虽然心脏移植是终末期心脏病患者的既定治疗方法，但同种异体移植物排斥反应是长期生存的主要问题。我们研究了吡格列酮在急性和慢性排斥反应中的作用，在小鼠心脏transplantationmodel.Methods和结果-我们进行异位小鼠心脏移植总allomismatch或主要组织相容性复合物II类不匹配的组合。给小鼠喂食标准食物或含有吡格列酮（3 mg（.）kg（-1.）d（-1））。在急性排斥反应中，给予吡格列酮的小鼠心脏移植物存活时间明显长于对照组小鼠（平均存活时间，34.6 ± 7.8天对8.4 ± 0.4天; P < 0.003）。吡格列酮治疗显著抑制干扰素-γ和单核细胞趋化蛋白-1的移植表达。在慢性排斥反应中，接受吡格列酮治疗的小鼠的同种异体移植物中新生内膜增生（管腔闭塞，25.1 ± 8.8%）显著低于对照小鼠（65.8 ± 7.3%，P < 0.001）。吡格列酮治疗的同种异体移植物显示干扰素-γ、白细胞介素-10和单核细胞趋化蛋白-1的表达显著降低。我们进行了混合淋巴细胞反应和平滑肌细胞的体外增殖试验。混合淋巴细胞反应中加入吡格列酮可抑制T细胞增殖。平滑肌细胞与活化的脾细胞共培养时显示出显著的增殖。这种增殖被显着抑制通过添加吡格列酮（1 μ mol/L）。结论-吡格列酮通过抑制平滑肌细胞的增殖，抑制同种异体移植物的存活和衰减新生内膜增生。吡格列酮可能是一种预防急性和慢性移植排斥反应的新方法。
Background - Peroxisome proliferator - activated receptor-gamma plays an important role in regulating inflammation. Although cardiac transplantation is an established therapy for patients with end-stage heart disease, allograft rejection is a major concern for long-term survival. We investigated the role of pioglitazone in acute and chronic rejection in a murine cardiac transplantation model.Methods and Results - We performed heterotopic murine cardiac transplantation in total allomismatch or major histocompatibility complex class II-mismatched combinations. Recipient mice were given standard chow or chow containing pioglitazone (3 mg(.)kg(-1.)d(-1)) beginning 1 day before cardiac transplantation. In acute rejection, animals given pioglitazone showed significantly longer cardiac allograft survival than control mice ( mean survival time, 34.6 +/- 7.8 versus 8.4 +/- 0.4 days; P < 0.003). Treatment with pioglitazone significantly suppressed graft expression of interferon-gamma and monocyte chemoattractant protein-1. In chronic rejection, neointimal hyperplasia was significantly lower in allografts from mice treated with pioglitazone ( luminal occlusion, 25.1 +/- 8.8%) than in those from control mice (65.8 +/- 7.3%, P < 0.001). Pioglitazone-treated allografts showed significantly reduced expression of interferon-gamma, interleukin-10, and monocyte chemoattractant protein-1. We performed mixed lymphocyte reactions and in vitro proliferation assays of smooth muscle cells. Addition of pioglitazone to mixed lymphocyte reactions inhibited proliferation of T cells. Smooth muscle cells showed significant proliferation when cocultured with activated splenocytes. This proliferation was significantly inhibited by the addition of pioglitazone (1 mu mol/L).Conclusions - Pioglitazone prolongs allograft survival and attenuates neointimal hyperplasia through the suppression of proliferation of smooth muscle cells. Pioglitazone may be a novel means to prevent acute and chronic allograft rejection.