丝裂霉素诱导的肺静脉闭塞病：来自人类疾病和动物模型的证据。
Mitomycin-Induced Pulmonary Veno-Occlusive Disease: Evidence From Human Disease and Animal Models.
机构信息
From Univ. Paris-Sud, Faculté de Médecine, Kremlin-Bicêtre, France (F.P., S.G., B.R., L.G., F.A., P.D., A.H., N.R., L.S., X.J., B.G., O.S., G.S., M.H., D.M.); AP-HP, Centre de Référence de l'Hypertension Pulmonaire Sévère, Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital de Bicêtre, Le Kremlin Bicêtre, France (F.P., S.G., B.R., L.G., F.A., A.H., L.S., X.J., B.G., O.S., G.S., M.H., D.M.); UMR_S 999, Univ. Paris-Sud, INSERM, Laboratoire d'Excellence (LabEx) en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France (F.P., S.G., B.R., L.G., F.A., M-C.C., P.D., H.R., L.S., X.J., B.G., O.S., G.S., M.H., D.M.); Univ. Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France (M-C.C.); Pulmonary Hypertension Research Group, Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec, Université Laval, Canada (F.P.); Service de Pneumologie, CHU Mont-Godinne - Université Catholique de Louvain, Yvoir, Belgium (L.G.); AP-HP, Service de Pharmacie, Département Hospitalo-Universitaire (DHU) Thorax Innovation, Hôpital Antoine Béclère, Clamart, France (M-C.C.); Department of Pathology, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France (P.D.); and National Reference Centre for Rare Pulmonary Diseases, Department of Respiratory Medicine, Louis Pradel Hospital, Lyon, France (V.C.).
出版信息
Circulation. 2015 Sep 1;132(9):834-47. doi: 10.1161/CIRCULATIONAHA.115.014207. Epub 2015 Jun 30.
BACKGROUND
Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension characterized by the obstruction of small pulmonary veins and a dismal prognosis. PVOD may be sporadic or heritable because of biallelic mutations of the EIF2AK4 gene coding for GCN2. Isolated case reports suggest that chemotherapy may be a risk factor for PVOD.
METHODS AND RESULTS
We reported on the clinical, functional, and hemodynamic characteristics and outcomes of 7 cases of PVOD induced by mitomycin-C (MMC) therapy from the French Pulmonary Hypertension Registry. All patients displayed squamous anal cancer and were treated with MMC alone or MMC plus 5-fluoruracil. The estimated annual incidence of PVOD in the French population that have anal cancer is 3.9 of 1000 patients, which is much higher than the incidence of PVOD in the general population (0.5/million per year). In rats, intraperitoneal administration of MMC induced PVOD, as demonstrated by pulmonary hypertension at right-heart catheterization at days 21 to 35 and major remodeling of small pulmonary veins associated with foci of intense microvascular endothelial-cell proliferation of the capillary bed. In rats, MMC administration was associated with dose-dependent depletion of pulmonary GCN2 content and decreased smad1/5/8 signaling. Amifostine prevented the development of MMC-induced PVOD in rats.
CONCLUSIONS
MMC therapy is a potent inducer of PVOD in humans and rats. Amifostine prevents MMC-induced PVOD in rats and should be tested as a preventive therapy for MMC-induced PVOD in humans. MMC-induced PVOD in rats represents a unique model to test novel therapies in this devastating orphan disease.
背景
肺静脉闭塞病（PVOD）是一种罕见的肺动脉高压形式，其特征是小肺静脉阻塞和预后不良。PVOD 可能是散发性的，也可能是遗传性的，因为 EIF2AK4 基因的双等位基因突变导致 GCN2 编码。孤立的病例报告表明，化疗可能是 PVOD 的一个危险因素。
方法和结果
我们报告了法国肺动脉高压登记处的 7 例由丝裂霉素 C（MMC）治疗引起的 PVOD 的临床、功能和血流动力学特征及结局。所有患者均表现为鳞状肛门癌，单独或联合 MMC 加 5-氟尿嘧啶治疗。法国患有肛门癌的人群中，PVOD 的估计年发病率为每 1000 例患者中有 3.9 例，远高于普通人群中 PVOD 的发病率（每年每百万患者中有 0.5 例）。在大鼠中，腹腔内给予 MMC 可诱导 PVOD，右心导管检查在第 21 至 35 天显示肺动脉高压，并伴有小肺静脉的主要重塑，与毛细血管床的微血管内皮细胞增殖焦点相关。在大鼠中，MMC 给药与肺 GCN2 含量的剂量依赖性耗竭和 smad1/5/8 信号的降低相关。氨磷汀可预防 MMC 诱导的大鼠 PVOD 的发生。
结论
MMC 治疗是人类和大鼠 PVOD 的有效诱导剂。氨磷汀可预防 MMC 诱导的大鼠 PVOD，应作为人类 MMC 诱导的 PVOD 的预防治疗进行测试。大鼠 MMC 诱导的 PVOD 代表了一种独特的模型，可用于测试这种毁灭性孤儿病的新疗法。
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