胺碘酮通过诱发炎症细胞积聚导致肺毒性的实验研究

Amiodarone induced pulmoary toxicity by accumulating inflammatory cells

目的本研究探讨长期胺碘酮不同剂量对大鼠肺脏的影响。方法随机选择雄性SD大鼠30只,随机分为对照组(NC,n=10),胺碘酮低剂量组[n=10,50 mg/(kg·d),AM50],胺碘酮高剂量组[n=10,200 mg/(kg·d),AM200],每天上午给药1次,对照组喂等量的自来水,连续15周。期间观察SD大鼠一般状况、体重,15周后麻醉后股动脉抽血测PⅢNP(Ⅲ型前胶原N端肽)、Ⅳ-Col(Ⅳ型胶原)水平,处死后称取肺脏重量,计算脏器系数,并进行病理组织检查。结果 AM200组体重增长慢于其他2组,从第2周起与其他2组比较差异均存在统计学意义(P<0.05),累积死亡3只,其余2组未见死亡;肺脏重量[NC(1.58±0.17)g;AM50(1.54±0.16)g;AM200(1.57±0.55)g]及脏器系数(NC 0.32±0.04;AM50 0.30±0.03;AM200 0.38±0.13),3组之间肺脏重量及脏器系数差异均无统计学意义(P>0.05);3组PⅢNP水平取Ln10后[NC(0.60±0.40)μg/L;AM50(0.36±0.26)μg/L;AM200(0.79±0.59)μg/L],Ⅳ-Col水平[NC(1.02±0.38)μg/L;AM50(0.81±0.23)μg/L;AM200(1.21±1.00)μg/L],3组PⅢNP、Ⅳ-Col水平差异未见统计学意义(P>0.05);病理检查AM50组可见泡沫细胞,AM200组可见有若干炎性坏死灶,伴轻度纤维化,有多个多核巨细胞,支气管、细支气管上皮节段空泡变性,肺泡腔内有大量巨噬细胞、脱落的上皮细胞及渗出液。电镜可见AM50组Ⅱ型肺上皮细胞板层体空泡,AM100组可见板层电体空泡,绒毛清晰。结论胺碘酮通过诱发炎症反应导致细胞损伤坏死,最终导致肺纤维化。

Objective To investigate the different dosages of long term amiodarone on lung in rats. Methods 30 SD rats were randomly divided into 3 groups ：Normal control group（ n = 10 ）, Low dosage amiodarone group[ ig 50 mg/（ kg · d ）, n = 10, AM501 and High dosage amidarone group [ig 200 mg,/（ kg · d）, n = 10, AM200 ], the normal control group were given saline of the same volume. Feeding drugs duration was for 15 weeks respectively. We observed the growth of weight, P Ⅲ NP, Ⅳ-Col level, and pulmonary weight, all the rats were sacrificed, pulmonary weight, pulmonary weigh/body weight coefficient as well as histological optical microscope pathologic and electron microscope examination were performed. Resuits The growth of weight of AM200 was slower than the other two groups, which had statistical differences compared with AM50 and NC group. 3 rats died in AM200 group. There were not statistical differences in the levels of P Ul NP, IV- Col in all three groups. Pulmonary weight [ NC （ 1.58 ± 0.17） g; AM50 （ 1.54 ± 0.16） g; AM200 （ 1.57 ± 0.55 ） g ], pulmonary weigh/body weight coefficient（ NC 0.32 ± 0.04 ; AM50 0.30 ± 0.03 ; AM200 0.38 ± 0.13 ） Pulmonary weight, pulmonary weigh/body weight coefficient were more in AM200 group, but had no statistical differences between three groups. Pulmonary HE examination found that macrophages and foam cells in AM50 group and inflammatory necrosis area, pulmonary fibrosis, vacuoles degeneration in bronchiolar epithelium cell, a large number of macrophages, epithelial cell and effusion in alveolar space existed in AM200 group. By transmission electron microscopy, the lamellar body cavity in Type II lung epithelial cells were found in AM50 and AM200 group. Conclusion Amiodarone induced pulmonary cell necrosis by inducing inflammatory reaction, eventually led pulmonary fibrosis..