Mezzaroma Eleonora, Mikkelsen Ross B, Toldo Stefano, Mauro Adolfo G, Sharma Khushboo, Marchetti Carlo, Alam Asim, Van Tassell Benjamin W, Gewirtz David A, Abbate Antonio
Virginia Commonwealth University (VCU) Pauley Heart Center, Richmond, Virginia, United States of America.
VCU Victoria Johnson Center, Richmond, Virginia, United States of America.
Mol Med. 2015 Mar 26;21(1):210-8. doi: 10.2119/molmed.2014.00243.
Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure. XRT-mediated injury to the heart induces an inflammatory response leading to cardiomyopathy. The aim of this study was to determine the role of interleukin (IL)-1 in response to XRT injury to the heart and on the cardiomyopathy development in the mouse. Female mice with genetic deletion of the IL-1 receptor type I (IL-1R1 knockout mice [IL-1R1 KO]) and treatment with recombinant human IL-1 receptor antagonist anakinra, 10 mg/kg twice daily for 7 d, were used as independent approaches to determine the role of IL-1. Wild-type (wt) or IL-1R1 KO mice were treated with a single session of XRT (20 or 14 gray [Gy]). Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson's trichrome was used to assess myocardial fibrosis and pericardial thickening. After 20 Gy, the contractile reserve was impaired in wt mice at d 3, and the LV ejection fraction (EF) was reduced after 4 months when compared with sham-XRT. IL-1R1 KO mice had preserved contractile reserve at 3 d and 4 months and LVEF at 4 months after XRT. Anakinra treatment for 1 d before and 7 d after XRT prevented the impairment in contractile reserve. A significant increase in LV end-diastolic pressure, associated with increased myocardial interstitial fibrosis and pericardial thickening, was observed in wt mice, as well as in IL-1R1 KO-or anakinra-treated mice. In conclusion, induction of IL-1 by XRT mediates the development of some, such as the contractile impairment, but not all aspects of the XRT-induced cardiomyopathy, such as myocardial fibrosis or pericardial thickening.
用于癌症治疗的胸部X线放疗（XRT）与心力衰竭风险增加相关。XRT介导的心脏损伤会引发炎症反应，进而导致心肌病。本研究的目的是确定白细胞介素（IL）-1在小鼠对XRT心脏损伤的反应以及心肌病发展过程中的作用。通过两种独立方法来确定IL-1的作用，一种是基因敲除I型IL-1受体的雌性小鼠（IL-1受体1基因敲除小鼠[IL-1R1 KO]），另一种是用重组人IL-1受体拮抗剂阿那白滞素治疗，剂量为10 mg/kg，每日两次，共7天。野生型（wt）或IL-1R1 KO小鼠接受单次XRT治疗（20或14戈瑞[Gy]）。进行超声心动图检查（异丙肾上腺素激发前后）和左心室（LV）插管，以评估左心室尺寸和功能的变化。采用Masson三色染色法评估心肌纤维化和心包增厚情况。给予20 Gy照射后，wt小鼠在第3天收缩储备功能受损，与假照射组相比，4个月后左心室射血分数（EF）降低。XRT后3天和4个月时，IL-1R1 KO小鼠的收缩储备功能得以保留，4个月时左心室射血分数也正常。在XRT前1天和后7天用阿那白滞素治疗可预防收缩储备功能受损。在wt小鼠以及IL-1R1 KO小鼠或阿那白滞素治疗的小鼠中，均观察到左心室舒张末期压力显著升高，同时伴有心肌间质纤维化和心包增厚增加。总之，XRT诱导的IL-1介导了XRT诱导的心肌病的某些方面，如收缩功能受损，但并非所有方面，如心肌纤维化或心包增厚。
