Lenarczyk Marek, Laiakis Evagelia C, Mattson David L, Johnson Bryon D, Kronenberg Amy, North Paula E, Komorowski Richard, Mäder Marylou, Baker John E
Medical College of Wisconsin Milwaukee Wisconsin USA.
Georgetown University Washington D.C USA.
FASEB Bioadv. 2020 Oct 23;2(12):705-719. doi: 10.1096/fba.2020-00071. eCollection 2020 Dec.
Cardiac disease is a frequent and significant adverse event associated with radiotherapy for cancer. Identifying the underlying mechanism responsible for radiation injury to the heart will allow interventions to be developed. In the present study, we tested if local kidney irradiation results in remodeling of the shielded, nontargeted heart. One kidney, two kidneys, or the total body of male WAG and Dahl SS rats were irradiated with 10 Gy of X-rays. Local kidney irradiation resulted in systemic hypertension, increased BUN, infiltration of T lymphocytes, natural killer cells, and macrophages into the renal cortex and medulla, and renal fibrosis. Local irradiation of kidneys in WAG rats resulted in remodeling in the nontargeted heart after 120 days, manifested by perivascular fibrosis and increased interventricular septal thickness, but was not seen in Dahl SS rats due to a high baseline level of fibrosis in the sham-irradiated animals. Genetic depletion of T cells mitigated the nephropathy after local kidney irradiation, indicating a role for the immune system in mediating this outcome. Local kidney irradiation resulted in a cascade of pro-inflammatory cytokines and low-molecular weight metabolites into the circulation associated with transmission of signals resulting in pathologic remodeling in the nontargeted heart. A new model is proposed whereby radiation-induced cardiac remodeling in susceptible animals is indirect, with lower hemi body organs such as the kidney exporting factors into the circulation that cause remodeling outside of the irradiated field in the shielded, nontargeted heart. This nontargeted effect appears to be mediated, in part, by the immune system.
心脏病是癌症放疗常见且严重的不良事件。明确心脏辐射损伤的潜在机制将有助于开发干预措施。在本研究中，我们测试了局部肾脏照射是否会导致受屏蔽的非靶器官心脏发生重塑。对雄性WAG和Dahl SS大鼠的一侧肾脏、双侧肾脏或全身进行10 Gy的X射线照射。局部肾脏照射导致系统性高血压、血尿素氮升高、T淋巴细胞、自然杀伤细胞和巨噬细胞浸润到肾皮质和髓质以及肾纤维化。WAG大鼠局部肾脏照射120天后，非靶器官心脏发生重塑，表现为血管周围纤维化和室间隔厚度增加，但在Dahl SS大鼠中未观察到，因为假照射动物的纤维化基线水平较高。T细胞的基因缺失减轻了局部肾脏照射后的肾病，表明免疫系统在介导这一结果中起作用。局部肾脏照射导致一系列促炎细胞因子和低分子量代谢产物进入循环，与信号传递相关，从而导致非靶器官心脏发生病理重塑。我们提出了一种新模型，即易感性动物中辐射诱导的心脏重塑是间接的，较低半身的器官如肾脏将因子输出到循环中，导致受屏蔽的非靶器官心脏在照射野之外发生重塑。这种非靶效应似乎部分由免疫系统介导。
