Jackson I L, Batinic-Haberle I, Sonveaux P, Dewhirst M W, Vujaskovic Z
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Int J Hyperthermia. 2006 Jun;22(4):263-73. doi: 10.1080/02656730600594027.
It has been well established that inadequate blood supply combined with high metabolic rates of oxygen consumption results in areas of low oxygen tension (<1%) within malignant tumours and that elevating tumour temperatures above 39 degrees Celsius results in significant improvement in tumour oxygenation. Macrophages play a dual role in tumour initiation and progression having both pro-tumour and anti-tumour effects. However, the response of macrophages to heat within a hypoxic environment has not yet been clearly defined.
Raw 264.7 murine macrophages were incubated under normoxia and chronic hypoxia at temperatures ranging from 37-43 degrees Celsius. Under normoxia at 41 degrees Celsius, macrophages start to release significant levels of superoxide. The combination of heat with hypoxia constitutes an additional stimulus leading to increased respiratory burst of macrophages.
The high levels of superoxide were found to be associated with changes in macrophage production of pro-angiogenic cytokines. While hypoxia alone (37 degrees Celsius) increased levels of hypoxia inducible factor-1alpha (HIF-1alpha) in macrophages, the combination of hypoxia and mild hyperthermia (39-41 degrees Celsius) induced a strong reduction in HIF-1alpha expression. The HIF-regulated vascular endothelial growth factor (VEGF) decreased simultaneously, revealing that heat inhibits both HIF-1alpha stabilization and transcriptional activity.
The data suggest that temperatures which are readily achievable in the clinic (39-41 degrees Celsius) might be optimal for maximizing hyperthermic response. At higher temperatures, these effects are reversed, thereby limiting the therapeutic benefits of more severe hyperthermic exposure.
众所周知，血液供应不足与高氧消耗代谢率相结合会导致恶性肿瘤内出现低氧张力区域（<1%），并且将肿瘤温度升高至39摄氏度以上会显著改善肿瘤氧合。巨噬细胞在肿瘤的起始和进展中发挥双重作用，既有促肿瘤作用，也有抗肿瘤作用。然而，巨噬细胞在缺氧环境中对热的反应尚未明确界定。
将Raw 264.7小鼠巨噬细胞在常氧和慢性缺氧条件下于37 - 43摄氏度的温度范围内孵育。在41摄氏度的常氧条件下，巨噬细胞开始释放大量超氧化物。热与缺氧的结合构成了一种额外的刺激，导致巨噬细胞的呼吸爆发增加。
发现高水平的超氧化物与巨噬细胞促血管生成细胞因子的产生变化有关。虽然单独缺氧（37摄氏度）会增加巨噬细胞中缺氧诱导因子-1α（HIF-1α）的水平，但缺氧与轻度热疗（39 - 41摄氏度）的结合会导致HIF-1α表达强烈降低。HIF调节的血管内皮生长因子（VEGF）同时减少，表明热抑制了HIF-1α的稳定和转录活性。
数据表明，临床中易于达到的温度（39 - 41摄氏度）可能最有利于最大化热疗反应。在更高温度下，这些效应会逆转，从而限制了更严重热疗暴露的治疗益处。
