Int J Hyperthermia. 2006 Jun;22(4):263-73.
ROS production and angiogenic regulation by macrophages in response to heat therapy.
Jackson IL, Batinic-Haberle I, Sonveaux P, Dewhirst MW, Vujaskovic Z.
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
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.
RESULTS: 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.
CONCLUSION: 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.