Superoxide dismutase mimetic reduces hypoxia-induced O2*-, TGF-beta, and VEGF production by macrophages.
Normal tissue injury poses a major limitation to the success of radiation therapy (RT) in the treatment of solid tumors. We propose that radiation-induced lung injury is a result of chronic oxidative stress propagated by hypoxia-induced macrophage activation and cytokine production. Therefore, the objective of our study was two-fold. First, in vivo studies were conducted to support our hypothesis suggesting radiation injury is characterized by chronic hypoxia associated with increased macrophage infiltration/activation and pro-fibrogenic/angiogenic cytokine production. Second, we investigated the proposed mechanism of radiation injury in vitro. We demonstrate that hypoxia (0.5% O2) elicits macrophages to produce higher levels of O2*-, TGF-beta, and VEGF than normoxia. Our hypothesis that O2*- is contributing to increased macrophage cytokine production was supported by a significant reduction in TGF-beta and VEGF when redox signaling was minimized using a small molecular weight metalloporphyrin antioxidant, MnTE-2-PyP5+ .
Jackson
Isabel L
IL
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Chen
Liguang
L
Batinic-Haberle
Ines
I
Vujaskovic
Zeljko
Z
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D002478:Cells, Cultured; D005260:Female; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008665:Metalloporphyrins / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism* / Q000528:radiation effects; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000187:drug effects
D000975:Antioxidants; D008665:Metalloporphyrins; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin; D013482:Superoxide Dismutase