Hypoxia inducible factor 1alpha signaling in fractionated radiation-induced lung injury: role of oxidative stress and tissue hypoxia.
To investigate the relationship of HIF1alpha signaling to oxidative stress, tissue hypoxia, angiogenesis and inflammation, female Fischer 344 rats were irradiated to the right hemithorax with a fractionated dose of 40 Gy (8 Gy x 5 days). The lung tissues were harvested before and at 4, 6, 10, 14, 18, 22 and 26 weeks after irradiation for serial studies of biological markers, including markers for hypoxia (HIF1alpha, pimonidazole and CA IX), oxidative stress (8-OHdG), and angiogenesis/capillary proliferation (VEGF/CD 105), as well as macrophage activation (ED-1) and cell signaling/fibrosis (NFkappaB, TGFbeta1), using immunohistochemistry and Western blot analysis. HIF1alpha staining could be observed as early as 4 weeks postirradiation and was significantly increased with time after irradiation. Importantly, HIF1alpha levels paralleled oxidative stress (8-OHdG), tissue hypoxia (pimonidazole and CA IX), and macrophage accumulation consistent with inflammatory response. Moreover, changes in HIF1alpha expression identified by immunohistochemistry assay parallel the changes in TGFbeta1, VEGF, NFkappaB and CD 105 levels in irradiated lungs. These results support the notion that oxidative stress and tissue hypoxia might serve as triggering signals for HIF1alpha activity in irradiated lungs, relating to radiation-induced inflammation, angiogenesis and fibrosis.
Rabbani
Z N
ZN
Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, USA. zahid@radonc.duke.edu
Mi
J
J
Zhang
Y
Y
Delong
M
M
Jackson
I L
IL
Fleckenstein
K
K
Salahuddin
F K
FK
Zhang
X
X
Clary
B
B
Anscher
M S
MS
Vujaskovic
Z
Z
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015153:Blotting, Western; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D019583:Dose Fractionation, Radiation; D005260:Female; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D008168:Lung / Q000528:radiation effects*; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018384:Oxidative Stress; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine