Long-term administration of a small molecular weight catalytic metalloporphyrin antioxidant, AEOL 10150, protects lungs from radiation-induced injury.
OBJECTIVE
To determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL 10150, with superoxide dismutase (SOD) mimetic properties, reduces the severity of radiation-induced injury to the lung from single-dose irradiation (RT) of 28 Gy.


METHODS
Rats were randomly divided into four different dose groups (0, 1, 10, and 30 mg/kg/day of AEOL 10150), receiving either short-term (1 week) or long-term (10 weeks) drug administration via osmotic pumps. Rats received single-dose irradiation (RT) of 28 Gy to the right hemithorax. Breathing rates, body weights, blood samples, histopathology, and immunohistochemistry were used to assess lung damage.


RESULTS
There was no significant difference in any of the study endpoints between the irradiated controls and the three groups receiving RT and short-term administration of AEOL 10150. For the long-term administration, functional determinants of lung damage 20 weeks postradiation were significantly worse for RT + phosphate-buffered saline (PBS) and RT + 1 mg/kg/day of AEOL 10150 as compared with the irradiated groups treated with higher doses of AEOL 10150 (10 or 30 mg/kg/day). Lung histology at 20 weeks revealed a significant decrease in structural damage and collagen deposition in rats receiving 10 or 30 mg/kg/day after radiation in comparison to the RT + PBS and 1 mg/kg/day groups. Immunohistochemistry demonstrated a significant reduction in macrophage accumulation, oxidative stress, and hypoxia in rats receiving AEOL 10150 (10 or 30 mg/kg/day) after lung irradiation compared with the RT + PBS and 1 mg/kg/day groups.


CONCLUSIONS
The chronic administration of a novel catalytic antioxidant, AEOL 10150, demonstrates a significant protective effect from radiation-induced lung injury. AEOL 10150 has its primary impact on the cascade of events after irradiation, and adding the drug before irradiation and its short-term administration have no significant additional benefits.
Rabbani
Zahid N
ZN
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Batinic-Haberle
Ines
I
Anscher
Mitchell S
MS
Huang
Jie
J
Day
Brian J
BJ
Alexander
Elaine
E
Dewhirst
Mark W
MW
Vujaskovic
Zeljko
Z
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D002452:Cell Count; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D005260:Female; D008168:Lung / Q000528:radiation effects*; D008264:Macrophages / Q000502:physiology; D008665:Metalloporphyrins / Q000008:administration & dosage*; D011832:Radiation Injuries / Q000517:prevention & control*; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344
C472668:AEOL 10150; D000975:Antioxidants; D008665:Metalloporphyrins; D011837:Radiation-Protective Agents; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine