title: Low molecular weight catalytic metalloporphyrin antioxidant AEOL 10150 protects lungs from fractionated radiation.
abstract: The objective of this study was to determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL10150, reduces the severity of long-term lung injury induced by fractionated radiation (RT). Fisher 344 rats were randomized into five groups: RT+AEOL10150 (2.5 mg/kg BID), AEOL10150 (2.5 mg/kg BID) alone, RT+ AEOL10150 (5 mg/kg BID), AEOL10150 (5 mg/kg BID) alone and RT alone. Animals received five 8 Gy fractions of RT to the right hemithorax. AEOL10150 was administered 15 min before RT and 8 h later during the period of RT treatment (5 days), followed by subcutaneous injections for 30 days, twice daily. Lung histology at 26 weeks revealed a significant decrease in lung structural damage and collagen deposition in RT+AEOL10150 (5 mg/kg BID) group, in comparison to RT alone. Immunohistochemistry studies revealed a significant reduction in tissue hypoxia (HIF1alpha, CAIX), angiogenic response (VEGF, CD-31), inflammation (ED-1), oxidative stress (8-OHdG, 3-nitrotyrosine) and fibrosis pathway (TGFbeta1, Smad3, p-Smad2/3), in animals receiving RT+ AEOL10150 (5 mg/kg BID). Administration of AEOL10150 at 5 mg/kg BID during and after RT results in a significant protective effect from long-term RT-induced lung injury. Low dose (2.5 mg/kg BID) delivery of AEOL10150 has no beneficial radioprotective effects.
authors.affiliation: Department of Radiation Oncology, Durham Regional Hospital/Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Zahid N
authors.initials: ZN
authors.lastname: Rabbani
authors.forename: Fawzia K
authors.initials: FK
authors.lastname: Salahuddin
authors.forename: Pavel
authors.initials: P
authors.lastname: Yarmolenko
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Thrasher
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gauter-Fleckenstein
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dewhirst
authors.forename: Mitchell S
authors.initials: MS
authors.lastname: Anscher
authors.forename: Zeljko
authors.initials: Z
authors.lastname: Vujaskovic
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D002384:Catalysis; D019610:Cytoprotection / Q000187:drug effects*; D019583:Dose Fractionation, Radiation; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D008168:Lung / Q000187:drug effects / Q000528:radiation effects; D008171:Lung Diseases / Q000209:etiology / Q000517:prevention & control*; D008665:Metalloporphyrins / Q000008:administration & dosage / Q000494:pharmacology*; D008954:Models, Biological; D008970:Molecular Weight; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: C472668:AEOL 10150; D000975:Antioxidants; D008665:Metalloporphyrins