Early and late administration of MnTE-2-PyP5+ in mitigation and treatment of radiation-induced lung damage.
Chronic production of reactive oxygen and nitrogen species is an underlying mechanism of irradiation (IR)-induced lung injury. The purpose of this study was to determine the optimum time of delivery of an antioxidant and redox-modulating Mn porphyrin, MnTE-2-PyP(5+), to mitigate and/or treat IR-induced lung damage. Female Fischer-344 rats were irradiated to their right hemithorax (28 Gy). Irradiated animals were treated with PBS or MnTE-2-PyP(5+) (6 mg /kg/24 h) delivered for 2 weeks by sc-implanted osmotic pumps (beginning after 2, 6, 12, 24, or 72 h or 8 weeks). Animals were sacrificed 10 weeks post-IR. Endpoints were body weight, breathing frequency, histopathology, and immunohistochemistry (8-OHdG, ED-1, TGF-beta, HIF-1alpha, VEGF A). A significant radioprotective effect on functional injury, measured by breathing frequency, was observed for all animals treated with MnTE-2-PyP(5+). Treatment with MnTE-2-PyP(5+) starting 2, 6, and 12 h but not after 24 or 72 h resulted in a significant decrease in immunostaining for 8-OHdG, HIF-1alpha, TGF-beta, and VEGF A. A significant decrease in HIF-1alpha, TGF-beta, and VEGF A, as well as an overall reduction in lung damage (histopathology), was observed in animals beginning treatment at the time of fully developed lung injury (8 weeks post-IR). The catalytic manganese porphyrin antioxidant and modulator of redox-based signaling pathways MnTE-2-PyP(5+) mitigates radiation-induced lung injury when given within the first 12 h after IR. More importantly, this is the first study to demonstrate that MnTE-2-PyP(5+) can reverse overall lung damage when started at the time of established lung injury 8 weeks post-IR. The radioprotective effects are presumably mediated through its ability both to suppress oxidative stress and to decrease activation of key transcription factors and proangiogenic and profibrogenic cytokines.
Gauter-Fleckenstein
Benjamin
B
Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
Fleckenstein
Katharina
K
Owzar
Kouros
K
Jiang
Chen
C
Rebouças
Júlio S
JS
Batinic-Haberle
Ines
I
Vujaskovic
Zeljko
Z
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D005260:Female; D008665:Metalloporphyrins / Q000008:administration & dosage*; D017564:Radiation Pneumonitis / Q000188:drug therapy* / Q000473:pathology; D011837:Radiation-Protective Agents / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D012119:Respiration; D013997:Time Factors
D000975:Antioxidants; D008665:Metalloporphyrins; D011837:Radiation-Protective Agents; C431023:manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin