Early and late administration of MnTE-2-PyP5+ in mitigation and treatment of radiation-induced lung damage.

Abstract

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.

• Authors: Benjamin Gauter-Fleckenstein, Katharina Fleckenstein, Kouros Owzar, Chen Jiang, Júlio S Rebouças, Ines Batinic-Haberle, Zeljko Vujaskovic
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 48 Issue 8 Pg. 1034-43 (Apr 15 2010) ISSN: 1873-4596 [Electronic] United States
• PMID: 20096348 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Metalloporphyrins
• Radiation-Protective Agents
• manganese (III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin

Topics

• Animals
• Antioxidants (administration & dosage)
• Female
• Metalloporphyrins (administration & dosage)
• Radiation Pneumonitis (drug therapy, pathology)
• Radiation-Protective Agents (pharmacology)
• Rats
• Rats, Inbred F344
• Respiration
• Time Factors