Post-Irradiation Treatment with a Superoxide Dismutase Mimic, MnTnHex-2-PyP5+, Mitigates Radiation Injury in the Lungs of Non-Human Primates after Whole-Thorax Exposure to Ionizing Radiation.

John Cline,Ines Batinic-Haberle,Greg Dugan,Artak Tovmasyan,Chen Jiang,John Bourland,Zeljko Vujaskovic,Donna Perry,Joel Stitzel,Ivan Spasojevic,Kouros Owzar,Ashley Weaver

doi:10.3390/antiox7030040

Abstract

Radiation injury to the lung is the result of acute and chronic free radical formation, and there are currently few effective means of mitigating such injury. Studies in rodents indicate that superoxide dismutase mimetics may be effective in this regard; however, studies in humans or large animals are lacking. We hypothesized that post-exposure treatment with the lipophilic mitochondrial superoxide dismutase mimetic, MnTnHex-2-PyP5+ (hexyl), would reduce radiation-induced pneumonitis and fibrosis in the lungs of nonhuman primates. Rhesus monkeys (Macaca mulatta) received 10 Gy whole thorax irradiation, 10 Gy + hexyl treatment, sham irradiation, or sham irradiation + hexyl. Hexyl was given twice daily, subcutaneously, at 0.05 mg/kg, for 2 months. Animals were monitored daily, and respiratory rates, pulse oximetry, hematology and serum chemistry panels were performed weekly. Computed tomography scans were performed at 0, 2, and 4 months after irradiation. Supportive fluid therapy, corticosteroids, analgesics, and antibiotics were given as needed. All animals were humanely euthanized 4.5 months after irradiation, and pathologic assessments were made. Multifocal, progressive lung lesions were seen at 2 and 4 months in both irradiated groups. Hexyl treatment delayed the onset of radiation-induced lung lesions, reduced elevations of respiratory rate, and reduced pathologic increases in lung weight. No adverse effects of hexyl treatment were found. These results demonstrate (1) development of a nonhuman primate model of radiation-induced lung injury, (2) a significant mitigating effect of hexyl treatment on lung pathology in this model, and (3) no evidence for toxicity of hexyl at the dose studied.

Highlights

Radiation-induced pulmonary injury causes substantial morbidity and mortality in both accidentally and therapeutically exposed individuals
We have provided the evidence and MnTnHex-2-PyP5+ exhibited therapeutic potential as a broadly applicable mitigator of oxidative the mechanistic basis that the SOD-like potency of Mn porphyrins is proportional to their ability to stress injury and radioprotector of normal tissue, while demonstrating anticancer effects
We described the effect of hexyl in a nonhuman primates (NHP) model of radiation-induced lung injury, described the effect of hexyl in produces a NHP model of radiation-induced lunga period injury, including an we irradiation strategy that that reliably pneumonitis and fibrosis within including an irradiation strategy that that reliablyevaluation produces pneumonitis and fibrosis within a period of

Summary

Introduction

Radiation-induced pulmonary injury causes substantial morbidity and mortality in both accidentally and therapeutically exposed individuals. Single-dose exposures of greater than 9 Gy in human patients induce a subacute inflammatory response (radiation pneumonitis) approximately. 2–3 months after exposure, and a more chronic, irreversible syndrome of pulmonary interstitial fibrosis occurring months to years after exposure [1,2]. Among patients receiving fractionated radiotherapy for malignancies of the thorax, the likelihood of lung injury is increased by irradiation of the inferior thorax and by a higher mean dose for normal lungs [3]. The standard of treatment for radiation pneumonitis is high-dose corticosteroids [4]. There is currently no treatment for radiation-induced fibrosis. As mortality due to the hematopoietic syndrome has diminished due to bone marrow transplant and cytokine therapy, pulmonary injury has emerged as an increasingly relevant syndrome

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