Partial volume rat lung irradiation: The protective/mitigating effects of Eukarion-189, a superoxide dismutase–catalase mimetic

Langan, Aimée R.; Khan, Mohammed; Yeung, Ivan; Dyk, Jake Van; Hill, Richard P.

doi:10.1016/j.radonc.2006.03.017

Cited by 60 publications

(75 citation statements)

References 45 publications

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“…Our observation on the importance of upregulation of the antioxidant enzyme SOD1 for MSC-mediated protection supports the current hypothesis that late pulmonary fibrosis develops from early damage to resident lung cells and that this early damage involves radiation-induced oxidative stress (29,48,80,87). Oxidative stress as a consequence of chemotherapy or radiotherapy or tissue inflammation promotes tissue damage, including damage to the vasculature by activating a series of signaling pathways (47,65).…”

Section: Murine Wt Bm (Xrt/bm) Cells From C57bl/6 Donor Mice Into Thesupporting

confidence: 86%

“…In line with these findings, continuous administration of EUK207 via implanted subcutaneous infusion pumps from 1 h until 14 weeks after irradiation also mitigated radiation-induced lung damage in rats (49). Even, when given after irradiation, a single injection of the SOD mimetic EUK189 had a small but mitigating effect in rodents, especially in the lung (48).…”

Section: Murine Wt Bm (Xrt/bm) Cells From C57bl/6 Donor Mice Into Thesupporting

confidence: 69%

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Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Klein

Steens

Wiesemann

et al. 2017

Antioxidants & Redox Signaling

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Aims: Radiation-induced normal tissue toxicity is closely linked to endothelial cell (EC) damage and dysfunction (acute effects). However, the underlying mechanisms of radiation-induced adverse late effects with respect to the vascular compartment remain elusive, and no causative radioprotective treatment is available to date. Results: The importance of injury to EC for radiation-induced late toxicity in lungs after whole thorax irradiation (WTI) was investigated using a mouse model of radiation-induced pneumopathy. We show that WTI induces EC loss as long-term complication, which is accompanied by the development of fibrosis. Adoptive transfer of mesenchymal stem cells (MSCs) either derived from bone marrow or aorta (vascular wall-resident MSCs) in the early phase after irradiation limited the radiation-induced EC loss and fibrosis progression. Furthermore, MSC-derived culture supernatants rescued the radiation-induced reduction in viability and longterm survival of cultured lung EC. We further identified the antioxidant enzyme superoxide dismutase 1 (SOD1) as a MSC-secreted factor. Importantly, MSC treatment restored the radiation-induced reduction of SOD1 levels after WTI. A similar protective effect was achieved by using the SOD-mimetic EUK134, suggesting that MSCderived SOD1 is involved in the protective action of MSC, presumably through paracrine signaling. Innovation: In this study, we explored the therapeutic potential of MSC therapy to prevent radiation-induced EC loss (late effect) and identified the protective mechanisms of MSC action. Conclusions: Adoptive transfer of MSCs early after irradiation counteracts radiation-induced vascular damage and EC loss as late adverse effects. The high activity of vascular wall-derived MSCs for radioprotection may be due to their tissue-specific action. Antioxid. Redox Signal. 26, 563-582.

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Section: Murine Wt Bm (Xrt/bm) Cells From C57bl/6 Donor Mice Into Thesupporting

confidence: 86%

Section: Murine Wt Bm (Xrt/bm) Cells From C57bl/6 Donor Mice Into Thesupporting

confidence: 69%

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Klein

Steens

Wiesemann

et al. 2017

Antioxidants & Redox Signaling

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“…MnP and manganese (III) salen complexes have been tested as radioprotectors in models of radiationinduced lung damage [10,13,14]. Recently, it has been shown, that EUK-189, a representative of the manganese (III) salen complexes is able to prevent irradiation-induced DNA-double strand breaks in partial lung irradiation if given immediately after RT.…”

Section: Discussionmentioning

confidence: 99%

“…for three days starting 5 min after RT in a model of whole lung irradiation (15.5 -18 -20.5 Gy) [14].…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have shown that chronic overproduction of ROS/RNS and subsequent pathological disease can be alleviated in a rodent model of radiation injury through overexpression of SOD [8,9]. Furthermore, it has been shown that manganese (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PYP 5+ , MnP) and other derivatives of SOD are effective radioprotectors [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Comparison of two Mn porphyrin-based mimics of superoxide dismutase in pulmonary radioprotection

Gauter-Fleckenstein

Fleckenstein

Owzar

et al. 2008

Free Radical Biology and Medicine

110

131

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Development of radiation (RT) induced lung injury is associated with chronic production of reactive oxygen and nitrogen species (ROS/RNS). MnTE-2-PyP 5+ is a catalytic Mn porphyrin (MnP) mimic of SOD, already shown to protect lungs from RT induced injury by scavenging ROS/RNS. The purpose of this study was to compare MnTE-2-PyP 5+ with the newly synthesized MnTnHex-2-PyP 5+ which is expected to be a more effective radioprotector due to its lipophilic properties. This study shows that Fischer rats which were irradiated to their right hemithorax (28 Gy) have less pulmonary injury as measured with breathing frequencies when treated with daily subcutaneous injections of MnTE-2-PyP 5+ (3 and 6 mg/kg) or MnTnHex-2-PyP 5+ (0.3 -0.6 -1.0 mg/kg) for 2 weeks after RT. However, at 16 weeks post RT, only MnTE-2-PyP 5+ at a dose of 6 mg/kg is able to ameliorate oxidative damage, block activation of HIF-1α and TGF-β and impair upregulation of CA-IX and VEGF. MnTnHex-2-PyP 5+ at a dose of 0.3 mg/kg is effective only in reducing RT-induced TGF-β and CA-IX expression. Significant loss in bodyweight was observed in animals receiving MnTnHex-2-PyP 5+ (0.3 and 0.6 mg/kg). MnTnHex-2-PyP 5+ has the ability to dissolve lipid membranes causing local irritations/necrosis at injection sites if given at doses of 1 mg/kg or higher. In conclusion, both compounds show ability to ameliorate lung damage as measured with breathing frequencies and histopathologic evaluation. However, MnTE-2-PyP 5+ at 6 mg/kg proved to be more effective in reducing expression of key molecular factors known to play an important role in radiation-induced lung injury.

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Development of Radiation Countermeasures

Pellmar

2008

Wiley Handbook of Science and Technology for Homeland Security

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Medical countermeasures are required to address the emerging radiological and nuclear threats. Radiation injury can result from exposure to external, penetrating radiation or internalized radionuclides. Countermeasures for internal contamination focus on decorporation and protecting the primary site of activity. No countermeasures are currently approved for the acute radiation syndrome that results from external exposures, but significant efforts are ongoing to develop new agents to counter the cascade of damage from ionizing radiation. Antioxidants and enzyme mimics are directed toward prevention of free radical damage to macromolecules. Other agents target the affected cell‐signaling pathways: preventing apoptosis, triggering cell cycle arrest, or modulating the inflammatory response. To counter the loss of progenitor cells, particularly in the bone marrow and the gut, drugs such as the cytokines and other immunomodulators are developed to promote proliferation of new cells. If radiation injury proceeds to organ failure and infection, supportive care and antibiotics provide significant therapeutic value. In addition to the radiation dose, several factors impact the severity of the injury. Among these are radiation quality (e.g. neutron–gamma mixed fields) and dose rate, combined injuries, and partial‐body exposures. In future efforts, it will be important to consider these factors, which can modulate the radiation response and possibly affect the efficacy of the treatments. Although an ideal countermeasure that is inexpensive, stable with a long shelf‐life, easily administered, nontoxic, and efficacious is yet to be attained, new options continue to arise. Many promising drugs are in the pipeline.

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Partial volume rat lung irradiation: The protective/mitigating effects of Eukarion-189, a superoxide dismutase–catalase mimetic

Cited by 60 publications

References 45 publications

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

Comparison of two Mn porphyrin-based mimics of superoxide dismutase in pulmonary radioprotection

Development of Radiation Countermeasures

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