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Targeting the Renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage.

ABSTRACT: To investigate the outcome of suppression of the renin angiotensin system using captopril combined with an antioxidant (Eukarion [EUK]-207) for mitigation of radiation-induced lung damage in rats.The thoracic cavity of female Sprague-Dawley rats was irradiated with a single dose of 11 Gy. Treatment with captopril at a dose of 40 mg/kg/d in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week after irradiation (PI) and continuing until 14 weeks PI. Breathing rate was monitored until the rats were killed at 32 weeks PI, when lung fibrosis was assessed by lung hydroxyproline content. Lung levels of the cytokine transforming growth factor-?1 and macrophage activation were analyzed by immunohistochemistry. Oxidative DNA damage was assessed by 8-hydroxy-2-deoxyguanosine levels, and lipid peroxidation was measured by a T-BARS assay.The increase in breathing rate in the irradiated rats was significantly reduced by the drug treatments. The drug treatment also significantly decreased the hydroxyproline content, 8-hydroxy-2-deoxyguanosine and malondialdehyde levels, and levels of activated macrophages and the cytokine transforming growth factor-?1 at 32 weeks. Almost complete mitigation of these radiation effects was observed by combining captopril and EUK-207.Captopril and EUK-207 can provide mitigation of radiation-induced lung damage out to at least 32 weeks PI after treatment given 1-14 weeks PI. Overall the combination of captopril and EUK-207 was more effective than the individual drugs used alone.

SUBMITTER: Mahmood J

PROVIDER: S-EPMC4146496 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Targeting the Renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage.

Mahmood Javed J Jelveh Salomeh S Zaidi Asif A Doctrow Susan R SR Medhora Meetha M Hill Richard P RP

International journal of radiation oncology, biology, physics 20140524 4

<h4>Purpose</h4>To investigate the outcome of suppression of the renin angiotensin system using captopril combined with an antioxidant (Eukarion [EUK]-207) for mitigation of radiation-induced lung damage in rats.<h4>Methods and materials</h4>The thoracic cavity of female Sprague-Dawley rats was irradiated with a single dose of 11 Gy. Treatment with captopril at a dose of 40 mg/kg/d in drinking water and EUK-207 given by subcutaneous injection (8 mg/kg daily) was started 1 week after irradiation ...[more]

PMID: 24867538

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Project description:There is an ongoing and significant need for radiation countermeasures to reduce morbidities and mortalities associated with exposure of the heart and lungs from a radiological or nuclear incidents. Radiation-induced late effects occur months to years after exposure, stemming from significant tissue damage and remodeling, resulting in fibrosis and loss of function. TGF-β is reported to play a role in both pulmonary and cardiac fibrosis. We investigated the ability of a small molecule TGF-β receptor 1 inhibitor, IPW-5371, to mitigate the effects of thoracic irradiation in C57L/J mice, a murine model that most closely resembles that observed in humans in the induction of fibrosis and dose response. To simulate a radiological event, radiation was administered in two doses: 5 Gy total-body irradiation (eliciting a whole-body response) and immediately after that, a thoracic "top-up" of 6.5 Gy irradiation, for a total dose of 11.5 Gy to the thorax. IPW-5371 was administered once daily, orally, starting 24 h postirradiation for 6 or 20 weeks at a dose of 10 mg/kg or 30 mg/kg. Animals were monitored for a period of 180 days for survival, and cardiopulmonary injury was assessed by echocardiography, breathing rate and arterial oxygen saturation. Exposure of the thorax (11.5 Gy) induced both pulmonary and cardiac injury, resulting in a reduced life span with median survival of 135 days. IPW-5371 treatment for 6 weeks, at both 10 mg/kg and 30 mg/kg, delayed disease onset and mortality, with median survival of 165 days. Twenty weeks of IPW-5371 treatment at 30 mg/kg preserved arterial O2 saturation and cardiac contractile reserve and resulted in significant decreases in breathing frequency and cardiac and pulmonary fibrosis. This led to dramatic improvement in survival compared to the irradiated, vehicle-treated group (P < 0.001), and was statistically insignificant from the nonirradiated group. We observed that IPW-5371 treatment resulted in decreased pSmad3 tissue levels, confirming the effect of IPW-5371 on TGF-β signaling. These results demonstrate that IPW-5371 represents a potentially promising radiation countermeasure for the treatment of radiation-induced late effects.

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Targeting the Renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage.

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Targeting the Renin-angiotensin system combined with an antioxidant is highly effective in mitigating radiation-induced lung damage.

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