Mitigation of Radiation-Induced Lung Injury with EUK-207 and Genistein: Effects in Adolescent Rats

Abstract

Exposure of civilian populations to radiation due to accident, war or terrorist act is an increasing concern. The lung is one of the more radiosensitive organs that may be affected in people receiving partial-body irradiation and radiation injury in lung is thought to be associated with the development of a prolonged inflammatory response. Here we examined how effectively damage to the lung can be mitigated by administration of drugs initiated at different times after radiation exposure and examined response in adolescent animals for comparison with the young adult animals that we had studied previously. We studied the mitigation efficacy of the isoflavone genistein (50 mg/kg) and the salen-Mn superoxide dismutase-catalase mimetic EUK-207 (8 mg/kg), both of which have been reported to scavenge reactive oxygen species and reduce activity of the NFkB pathway. The drugs were given by subcutaneous injection to 6- to 7-week-old Fisher rats daily starting either immediately or 2 weeks after irradiation with 12 Gy to the whole thorax. The treatment was stopped at 28 weeks post irradiation and the animals were assessed for levels of inflammatory cytokines, activated macrophages, oxidative damage and fibrosis at 48 weeks post irradiation. We demonstrated that both genistein and EUK-207 delayed and suppressed the increased breathing rate associated with pneumonitis. These agents also reduced levels of oxidative damage (50–100%), levels of TGF-β1 expression (75–100%), activated macrophages (20–60%) and fibrosis (60–80%). The adolescent rats developed pneumonitis earlier following irradiation of the lung than did the adult rats leading to greater severe morbidity requiring euthanasia (~37% in adolescents vs. ~10% in young adults) but the extent of the mitigation of the damage was similar or slightly greater.

Radioprotection of Lung Tissue by Soy Isoflavones

“…Supplementation with soy isoflavones prior to and after radiation blocked the increase in breathing rate. These findings are in agreement with recent studies in rats showing that the genistein isoflavone or EUK-207 superoxide dismutase (SOD) catalase mimetic delayed and suppressed radiation increased breathing rate, confirming a radioprotective effect of genistein, which is the most active component of soy (24). A natural extract of soy isoflavones, containing genistein, daidzein and glycetein isoflavones, was used for the current lung study because it was found to be more potent and safer than purified genistein (10).…”

“…In contrast, lungs treated with radiation combined with soy showed milder pneumonitis and reduced fibrosis. A decrease in fibrosis caused by genistein or EUK-207 was also observed in irradiated lungs of naïve rats that could be associated with anti-oxidant and anti-inflammatory mechanisms involving inhibition of TGF-β1 expression which is a major fibrogenic cytokine (4, 24). …”

Radioprotective effects of genistein on HL-7702 cells via the inhibition of apoptosis and DNA damage

“…Some studies have demonstrated that GEN can increase the survival rate of radiation-induced myelosuppressed mice [14][15][16]. Other data demonstrated that GEN also had radioprotective effects in nonhematopoietic tissues, including the lung, testis and intestine [17][18][19]. Son et al [20] found that GEN had a protective effect on intestinal damage induced by irradiation and inhibited tumor growth.…”

Drug therapy to prevent and diminish radiation injury of the lungs

“…EUK 207 (Eukarion), также обладающий способ ностью ликвидировать активные формы кислорода, применялся у крыс путем ежедневной подкожной инъекции с момента начала и до 14 й недели после тотального облучения грудной клетки [43,44]. Пре парат обеспечил частичное смягчение симптомов лучевых повреждений легких в фазе пневмонита и поздней фазе фиброза (снижение уровня окисли тельного повреждения и количества активирован ных макрофагов), отмечен ограниченный эффект на экспрессию цитокинов.…”

“…В исследованиях [44,51] при тотальном облуче нии легких у крыс в пищу животных основной груп пы добавлялось 750 мг / кг гинестеина (изофлавон сои). Показано, что действие гинестеина направлено на частичную защиту легких от развития ранней пневмотоксичности (пневмонита) на 6-10 й неделе после лучевой терапии, уменьшение степени пнев мофиброза и увеличение сроков выживаемости жи вотных на 50-80 дней.…”