Long-Term Administration of a Small Molecular Weight Catalytic Metalloporphyrin Antioxidant AEOL 10150 Protects Lungs From Radiation-Induced Injury

Abstract

Purpose-To determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N′-diethylimidazolium-2-yl) porphyrin, AEOL 10150, with SOD mimetic properties reduces the severity of radiation-induced injury to the lung from single dose irradiation (RT) of 28 Gy.Materials/Methods-Animals were randomly divided into four different dose groups (0, 1, 10 and 30 mg/kg/day of AEOL 10150), receiving either short (1 week) or long-term (10 weeks) drug administration via osmotic pumps. Animals received single dose irradiation (RT) of 28 Gy to the right hemithorax. Breathing rates, body weights, blood samples, histopathology and immunohistochemistry were used to assess lung damage.Results-There was no significant difference in any of the study endpoints between the irradiated controls and the 3 groups receiving RT and short-term administration of AEOL 10150. For the long term administration functional determinants of lung damage 20 weeks post radiation were significantly worse for RT+PBS and RT+1mg/kg/day of AEOL 10150 as compared to the irradiated groups treated with higher doses of AEOL 10150 (10 or 30mg/kg/day), Lung histology at 20 weeks revealed a significant decrease in structural damage and collagen deposition in animals receiving 10 or 30mg/kg/day after radiation in comparison to RT+PBS and 1mg/kg/day groups. Immunohistochemistry demonstrated a significant reduction in macrophage accumulation, oxidative stress and hypoxia in animals receiving AEOL 10150 (10 or 30mg/kg/day) after lung irradiation compared to RT+PBS and 1mg/kg/day groups. Conclusion-The chronic administration of novel catalytic antioxidant, AEOL 10150, demonstrates a significant protective effect from radiation-induced lung injury. AEOL 10150 has its primary impact on the cascade of events following irradiation and adding drug prior to irradiation and its short-term administration have no significant additional benefits.

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…At 26 weeks after single-dose irradiation, and 16 weeks after the administration of Mn porphyrin ceased, rat pulmonary radioprotection was detected with respect to oxidative stress, lung histology, and collagen deposition. MnTDE-2-ImP 5þ was administered for 10 weeks (10 and 30 mg=kg=day, subcutaneous osmotic pumps) starting at 24 h after 28-Gy right hemithorax radiation (257). Similar effects were observed with fractionated radiation, in which the injection of MnP started 15 min before radiation (258).…”

“…When mice were treated 14 days before whole-body radiation with MnTM-2-PyP 5þ at 5 mg=kg, *80% survival was observed. The imidazolyl derivative, MnTDE-2-ImP 5þ , also was radioprotective in two studies with single and fractionated radiation (257,258). At 26 weeks after single-dose irradiation, and 16 weeks after the administration of Mn porphyrin ceased, rat pulmonary radioprotection was detected with respect to oxidative stress, lung histology, and collagen deposition.…”

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

“…12 mm lead blocks were used to protect the left thorax and the rest of the body. This is a prerequisite for studying long-term changes (months, [5,6,11,13]) after RT which might not be tolerated by the animals if both lungs were irradiated with 28 Gy, a dose necessary to induce a robust fibrotic damage in the lung.…”

“…Image analysis was carried out as previously described [13]. Eight digital images were acquired from each slide using a 20x (VEGF, TGF-β, CA-IX, ED-1) or 40x (HIF-1, 8-OHDG) objective.…”

“…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].…”