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.

Introduction Chronic production of reactive oxygen and nitrogen species is an underlying mechanism of radiation (IR)-induced lung injury. The purpose of this study was to determine the optimum time of an antioxidant and redox-modulating Mn porphyrin, MnTE-2-PyP5+, delivery to mitigate and/or treat IR-induced lung damage. Methods Female Fischer-344 rats were irradiated to their right hemithorax (28 Gy). Irradiated animals were treated with PBS or MnTE-2-PyP5+ (6 mg/kg/24h) delivered for 2 weeks by s.c.- implanted osmotic pumps (beginning after 2, 6, 12, 24, 72 hours or 8 weeks). Animals were sacrificed 10 weeks post IR. Endpoints were: body weight, breathing frequency, histopathology, and immunohistochemistry (8-OHdG; ED-1; TGF-β; HIF-1α; VEGF [A]). Results A significant radioprotective effect on functional injury, measured by breathing frequencies, was observed for all animals treated with MnTE-2-PyP5+. Treatment with MnTE-2-PyP5+ starting 2 h, 6 h, and 12 h but not after 24 h or 72 h resulted in a significant decrease in immunostaining for 8-OHdG, HIF-1α, TGF-β, and VEGF (A). A significant decrease in HIF-1α, TGF-β, and VEGF (A), as well as an overall reduction in lung damage (histopathology) was observed in animals beginning treatment at the time of fully developed lung injury (8 weeks post IR). Conclusion The catalytic manganese porphyrin antioxidant and modulator of redox-based signalling pathways, MnTE-2-PyP5+, mitigates radiation-induced lung injury when given within the first 12 hours after IR. More importantly, this is the first study to demonstrate MnTE-2-PyP5+ can reverse overall lung damage when started at the time of established lung injury 8 weeks post IR. The radioprotective effects are presumably mediated through both its ability to suppress oxidative stress as well as to decrease activation of key transcription factors and proangiogenic and profibrogenic cytokines.

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