Early and late administration of MnTE-2-PyP5+ in mitigation and treatment of radiation-induced lung damage

Abstract

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.

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Both drugs are similarly potent SOD mimics with respect to k cat , yet MnTnHex-2-PyP 5þ was effective in vivo at a 120-fold lower dose (123,32). Importantly, protection was observed even when the administration started as late as 8 weeks (and lasted 2 weeks) after the lung irradiation (124). The decrease in the breathing-rate frequencies and tissue damage, and suppression of oxidative stress and signaling pathways, involving activated macrophages, HIF-1a, VEGF, and TGF-b were detected.…”

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

“…Further exploration indicated that at least one major transcription factor, NF-jB, has been inactivated by the action of MnP (240). Similarly, the radioprotective effect of MnP was demonstrated when it was given for the duration of two weeks starting at any time postradiation from 2 h up to 8 weeks (96). HIF-1a and the genes it controls (VEGF, TGF-b) have been involved (95,96).…”

“…Similarly, the radioprotective effect of MnP was demonstrated when it was given for the duration of two weeks starting at any time postradiation from 2 h up to 8 weeks (96). HIF-1a and the genes it controls (VEGF, TGF-b) have been involved (95,96). In cancer studies, the impact of MnP on activator protein-1 (AP-1) has been shown (304).…”

Advances in Mitigation of Injuries from Radiological Terrorism or Nuclear Accidents

“…In the laboratory, a wide range of late normal tissue injuries can be mitigated using therapies that are not started until days to weeks after irradiation 25,[46][47][48][49][50][51][52][53][54] . Such mitigation was first demonstrated in models of renal injury using angiotensin-converting enzyme inhibitors (ACEis) that are commonly used in human beings to treat hypertension and heart disease 46 .…”

“…A second class of agents that has shown promise for mitigation of late radiation injuries are the superoxide and catalase mimetics 25,[52][53][54] . Unfortunately, the superoxide/ catalase mimetics that show promise as radiation mitigators in laboratory studies are not yet approved for human use.…”