AEOL 10150 Mitigates Radiation-Induced Lung Injury in the Nonhuman Primate: Morbidity and Mortality are Administration Schedule-Dependent.

Pneumonitis and fibrosis are potentially lethal, delayed effects of acute radiation exposure. In this study, male rhesus macaques received whole-thorax lung irradiation (WTLI) with a target dose of 10.74 Gy prescribed to midplane at a dose rate of 0.80 ± 0.05 Gy/min using 6 MV linear accelerator-derived photons. The study design was comprised of four animal cohorts: one control and three treated with AEOL 10150 (n = 20 animals per cohort). AEOL 10150, a metalloporphyrin antioxidant, superoxide dismutase mimetic was administered by daily subcutaneous injection at 5 mg/kg in each of three schedules, beginning 24 ± 2 h postirradiation: from day 1 to day 28, day 1 to day 60 or a divided regimen from day 1 to day 28 plus day 60 to day 88. Control animals received 0.9% saline injections from day 1 to day 28. All animals received medical management and were followed for 180 days. Computed tomography (CT) scan and baseline hematology values were assessed prior to WTLI. Postirradiation monthly CT scans were collected, and images were analyzed for evidence of lung injury (pneumonitis, fibrosis, pleural and pericardial effusion) based on differences in radiodensity characteristics of the normal versus damaged lung. The primary end point was survival to 180 days based on all-cause mortality. The latency, incidence and severity of lung injury were assessed through clinical, radiographic and histological parameters. A clear survival relationship was observed with the AEOL 10150 treatment schedule and time after lethal WTLI. The day 1-60 administration schedule increased survival from 25 to 50%, mean survival time of decedents and the latency to nonsedated respiratory rate to >60 or >80 breaths/min and diminished quantitative radiographic lung injury as determined by CT scans. It did not affect incidence or severity of pneumonitis/fibrosis as determined by histological evaluation, pleural effusion or pericardial effusion as determined by CT scans. Analysis of the Kaplan-Meier survival curves suggested that treatment efficacy could be increased by extending the treatment schedule to 90 days or longer after WTLI. No survival improvement was noted in the AEOL 10150 cohorts treated from day 1-28 or using the divided schedule of day 1-28 plus day 60-88. These results suggest that AEOL 10150 may be an effective medical countermeasure against severe and lethal radiation-induced lung injury.

A non-human primate model of radiation-induced cachexia.

Cachexia, or muscle wasting, is a serious health threat to victims of radiological accidents or patients receiving radiotherapy. Here, we propose a non-human primate (NHP) radiation-induced cachexia model based on clinical and molecular pathology findings. NHP exposed to potentially lethal partial-body irradiation developed symptoms of cachexia such as body weight loss in a time- and dose-dependent manner. Severe body weight loss as high as 20-25% was observed which was refractory to nutritional intervention. Radiographic imaging indicated that cachectic NHP lost as much as 50% of skeletal muscle. Histological analysis of muscle tissues showed abnormalities such as presence of central nuclei, inflammation, fatty replacement of skeletal muscle, and muscle fiber degeneration. Biochemical parameters such as hemoglobin and albumin levels decreased after radiation exposure. Levels of FBXO32 (Atrogin-1), ActRIIB and myostatin were significantly changed in the irradiated cachectic NHP compared to the non-irradiated NHP. Our data suggest NHP that have been exposed to high dose radiation manifest cachexia-like symptoms in a time- and dose-dependent manner. This model provides a unique opportunity to study the mechanism of radiation-induced cachexia and will aid in efficacy studies of mitigators of this disease.

The Evolving Mcart Multimodal Imaging Core: Establishing a Protocol for Computed Tomography and Echocardiography in the Rhesus Macaque to Perform Longitudinal Analysis of Radiation-Induced Organ Injury.

Computed Tomography (CT) and Echocardiography (EC) are two imaging modalities that produce critical longitudinal data that can be analyzed for radiation-induced organ-specific injury to the lung and heart. The Medical Countermeasures Against Radiological Threats (MCART) consortium has a well established animal model research platform that includes nonhuman primate (NHP) models of the acute radiation syndrome and the delayed effects of acute radiation exposure. These models call for a definition of the latency, incidence, severity, duration, and resolution of different organ-specific radiation-induced subsyndromes. The pulmonary subsyndromes and cardiac effects are a pair of interdependent syndromes impacted by exposure to potentially lethal doses of radiation. Establishing a connection between these will reveal important information about their interaction and progression of injury and recovery. Herein, the authors demonstrate the use of CT and EC data in the rhesus macaque models to define delayed organ injury, thereby establishing: a) consistent and reliable methodology to assess radiation-induced damage to the lung and heart; b) an extensive database in normal age-matched NHP for key primary and secondary endpoints; c) identified problematic variables in imaging techniques and proposed solutions to maintain data integrity; and d) initiated longitudinal analysis of potentially lethal radiation-induced damage to the lung and heart.

A MALDI-MSI Approach to the Characterization of Radiation-Induced Lung Injury and Medical Countermeasure Development.

Radiation-induced lung injury is highly complex and characterized by multiple pathologies, which occur over time and sporadically throughout the lung. This complexity makes biomarker investigations and medical countermeasure screenings challenging. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) has the ability to resolve differences spatially in molecular profiles within the lung following radiation exposure and can aid in biomarker identification and pharmaceutical efficacy investigations. MALDI-MSI was applied to the investigation of a whole-thorax lung irradiation model in non-human primates (NHP) for lipidomic analysis and medical countermeasure distribution.