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Mechanisms Regulating Pulmonary Sensitivity to Radiation by Isabel

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Mechanisms Regulating Pulmonary Sensitivity to Radiation by Isabel Mechanisms Regulating Pulmonary Sensitivity to Radiation by Isabel Lauren Jackson Department of Pathology Duke University Date: _______________________ Approved: ___________________________ Zeljko Vujaskovic, Supervisor ___________________________ Mark W. Dewhirst ___________________________ Mary Elizabeth Sunday ___________________________ Laura Hale ___________________________ Salvatore Pizzo Dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pathology in the Graduate School of Duke University 2012 ABSTRACT Mechanisms Regulating Pulmonary Sensitivity to Radiation by Isabel Lauren Jackson Department of Pathology Duke University Date:_______________________ Approved: ___________________________ Zeljko Vujaskovic, Supervisor ___________________________ Mark W. Dewhirst ___________________________ Mary E. Sunday ___________________________ Laura Hale ___________________________ Salvatore Pizzo An abstract of a dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pathology in the Graduate School of Duke University 2012 Copyright by Isabel Lauren Jackson 2012 Abstract At the present time, there is no approved medical countermeasure (MCM) for mitigating or treating pneumonitis/fibrosis following acute radiation eXposure. Since it is neither ethical nor feasible to evaluate potential MCMs against radiation injury in the clinical setting, the FDA permits MCM licensure under an alternative drug development pathway (“Animal Efficacy Rule”) that relies on the predictive validity of animal models. The purpose of the current project was to design a research platform that addresses many of the critical knowledge gaps associated with successful adherence to the FDA Animal Rule. In these studies, we evaluated the dose-response relationship for survival and functional injury among CBA/J, C57L/J, and C57BL/6J mouse strains. These strains were previously identified to represent the full spectrum of pulmonary pathology associated with acute radiation eXposure to the thoraX. We neXt evaluated ultrastructural pathology to identify differences in tissue response among strains as early as twenty-four hours after radiation. Global differential gene eXpression analysis was utilized to identify the major signaling pathways and genes associated with the development of radiation pneumonitis and/or fibrosis by eXploiting the phenotypic differences in radiation-injury among strains. Genes with significant differences were validated by quantitative real- time polymerase chain reaction and their protein products validated by western blot. iv Finally, we performed longitudinal analysis of hypoXia-associated gene expression to elucidate the natural history of disease progression in “fibrosis prone” C57BL/6J mice. In these studies, we identified significant differences in the dose-response, temporal onset, disease progression, and pathologic manifestations of radiation lung injury among murine strains. The severity of ultrastructural damage at twenty-four hours also differed among strains indicating the early tissue response to the radiation insult was dissimilar. A significant difference was found in gene eXpression among strains. The most interesting differences were associated with the acute-phase response, iron homeostasis, cell cycle/proliferation, and cell death. Lastly, hypoXia-associated gene eXpression, including hypoXia-inducible factor-1 alpha (HIF-1α) and HIF-2α mRNA and protein stabilization, was dynamically altered during the temporal course of radiation pathogenesis in the “fibrosis-prone” C57BL/6J mice. As the C57BL/6J strain is more “resistant” to radiation-induced lung injury, a better understanding of the pathways involved in tissue response to radiation in this strain might elucidate the mechanisms that make the lungs of this strain significantly more radiotolerant than their counterparts. The research platform developed in this project provides essential information to interpret and define the compleX interrelationships in clinically relevant models of the human response to potentially lethal irradiation and treatment. The overall goal is to provide a rigorous scientific platform for MCM development under the Animal Efficacy v Rule with reasonable eXpectation that MCMs acquired for the Strategic National Stockpile will effectively prevent, treat, or mitigate radiation-induced lung injury and improve survival among the eXposed population. vi Dedication To my Father, who taught me the value of hard work; To my Mother, who taught me to believe in myself; To my Sister, for my being my closest friend; To Zeljko, for always providing support and encouragement vii Contents Abstract .......................................................................................................................................... iv Dedication .................................................................................................................................... vii List of Tables ............................................................................................................................... xiii List of Figures ............................................................................................................................. xiv Acknowledgements ................................................................................................................... xvi Abbreviations ............................................................................................................................ xxii 1. Background ............................................................................................................................. 1 1.1 Ionizing Radiation ............................................................................................................ 1 1.1.1 From Discovery to Application ................................................................................. 1 1.1.2 Principles of Radiation ................................................................................................ 4 1.1.2.1 Radiation Units ..................................................................................................... 4 1.1.2.2 Radiation Types .................................................................................................... 6 1.2 Medical Aspects of Ionizing Radiation Exposure ...................................................... 10 1.2.1 Radiation Threats ...................................................................................................... 10 1.2.2 Medical Syndromes Associated with Radiation Exposure ................................. 16 1.2.2.1 Adverse health effects of low dose radiation exposure ............................... 16 1.2.2.2 Acute radiation syndrome/delayed effects of acute radiation exposure ... 18 1.2.3 Medical Management of Acute and Delayed Radiation Sickness ...................... 25 1.3 Radiation-Induced Lung Injury .................................................................................... 29 1.3.1 Radiation-induced lung injury: relevance and clinical pathology ..................... 29 viii 1.3.2 Physiologic effects and molecular mechanisms of radiation-induced lung injury .................................................................................................................................... 33 1.3.3 Pre-clinical murine models of radiation-induced lung injury ............................ 44 1.4 Drug Discovery, Development, and Acquisition for the Strategic National Stockpile: Meeting the FDA Animal Efficacy Rule Criteria ........................................... 49 1.4.1 Drug licensure through the FDA “Animal Efficacy Rule” .................................. 49 1.4.2 Importance of logistical, medical, and scientific challenges to drug development for DEARE-lung ......................................................................................... 51 1.5 Research Objectives ........................................................................................................ 56 1.6 Summary .......................................................................................................................... 57 2. Experimental Procedures ....................................................................................................... 60 2.1 Methods for development of a pre-clinical animal research model for radiation- induced lung injury .............................................................................................................. 60 2.1.1 Animals ....................................................................................................................... 60 2.1.2 Radiation ..................................................................................................................... 60 2.1.3 Survival Analysis ....................................................................................................... 61 2.1.4 Analysis of Respiratory Function ............................................................................ 62 2.1.5 Gross Morphology and Histopathology ................................................................ 62 2.1.6 Statistical Design and Analysis ............................................................................... 63 2.2 Methods for differential gene expression analysis and validation ......................... 63 2.2.1 Animals and Radiation EXposure ..........................................................................
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