Role of the CD73/adenosine system for radiation-induced normal tissue toxicity in the lung

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The CD73/adenosine system is an important endogenous regulator of tissue homeostasis in the lung. Dependent on the cellular context it exerts pro-inflammatory, anti-inflammatory or regeneration-promoting effects. Own previous work shows that loss of CD73 protects C57Bl/6 mice from radiation-induced fibrosis suggesting a disease-promoting effect of CD73 for this dose-limiting side effect of thorax or whole body irradiation. In the proposed project we aim at (i) a detailed analysis of the time course of radiation-induced activation of the CD73/adenosine system, (ii) the elucidation of the role of CD73 and adenosine for the creation of pro-fibrotic signals in the irradiated lungs, and (iii) the identification of the involved cellular and molecular mechanisms in a murine model (iv) Finally, the benefit of a pharmacologic inhibition of CD73 for the prevention of radiation-induced fibrosis in irradiated wild type mice will be evaluated. These investigations shall provide a scientific basis for a future exploitation of the CD73/adenosine system as a pharmacological target for the prevention or treatment of radiation-induced unwanted late effects after therapeutic whole-body or thorax irradiation.