Triterpenoids in mitigation of radiation induced acute or delayed inflammation

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Project Summary Currently, there is a need for strategies that mitigate acute and delayed radiation syndrome. The risk of large populations encountering radiation exposure is real and growing. Radiation induced inflammation plays significant role in inducing radiation toxicity. Chemokine signaling plays key role in systemic and local inflammation by modulating egress and recruitment inflammatory immune cells such as inflammatory monocytes and T cells. Radiation exposure induces recruitment of inflammatory cells and promotes systemic and local inflammation. We have observed that deletion of genes expressing chemokine receptor 2 in mice promotes resistance radiation induced acute and delayed inflammation. Triterprenoids are very potent anti-inflammatory agents. Recent findings suggest that synthetic derivatives of oleanolic acid that are more potent at suppressing production of the inflammatory mediator such as chemokine ligand 2. Under NIAID Chemical Countermeasures Research Program (CCRP) Triterprenoids such as CDDO- methyl ester (CDDO-Me) has been shown to mitigate chemical induced ocular injury by nrf2 dependent manner. In this proposal we will examine the effect of CDDO- Me against radiation induced acute and delayed inflammation using mice model of radiation induced gastrointestinal syndrome and radiation induced pulmonary syndrome respectively. We will also characterize the effect of CDDO-Me in modulation of bone marrow derived inflammatory immune cell recruitment in injured tissue. Determination of mechanism of action of will facilitate CDDO-Me as a medical countermeasure against radiation under the FDA’s Animal Rule.