Although radiation remains an important therapeutic modality in the treatment of malignancies, there is no effective treatment for the resulting injury to the Gl tissue. Preliminary observations in the Brown lab have demonstrated the ability of myeloid progenitor cells (MP) to attenuate radiation-induced Gl injury in addition to the previously observed mitigation of hematopoietic injury. The experiments described in this proposal aim to characterize this role of MP. The hypothesis of this proposal is that direct cellular disruption, upregulation of chemokine/cytokine production, microbial invasion in the setting of impaired innate immunity and coagulation all contribute to Gl injury induced by radiation. Furthermore, the repletion of the myeloid/megakaryocyte progenitor pools will protect against radiation-induced injury by the replacement of hematopoietic precursors and immunomodulation of the gastrointestinal mucosa.
The specific aims of this proposal will address this hypothesis by characterizing the capacity of MP to protect in the setting of different MP doses, administration of MP at different times after irradiation and with increasing radiation dose. The effect of MP on hematopoietic reconstitution will also be examined. To address Gl damage, the trafficking of MP and MP-derived cells to the Gl tract will be examined in addition to the effect of MP administration on Gl tract histology, epithelial and endothelial cell proliferation and apoptotic death and production of reactive oxygen species. The levels of cytokines and chemokines in the serum and Gl tissue following irradiation and MP infusion will be quantified. In addition, the effect of MP administration on the reduction in translocation of bacterial pathogens through the gastrointestinal mucosa will also be examined. Altogether the proposed experiments will characterize the role of MP in mitigation of radiation-induced Gl damage and will determine the mechanism of the protective effect mediated by MP. Several studies have chronicled the significant clinical and economic burdens of mucositis whether induced by radiation or chemotherapy or both. Patients that develop mucositis in the setting of neutropenia have an increased incidence of infection and infection-related mortality. In the setting of hematopoietic cell transplantation (HCT), conditioning or preparative regimens commonly include total body or total lymphoid irradiation and are at high risk for complications related to the Gl tract. Furthermore, mucositis is a frequent dose-limiting side effect of cancer therapies and may, thus, influence cancer-free survival. These findings highlight the importance of research in this area to public health. ? ? ?
