Burn injury is accompanied by marked changes in host defense mechanisms. Despite advances in topical and systemic antimicrobial therapy and techniques of wound closure, sepsis remains the main cause of mortality in severely burned patients. Successful host defense and repair after thermal injury is, in part, dependent on the presence of adequate numbers of functionally competent highly motile myeloid cells such as granulocytes, monocytes and macrophages. However, myelosuppression has been demonstrated following thermal injury and is felt to be in part responsible for the altered susceptibility of burn injured victims to infection. The recent availability of recombinant hematopoietic growth factors allows modulation of the numbers and functions of myeloid elements in an attempt to improve host resistance to infection. We propose to systematically analyze the effects of burn injury as well as bacterial burn wound seeding on the myelopoietic response in mice. We will seek to determine the capability of human recombinant granulocyte colony-stimulating factor (G-CSF) to significantly improve survival and augment the myeloid response following injury. G-CSF will be tested alone and in combination with granulocyte colony-stimulating factor (GM- CSF) and Interleukin-1 beta (1L-1 beta) and/or conventional antimicrobial therapy on ameliorating myelosuppression and altering outcome. Potential toxicities associated with large numbers of activated neutrophils and monocytes will be systematically analyzed by performing complete necropsy, histopathologic analysis and bronchopulmonary lavage fluid assay. These studies will provide information to further characterize the myelopoietic response following burn injury and infection of the burn wound, the safety and efficacy of hematopoietic stimulants in the setting of response to burn injury represents a prototypical response to trauma and sepsis and, therefore, knowledge gained in the study of burn injury is applicable to postsurgical and posttraumatic infectious complications.
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