Despite advances in critical care, patients with major burns remain at significant risk for septic complications. Previous work from our laboratory has shown that in the murine model of thermal injury and superimposed sepsis there is a bone marrow myeloid shift resulting in increased monocytopoiesis and arrest in granulocytopoiesis. Although sympathetic stimulation is known to accompany both clinical and experimental thermal injury and adrenergic stimulation modulates immune cell function, cytokine release and myelopoiesis under non-stressed conditions there is a lack of information on bone marrow noepinephrine (NE) release during trauma and its impact on myeloid commitment. Therefore, we hypothesize that burn injury and sepsis lead to increased bone marrow NE release which influences myeloid commitment and thus contributes to the subsequent cytokine dysregulation. We will test this premise in Specific Aim #1 by establishing that bone marrow sympathetic nerves are activated with thermal injury and sepsis leading to increased release of norepinephrine. Using pharmacologic, surgical and genetic models of sympathetic denervation we will establish that monocytopoiesis and granulocytopoiesis consequent to bum with infection are mediated by adrenergic stimulation in bone marrow.
Specific Aim #2 will establish that bone marrow sympathetic stimulation with burn plus sepsis changes monocyte as well as monocyte progenitors to release enhanced amounts of cytokine in response to bacterial endotoxin. Using both tissue macrophage and those derived from bone marrow progenitors, cytokine responses to endotoxin as well as phagocytosis and chemotaxis will be determined in mice with denervated compared to neural intact bone marrow. Having established the role of sympathetic stimulation in mediating changes bone marrow myeloid commitment and function Specific Aim #3 will focus on the elucidation of cellular mechanisms by which NE mediates the observed changes.
This aim will use paradigms involving bone marrow monocyte progenitor cells subjected to adrenergic agomsts and antagonists to examine the proliferation and differentiation. Such findings will be extended using murine and human monocytic cell lines to investigate specific cell-signaling mechanisms. Results of the proposed research will provide important new information on the pathophysiology of thermal injury and sepsis and will lead to therapeutic approaches to enhance the survival of the critically injured.
