Norepinephrine modulates myelopoiesis after experimental thermal injury with sepsis.

Profound release of sympathetic neurotransmitters and hormones through activation of the autonomic nervous system is the central feature of the traditional cognitive “fight or flight” stress response. 1–3 In addition to cognitive stress, clinical examples of traumatic injury and bacterial infection also provoke intense sympathetic responses that may have important consequences on the death and complication rates. 4–9 Sympathetic responses to thermal injury, bacterial infection, or a combined insult are likely to serve important compensatory functions in maintaining both cardiovascular and metabolic homeostasis. 10–14 The more important question regarding sympathetic activation in thermal injury involves its potential influence on immune function. Indeed, severe thermal injury results in increased susceptibility to infection, 15,16 and patients with severe burn trauma often display significant impairment in cell-mediated immunity involving defective neutrophil chemotaxis, phagocytosis, and superoxide production. 17–20 Patients with sepsis and systemic inflammatory response may also have monocytosis, 21,22 suggesting excessive cytokine production through increased circulating and tissue monocyte/macrophages. Because adrenergic mechanisms are reported to be involved in various host-defense functions, 23–25 we have begun to consider the possibility that sympathetic activation after thermal injury may in some way contribute to the immune components of the pathophysiology. Investigations into mechanisms that could account for the immunosuppression of patients with severe burns have focused primarily on functional alterations in circulating and tissue leukocytes. 26–33 In contrast, our group has focused on the bone marrow responses that follow thermal injury with sepsis, because the bone marrow is a major source of immune cells both in the circulation and tissues. Using a murine model, we have demonstrated that severe thermal injury with sepsis results in a shift in myeloid commitment toward monocytopoiesis and away from granulocytopoiesis. 34,35 Several key factors suggest the possibility that the observed changes in myelopoiesis may be in part mediated by sympathetic nerve activation associated with thermal injury. First, adrenergic signaling has been shown by others to function in the regulation and control of hematopoiesis. 36,37 Maestroni and Conti 37 have shown the presence of adrenergic receptors on bone marrow immune cells and have also shown that adrenergic agonists stimulate lymphopoiesis while attenuating myelopoiesis. These findings are strengthened by work in different animal models showing that adrenergic agents can modulate lymphopoiesis and myelopoiesis. 38–41 A second important finding is the demonstration of sympathetic activation in the bone marrow compartment itself, where nerve-stimulated release of norepinephrine could reach high concentrations in close proximity to proliferating immune cells. We have recently reported the increase in bone marrow norepinephrine release in response to either cold exposure or bacteria 42 through the use of traditional pulse-chase experiments. More recently we have extended such measurements to our murine model of burn sepsis in preliminary experiments and showed increased bone marrow norepinephrine release in response to burn sepsis. 43 Taken together, these findings argue for a relation between sympathetic activation and alterations in the bone marrow production of immune cells that may lead to the development of opportunistic bacterial infection. Whereas experimental evidence suggests adrenergic regulation of myelopoiesis under normal conditions, evidence demonstrating such cause-and-effect relationships in injury states has never been examined. Therefore, we hypothesize that immune alterations induced by burn sepsis are mediated at least in part by sympathetic modulation of myelopoiesis in bone marrow consequent to the burn trauma. We tested this premise of neural modulation of myeloid function in our murine model of thermal injury and infection by manipulating the peripheral stores of norepinephrine. Peripheral norepinephrine levels were reduced by using 6-hydroxydopamine (6-OHDA), and then animals were subjected to burn sepsis. Whereas bone marrow cells taken from mice subjected to burn sepsis and increased bone marrow norepinephrine release showed an increase in monocytopoietic potential, mice with reduced bone marrow norepinephrine stores did not. These results suggest that injury-induced sympathetic responses may have marked effects on bone marrow progenitor cells and may significantly alter leukocyte production after traumatic injury.