Critical injury and sepsis continues to be a major health concern in the US. Many of these patients succumb to infections that lead to unabated systemic inflammatory response and multiple organ failure. Burn trauma is associated with loss of the barrier and immune protection afforded by the skin. As a consequence, severe disturbances in physiological, metabolic, nutritional and immunological parameters ensue. One of the sentinel cellular features of critical injury and sepsis is the dysregulation of leukocyte function. Our group has demonstrated a significant role for bone marrow myelopoiesis (a developmental program that is responsible for the continuous production of many leukocytes) in the pathophysiology of burn injury and sepsis. In the last funding period, we have been able to demonstrate that burn injury and sepsis enhance bone marrow monocytopoiesis through upregulation of M-CSF receptors while causing granulocytopoietic arrest through a down regulation in G-CSF receptor expression. During that period we have also identified mediators, prostaglandin E2 (PGE2) and granulocyte colony stimulating factor (G-CSF) that play a significant role in the myelopoietic alterations of burn injury. We have also demonstrated that the thermal injury and sepsis-mediated alterations in monocyte development in the bone marrow and the function of progenitor derived macrophages (PDMo) are regulated by PGE2, G-CSF and by the severity of burn injury and sepsis. The responses of PDMo are similar to the responses of peritoneal macrophages (PMo) emphasizing the relevance of PDMo to the pathobiology of injury and sepsis. Building on our findings during the previous funding, we propose to study the regulation of bone marrow monocyte development and function by the micro-environmental changes imposed by thermal injury and sepsis. We will test this premise in our established murine model of burn injury and sepsis at clinically relevant times following thermal injury and sepsis. In the first aim we will establish that functional phenotype of monocytes and macrophages in burn injury and sepsis is initiated and set in motion during monocyte development within the bone marrow. Changes in cytokine responses, phagocytosis, and antigen presentation are some of the cellular functions that will be documented. Since monocytopoiesis is enhanced in the presence of elevated G-CSF levels in burn injury and sepsis, second aim will establish how G-CSF may moduate monocyte development, function and hematopoietic gene expression patterns. In the last aim, we will study the capacity of G-CSF and PGE2 to modulate monocyte progenitor differentiation into macrophages and their ability to induce gentotypic and phenotypic changes. Completion of these aims will provide critical information on mechanisms underlying the observed macrophage phenotypic heterogeneity seen under injury conditions and allow us to appropriately formulate, and test new therapies against sepsis.
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