Myelopoietic Stimulation Following Burn Injury

严重损伤和败血症仍然是美国的主要健康问题。这些患者中的许多人死于感染，导致全身炎症反应和多器官衰竭。烧伤创伤与皮肤提供的屏障和免疫保护的丧失有关。因此，生理、代谢、营养和免疫参数的严重紊乱随之而来。严重损伤和脓毒症的前哨细胞特征之一是白细胞功能失调。我们的研究小组已经证明了骨髓造血（一种负责持续产生许多白细胞的发育程序）在烧伤和脓毒症的病理生理学中的重要作用。在上一个资助期，我们已经能够证明烧伤和脓毒症通过上调M-CSF受体增强骨髓单核细胞生成，同时通过下调G-CSF受体表达引起粒细胞生成停滞。在此期间，我们还确定了介质，前列腺素E2（PGE 2）和粒细胞集落刺激因子（G-CSF），发挥了重要作用，在烧伤的骨髓造血改变。我们还证明了热损伤和脓毒症介导的骨髓中单核细胞发育和祖细胞衍生的巨噬细胞（PDMo）功能的改变受PGE 2、G-CSF以及烧伤和脓毒症的严重程度调节。PDMo的反应类似于腹膜巨噬细胞（PMo）的反应，强调了PDMo与损伤和脓毒症的病理生物学的相关性。基于我们在先前资助期间的发现，我们建议研究热损伤和脓毒症引起的微环境变化对骨髓单核细胞发育和功能的调节。我们将在热损伤和脓毒症后的临床相关时间，在我们建立的烧伤和脓毒症小鼠模型中测试这一前提。在第一个目标中，我们将确定烧伤和脓毒症中单核细胞和巨噬细胞的功能表型在骨髓内单核细胞发育期间启动并启动。细胞因子反应、吞噬作用和抗原呈递的变化是将记录的一些细胞功能。由于单核细胞生成在烧伤和脓毒症中G-CSF水平升高的情况下增强，第二个目标将确定G-CSF如何调节单核细胞发育、功能和造血基因表达模式。在最后一个目标中，我们将研究G-CSF和PGE 2调节单核细胞祖细胞分化为巨噬细胞的能力及其诱导基因型和表型变化的能力。这些目标的完成将为在损伤条件下观察到的巨噬细胞表型异质性的机制提供关键信息，并使我们能够适当地制定和测试针对脓毒症的新疗法。

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.