Myelopoietic Stimulation Following Burn Injury

在美国，重伤和败血症仍然是一个主要的健康问题。这些患者中的许多人死于感染，导致全身炎症反应有增无减和多器官衰竭。烧伤与皮肤提供的屏障和免疫保护的丧失有关。其结果是，生理、代谢、营养和免疫学参数出现严重紊乱。严重创伤和脓毒症的前哨细胞特征之一是白细胞功能失调。我们小组已经证明了骨髓生成(一种发育程序，负责许多白细胞的持续产生)在烧伤和脓毒症的病理生理学中发挥了重要作用。在上一个资助阶段，我们已经能够证明，烧伤和脓毒症通过上调M-CSF受体而增强骨髓单核细胞生成，而通过下调G-CSF受体表达而导致粒细胞生成停滞。在此期间，我们还发现了前列腺素E_2(PGE_2)和粒细胞集落刺激因子(G-CSF)在烧伤后骨髓细胞改变中起重要作用的介质。我们还证明了烫伤和脓毒症引起的骨髓单核细胞发育和祖细胞来源巨噬细胞(PDMO)功能的改变受PGE2、G-CSF以及烧伤和脓毒症的严重程度的调节。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。基于我们在之前的资助中的发现，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。我们将在我们建立的烧伤和脓毒症的小鼠模型中，在热损伤和脓毒症之后的临床相关时间测试这一前提。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是在骨髓内单核细胞发育过程中启动和启动的。细胞因子反应、吞噬和抗原提呈的变化是将被记录的细胞功能的一部分。由于烧伤和脓毒症中G-CSF水平升高会增强单核细胞的生成，第二个目标是确定G-CSF如何调节单核细胞的发育、功能和造血基因表达模式。在最后一个目的中，我们将研究G-CSF和PGE2调节单核细胞向巨噬细胞分化的能力，以及它们诱导正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潜在机制提供关键信息，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.