MYELOPOIETIC STIMULATION FOLLOWING BURN INJURY

烧伤伴随着宿主防御的显著变化。尽管 局部和全身抗菌治疗及治疗技术进展 伤口闭合、脓毒症仍是严重烧伤患者死亡的主要原因 烧伤的病人。烫伤后成功的宿主防御与修复 在一定程度上取决于是否存在足够数量的功能 具有高度运动性的髓系细胞，如粒细胞、单核细胞和 巨噬细胞。在之前的两个资助时期，使用我们的小鼠 热损伤+感染模型，我们发现：明显改变 髓系的产生和功能；能够通过以下方式提高存活率 应用G-CSF、IL-1或GM-CSF；G-CSF可导致WBC增加 和中性粒细胞计数，增加股骨骨髓的数量 粒细胞-巨噬细胞前体细胞(GM-CFCs)，腹膜激发 粒细胞，中性粒细胞趋化功能缺陷的恢复； 环氧合酶抑制导致GM-CFCs数量和WBC增加， 烧伤+感染后GM-CFCs DNA有明显变化 合成活动；在正常动物和烧伤动物中，我们可以复制这一点 用内毒素注射，并用消炎痛阻断。我们的假设是 烧伤+感染通过内毒素介导的事件改变骨髓生成 从而增强巨噬细胞前列腺素E_2的产生。具体目标是 这笔拨款是为了：1)研究控制变化的机制 在烧伤后的骨髓反应=/-感染；2)确定 外源性造血生长作用机制的研究进展 各种因素。通过使用我们的小鼠烫伤模型，粒细胞- 巨噬细胞克隆性培养直接评价骨髓增殖性 用氚胸苷自杀试验技术进行活性评估 粒细胞和巨噬细胞功能及巨噬细胞分泌物分析 产品，我们将确定在此范围内发生的网络连接 细胞系统，促进和抑制其反应。更大 体温过高后宿主防御系统的变化 损伤将为制定新的治疗方法提供基础 战略。

Burn injury is accompanied by marked changes in host defense. Despite advances in topical and systemic antimicrobial therapy and techniques of wound closure, sepsis remains the main cause of mortality in severely burned patients. Successful host defense and repair after thermal injury is, in part, dependent on the presence of adequate numbers of functionally competent highly motile myeloid cells such as granulocytes, monocytes, and macrophages. During two previous grant-funded periods, using our murine model of thermal injury + infection, we found: marked alterations in myeloid production, and function; were able to improve survival by administration of G-CSF, IL-1, or GM-CSF; G-CSF resulted in increased WBC and neutrophil counts, an increase in the number of femoral marrow granulocyte-macrophage progenitor cells (GM-CFC), peritoneal elicitation of granulocytes, and a restoration in defective neutrophil chemotaxis; cyclooxygenase inhibition caused an increase in GM-CFC numbers and WBC, that following burn + infection there is a marked alteration in GM-CFC DNA synthetic activity; in normals and burn animals, we can replicate this pattern with endotoxin and block this with indomethacin. Our hypothesis is that burn injury + infection alters myelopoieses via LPS mediated events resulting in enhanced macrophage PGE2 production. The specific aims for this grant are to: 1) Investigate the mechanisms controlling alterations in myeloid response following burn =/- infection; 2) Determine the mechanisms of action of exogenously administered hematopoietic growth factors. By use of our murine model of thermal injury, granulocyte- macrophage clonal culture, direct assessment of marrow proliferative activity with the tritiated thymidine suicide assay technique, assessment of granulocyte and macrophage function and analysis of macrophage secretor products, we will determine the networking which is occurring within this cell system, facilitating, as well as inhibiting, its response. Greater understanding of the alterations in the host defense subsequent to thermal injury will provide the basis upon which to formulate new treatment strategies.