SYSTEMIC HOST DEFENSE FOLLOWING TRAUMA

创伤后的系统性宿主防御

基本信息

批准号：
3270504
负责人：
THOMAS G SABA
金额：
$ 19.11万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1977
资助国家：
美国
起止时间：
1977-12-01 至 1993-06-30
项目状态：
已结题

项目摘要

The macrophage system or reticuloendothelial system (RES) is important to host defense against trauma, burn, sepsis, and intravascular coagulation. Plasma fibronectin is identical to cold-insoluble globulin or opsonic Alpha2 glycoprotein. It has domains with high affinity for denatured collagen, fibrin, actin, certain bacteria, and injured tissues. Plasma fibronectin is an opsonic protein which augments macrophage phagocytic clearance of nonbacterial particulates such as collagenous debris, cytoskeletal debris, and products of intravascular coagulation and sepsis. Plasma fibronectin deficiency exists in patients early after major surgery, trauma and burn and is often further depressed with sepsis post-trauma. Post-trauma pulmonary insufficiency may be, in part, mediated by lung microembolization and vascular injury due to the co-existence of RES depression, increased blood-borne nonbacterial particulates and pulmonary leukostasis. Reversal of this opsonic deficiency in patients can be accomplished by infusion of purified fibronectin or fibronectin-rich plasma cryoprecipitate. Our goal is to define the importance of plasma fibronectin deficiency and RES phagocytic failure in the etiology of multiple organ failure during sepsis following trauma or burn. We hypothesize that plasma fibronectin deficiency contributes to RES phagocytic depression after trauma. Since plasma fibronectin incorporates into the lung adhesive "tissue fibronectin" pool, disturbances of fibronectin may also alter lung vascular permeability. This interdisciplinary project will investigate the: 1) influence of surgical trauma and burn with or without sepsis on plasma fibronectin, opsonic activity and RES function; 2) mechanism of restoration of plasma fibronectin after injury and influence of burn and surgery with or without sepsis on plasma fibronectin synthesis; 3) influence of sepsis and injury on clearance kinetics and tissue distribution of plasma fibronectin as well as lung tissue content of extractable fibronectin; 4) effect of activated leukocytes on fragmentation of matrix fibronectin and endothelial cell adhesion in vitro; 5) opsonic activity of fibronectin produced by endothelial cells, Kupffer cells, and hepatocytes; 6) influence of plasma fibronectin on RES function and survival during sepsis after surgery or burn in rats; 7) influence of therapy with human plasma fibronectin on RE function and lung transvascular protein clearance in sheep during post-operative sepsis; and 8) influence of fibronectin-rich cryoprecipitate on organ function in septic trauma and burn patients. Our long-range goal is to improve the treatment of organ failure in septic burn and trauma patients.

巨噬细胞系统或网状内皮系统（RES）对于宿主对创伤、烧伤、败血症和血管内凝血的防御。血浆纤连蛋白与冷不溶性球蛋白或调理素相同 α2糖蛋白。它具有对变性具有高亲和力的结构域胶原蛋白、纤维蛋白、肌动蛋白、某些细菌和受伤的组织。等离子体纤连蛋白是一种调理蛋白，可增强巨噬细胞的吞噬能力清除非细菌颗粒，例如胶原碎片，细胞骨架碎片以及血管内凝血和败血症的产物。大手术后早期患者存在血浆纤连蛋白缺乏症，外伤和烧伤，并且经常因外伤后脓毒症而进一步抑郁。创伤后肺功能不全可能部分由肺介导 RES共存导致的微栓塞和血管损伤抑郁症、血源性非细菌颗粒物增加和肺部疾病白细胞停滞。逆转患者的这种调理缺陷可以通过输注纯化的纤连蛋白或富含纤连蛋白的血浆来完成冷沉淀。我们的目标是明确血浆的重要性纤连蛋白缺乏和 RES 吞噬细胞衰竭的病因创伤或烧伤后败血症期间的多器官衰竭。我们假设血浆纤连蛋白缺乏导致 RES 创伤后吞噬细胞抑制。由于血浆纤连蛋白含有进入肺粘连“组织纤连蛋白”库，扰乱纤连蛋白还可能改变肺血管通透性。这跨学科项目将调查：1）手术的影响创伤和烧伤伴或不伴脓毒症血浆纤连蛋白、调理剂活性和RES功能； 2) 血浆修复机制损伤后纤连蛋白以及烧伤和手术有或没有的影响脓毒症对血浆纤连蛋白合成的影响； 3）败血症和损伤的影响血浆纤连蛋白的清除动力学和组织分布作为可提取纤连蛋白的肺组织含量； 4）激活效果白细胞对基质纤连蛋白和内皮细胞碎片的影响体外粘附； 5) 纤连蛋白的调理活性内皮细胞、库普弗细胞和肝细胞； 6) 等离子体的影响纤连蛋白对手术后败血症期间 RES 功能和生存的影响大鼠烧伤； 7)人血浆纤连蛋白治疗对RE的影响绵羊的功能和肺经血管蛋白清除率术后败血症； 8) 富含纤连蛋白的冷沉淀的影响对脓毒症创伤和烧伤患者器官功能的影响。我们的长期目标是为了改善化脓性烧伤和创伤中器官衰竭的治疗患者。