TRAUMA & ORGAN FAILURE--ROLE OF LPS BINDING PROTEIN

创伤

• 批准号: 6164814
• 负责人: STEWART C WANG
• 金额: $ 10.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-03-01 至 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164814
• 关键词: bacterial toxins; binding proteins; endotoxins; gram negative bacteria; immune tolerance /unresponsiveness; inflammation; kidney cell; laboratory rat; lipopolysaccharides; liver cells; multiple organ failure; protein biosynthesis; protein structure function; respiratory epithelium; trauma

Sepsis and septic shock are still major causes of morbidity and mortality among critically ill surgical patients. During gram-negative sepsis, endotoxins (LPS) binds to CD14 receptors on mononuclear cells, causing release of inflammatory mediators which can cause tissue injury and organ failure. LPS-binding protein (LBP) enhances binding of LPS to the CD14 complex. When bound to LBP, many fold smaller concentrations of LPS can activate host cells. We have recently been the first to report that LBP production is induced in extrahepatic tissues in rats by injury. We have now confirmed extrahepatic LBP production in humans also. We hypothesize that locally produced LBP modulates the local immune response to LPS and Gram-negative infection, serving to localize the infecting agent and focusing host defenses at the local site. If, however, the local immune activation is too great and spills into the circulation or if the activation persists for too long, extrahepatic induction of LBP may predispose toward MSOF. We propose to study the factors controlling the production of LBP by cells other than hepatocytes and to compare them to production by hepatocytes themselves. In preparation, we have cloned rat LBP cDNA, purified rat LBP protein, generated anti-LBP antibody, defined in vitro as well as in vivo models of LBP regulation and are about to isolate and sequence the rat LBP promoter and express recombinant rat LBP. AIM I will define the factors regulating lipopolysaccharide-binding protein production by pulmonary, renal and extrahepatic cells in vitro. Studies will be done in non-hepatocytes as well as hepatocytes and contrasted to better define the mechanism behind the tissue-specific regulation of LBP. We begin by defining the cytokines which regulate LBP production. Nuclear run-on assays will be done to confirm and quantify transcriptional induciton. We will characterize the promoter DNA elements and nuclear factors controlling transcription of the LBP gene. Finally, we will determine whether LBP production is controlled by alteractions in mRNA stability or translational efficiency as elements in the 3'-UTR of its mRNA suggest. AIM II will define the regulation of lipopolysaccharide-binding protein production by extrahepatic tissues in vivo. Using two models of injury (hindlimb turpentine injection and hemorrhagic shock), we will determine whether the same cytokines that regulate LBP production in vitro also regulate LBP production in vivo. Further characterization of the cells that produce the LBP will also be done. AIM III will determine the functional role of locally produced (pulmonary) lipopolysaccharide-binding protein on host responses to LPS. Using hemorrhage, injury, or an adenovirus vector containing the LBP cDNA, we will induce increased local pulmonary production of lBP and determine to what extent increased local levels of LBP potentiates intrapulmonary immune cell activation and tissue injury by systemic or intratracheal LPS. At the completion of our studies, we will have defined how LBP is induced in extrahepatic tissues after injury as well as the pathophysiologic significance of such local LBP production. This information will provide important and previously unavailable insights into post-traumatic responses to Gram-negative sepsis and endotoxemia.

脓毒症和脓毒性休克仍然是发病率和死亡率的主要原因

项目成果

Thermal injury induces expression of CD14 in human skin.

• DOI: 10.1016/s0305-4179(02)00034-7
• 发表时间: 2002-05
• 期刊: Burns : journal of the International Society for Burn Injuries
• 作者: L. Steinstraesser;W. Alarcon;M. Fan;R. Klein;A. Aminlari;C. Zuccaro;G. Su;Stewart C. Wang

Burn wounds infected with Pseudomonas aeruginosa triggers weight loss in rats.

• DOI: 10.1186/1471-2482-5-19
• 发表时间: 2005-09-17
• 期刊: BMC surgery
• 影响因子: 1.9
• 作者: Steinstraesser, Lars;Burkhard, Olaf;Wang, Stewart C
• 通讯作者: Wang, Stewart C

An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction.

• DOI: 10.1084/jem.20051207
• 发表时间: 2006-01-23
• 期刊: The Journal of experimental medicine
• 作者: Niederbichler AD;Hoesel LM;Westfall MV;Gao H;Ipaktchi KR;Sun L;Zetoune FS;Su GL;Arbabi S;Sarma JV;Wang SC;Hemmila MR;Ward PA
• 通讯作者: Ward PA

CD14 and lipopolysaccharide binding protein expression in a rat model of alcoholic liver disease.

酒精性肝病大鼠模型中 CD14 和脂多糖结合蛋白的表达。

• 发表时间: 1998
• 期刊: The American journal of pathology
• 作者: Su,GL;Rahemtulla,A;Thomas,P;Klein,RD;Wang,SC;Nanji,AA
• 通讯作者: Nanji,AA