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Molecular biological approach to the treatment of endotoxin shock

治疗内毒素休克的分子生物学方法

基本信息

批准号：
07670852
负责人：
YASUI Kozo
金额：
$ 1.41万
依托单位：
Department of Pediatrics, Shinshu Univ. school of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Endotoxin (lipopolysaccharide ; LPS) is a potent biological response modifier of cells, including macrophages, neutrophils and endothelial cells (EC). LPS stimulation is mediated through a cell surface receptor, known as CD14. In our study, it is clarified that LPS primes neutrophils in the combination with serum via CD14 and the expression of ICAM-1 on EC is also enhanced under the condition with serum. The adhesion and O_2-production of neutrophils are markedly enhanced on the EC monolayr by treatment with TNF-alpha or LPS+serum. Monoclonal antibody (mAb) against CD18 inhibits neutrophil-EC adhesion and O_2-production. Anti-CD11b mAb inhibits adhesion, however, stimulates O_2-production These findings indicate that the adhesion mediated by CD11b provides the signal (trigger) for superoxide production by neutrophils. These effects are not blocked by anti-TNF antibody.Superoxide production by neutrophils plays a crucial role in the pathogenesis of endotoxin shock. The excessive priming of neutrophils may bring some toxicity to normal tissue. In the process, apoptosis may provide a mechanism for clearance of the unwanted cells. GM-CSF and G-CSF have different effects on the apoptosis of human mature neutrophils induced by anti-Fas antibody. GM-CSF suppress the apoptosis and retain neutrophil functions of superoxide production. It is postulated that GM-CSF works as an inflammatory cytokine which maintain neutrophil survival.Behcet disease is a chronic condition in which the functions of neutrophils are characteristically increased. Pentoxifylline is a membrane fluidizer that modulates receptor-mediated cellular functions. It is wellknown that pentoxifylline reduces neutrophil-induced tissue damage. We examined the effect of pentoxifylline in controlling Behcet disease and get improved clinical conditions and normalized neutrophil functions in all of our patients.

内毒素（脂多糖；LPS）是一种有效的细胞生物反应调节剂，包括巨噬细胞、中性粒细胞和内皮细胞（EC）。LPS刺激是通过细胞表面受体介导的，称为CD14。在我们的研究中，明确了LPS通过CD14与血清结合启动中性粒细胞，并且在与血清结合的情况下，ICAM-1在EC上的表达也增强。tnf - α或LPS+血清可显著增强中性粒细胞在EC单分子膜上的粘附和o_2生成。抗CD18单克隆抗体（mAb）抑制中性粒细胞- ec粘附和o_2生成。然而，抗CD11b单抗抑制粘附，刺激o_2的产生。这些发现表明，CD11b介导的粘附为中性粒细胞产生超氧化物提供了信号（触发）。这些作用不被抗tnf抗体阻断。中性粒细胞产生超氧化物在内毒素休克的发病机制中起着至关重要的作用。过量的中性粒细胞会对正常组织产生一定的毒性。在这个过程中，细胞凋亡可能提供了一种清除不需要细胞的机制。GM-CSF和G-CSF对抗fas抗体诱导的人成熟中性粒细胞凋亡有不同的影响。GM-CSF抑制细胞凋亡，保留超氧化物产生中性粒细胞的功能。GM-CSF被认为是一种维持中性粒细胞存活的炎性细胞因子。白塞病是一种以中性粒细胞功能增高为特征的慢性疾病。己酮茶碱是一种调节受体介导的细胞功能的膜流化剂。众所周知，己酮茶碱可以减少中性粒细胞引起的组织损伤。我们检查了己酮茶碱在控制白塞病中的作用，所有患者的临床状况得到改善，中性粒细胞功能正常化。