1996 Fiscal Year Final Research Report Summary
Molecular biological approach to the treatment of endotoxin shock
| Project/Area Number |
07670852
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Pediatrics
|
|---|
| Research Institution | Department of Pediatrics, Shinshu Univ. school of Medicine |
|---|
Principal Investigator |
YASUI Kozo Shool of Medicine, Shinshu University, 医学部・附属病院, 講師 (90200493)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
TSUNO Takahisa Shool of Medicine, Shinshu University, 助手 (10242695)
MATSUOKA Takafumi Shool of Medicine, Shinshu University, 医学部, 講師 (70270965)
|
|---|
| Project Period (FY) |
1995 – 1996
|
| Keywords | neutrophil / endotoxin / CD14 / adhesion molecule / apoptosis / Behcet disease / pentoxifylline |
|---|
| Research Abstract |
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.
|
