PAF and CD18 mediate neutrophil infiltration in upper gastrointestinal tract during intra-abdominal sepsis.
Neutrophil infiltration is a critical event in the development of multiple organ failure during sepsis. We hypothesized that platelet-activating factor (PAF) release contributes to neutrophil infiltration in the gastrointestinal tract during sepsis. In the first experiments we administered exogenous PAF (1.56, 6.25, 25, and 100 ng . kg-1 . min-1 for 30 min) to urethan-anesthetized Sprague-Dawley rats. PAF was administered alone or in combination with either the PAF antagonist WEB-2086 (250 microg . kg-1 . min-1), a monoclonal antibody (MAb) to CD18, or a MAb to intercellular adhesion molecule 1 (ICAM-1). In separate groups of rats, cecal ligation and incision (CLI) was performed to create intra-abdominal sepsis, which we hypothesized would stimulate the release of endogenous PAF. CLI was performed in rats given either saline, WEB-2086, anti-CD18, or anti-ICAM-1 MAb. After these experiments, tissue myeloperoxidase (MPO) levels were determined as a marker of neutrophil infiltration. Both exogenous PAF and CLI induced significant increases in MPO activity in the stomach and duodenum. These increases were significantly attenuated by WEB-2086, anti-CD18 MAb, and anti-ICAM-1 MAb in both PAF- and CLI-treated rats. These results suggest that both the inflammatory mediator PAF and the CD18 integrins play a major role in neutrophil infiltration in the upper gastrointestinal tract during sepsis.
Beyer
A J
AJ
Department of Surgery, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Smalley
D M
DM
Shyr
Y M
YM
Wood
J G
JG
Cheung
L Y
LY
D000005:Abdomen; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D001794:Blood Pressure; D018821:CD18 Antigens / Q000276:immunology / Q000502:physiology*; D002432:Cecum; D006400:Hematocrit; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology / Q000502:physiology; D007422:Intestines / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology; D007958:Leukocyte Count; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009195:Peroxidase / Q000032:analysis; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000503:physiopathology*; D014230:Triazoles / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D001381:Azepines; D018821:CD18 Antigens; D010972:Platelet Activating Factor; D014230:Triazoles; C052518:WEB 2086; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase