Role of platelet-activating factor in leukocyte-independent plasma extravasation and mast cell activation during endotoxemia.
BACKGROUND
Independently from leukocyte adherence, endothelial factors and mast cell activation seems to promote microvascular permeability. Platelet-activating factor (PAF) has been shown to play a significant role in endotoxin-induced leukocyte adherence. The aim of our study was to investigate if there is also a role for PAF in mediating leukocyte-independent microvascular permeability changes and activation of mast cells during endotoxemia. Therefore, during endotoxemia microvascular permeability and mast cell activation were determined after inhibition of L-selectin-mediated leukocyte adherence by fucoidin and after inhibition of PAF effects by the PAF receptor antagonist BN52021.


METHODS
In male Wistar rats, red cell velocity (V(RBC)), venular wall shear rate, microvascular permeability, leukocyte adherence, and mast cell activation were determined in mesenteric postcapillary venules using intravital microscopy at baseline and 60 and 120 min after start of a continuous infusion of endotoxin (ETX; 2 mg/kg/h, Escherichia coli O26:B6) (ETX group). Animals in the FUCO/ETX group received fucoidin (25 mg/kg body wt) in addition to the procedure described above. Animals in the FUCO/ETX/PAF-ANT group received fucoidin and the PAF receptor antagonist BN52021 (5 mg/kg body wt) prior to the continuous endotoxin infusion. Control animals (control group) received only equivalent volumes of NaCl 0.9%.


RESULTS
There were no microhemodynamic and macrohemodynamic differences between groups. In all endotoxin-challenged groups macromolecular leakage and mast cell activity increased significantly, starting at 60 min. Both macromolecular leakage and mast cell activity were significantly higher in the FUCO/ETX group than in the FUCO/ETX/PAF-ANT group and control group. Differences in macromolecular leakage between groups were significant at 120 min. Differences in mast cell activity between groups were significant at 60 and 120 min.


CONCLUSIONS
The results of our study demonstrate a leukocyte-independent plasma extravasation that can be inhibited by the PAF receptor antagonist BN52021, indicating the involvement of PAF in the pathophysiology of leukocyte-independent microvascular damage during early endotoxemia. Mast cell activity seems to precede leukocyte-independent macromolecular leakage.
Walther
A
A
Department of Anesthesiology, Department of Experimental Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg, D-69120, Germany. Andres_Walther@med.uni-heidelberg.de
Yilmaz
N
N
Schmidt
W
W
Bach
A
A
Gebhard
M M
MM
Martin
E
E
Schmidt
H
H
D000818:Animals; D001769:Blood / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D004224:Diterpenes; D019446:Endotoxemia / Q000378:metabolism / Q000503:physiopathology*; D004731:Endotoxins / Q000494:pharmacology; D046934:Ginkgolides; D006439:Hemodynamics; D007783:Lactones / Q000494:pharmacology; D007962:Leukocytes / Q000502:physiology*; D046911:Macromolecular Substances; D008297:Male; D008407:Mast Cells / Q000502:physiology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011134:Polysaccharides / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled
D004224:Diterpenes; D004731:Endotoxins; D046934:Ginkgolides; D007783:Lactones; D046911:Macromolecular Substances; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011134:Polysaccharides; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C007789:fucoidan; C045856:ginkgolide B