title: Rapid mast cell activation causes leukocyte-dependent and -independent permeability alterations.
abstract: The major objective of this study was to systematically elucidate the mechanisms underlying microvascular permeability in rat mesenteric venules after the activation of perivascular mast cells. Intravital microscopy was used to assess polymorphonuclear leukocyte (PMN) infiltration and microvascular permeability alterations in single 25- to 40-micron diameter venules. Ruthenium red was used to detect mast cell activation on-line. Exposure of mast cells to compound 48/80 (CMP 48/80) caused a rapid mast cell activation and increase in microvascular permeability (within 15 min) that was maintained for the duration of the experiment. CMP 48/80 also increased PMN adhesion to the microvascular endothelium. Anti-PMN serum, as well as various antiadhesion therapies, including CL26 (anti-CD18 antibody) and fucoidan (selectin-immunoneutralizing carbohydrate), revealed that the early microvascular permeability was PMN independent. However, these regimens significantly reduced plasma protein leakage out of venules between 30 and 60 min. Methysergide (serotonin receptor antagonist), but not diphenhydramine (histamine receptor antagonist), inhibited the early PMN-independent microvascular permeability. Finally, a platelet-activating factor (PAF)-receptor antagonist did not affect the early phase of microvascular permeability but reversed the later phase, consistent with PAF's role as a proadhesive molecule for PMN during mast cell activation. These data demonstrate that, within the first hour of mast cell activation, a biphasic PMN-independent and -dependent response in microvascular permeability is observed. The data also raise the possibility that histamine's physiological role in this model may be unrelated to alterations in microvascular permeability.
authors.affiliation: Immunology Research Group, University of Calgary Medical Centre, Alberta, Canada.
authors.forename: P
authors.initials: P
authors.lastname: Kubes
authors.forename: J P
authors.initials: JP
authors.lastname: Gaboury
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D004396:Coloring Agents; D004155:Diphenhydramine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology*; D008784:Methysergide / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012430:Ruthenium Red; D012702:Serotonin Antagonists / Q000494:pharmacology; D013997:Time Factors; D014699:Venules / Q000502:physiology; D003189:p-Methoxy-N-methylphenethylamine / Q000494:pharmacology
chemical_list: D004396:Coloring Agents; D006634:Histamine H1 Antagonists; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012702:Serotonin Antagonists; C039351:platelet activating factor receptor; D012430:Ruthenium Red; D003189:p-Methoxy-N-methylphenethylamine; D004155:Diphenhydramine; D008784:Methysergide