title: Roles of leukocytosis and cysteinyl leukotriene in polymorphonuclear leukocyte-dependent plasma extravasation.
abstract: The PMN-dependent plasma extravasation is a major mechanism of permeability enhancement in acute inflammation. To reveal the pathophysiological significance of the PMN-dependent plasma extravasation, we prepared a systemic leukocytotic guinea pig model by a daily injection of recombinant human (rh)G-CSF. The extent of the PMN-dependent plasma extravasation, regarded as the late-phase permeability induced by an intradermal injection of zymosan-activated guinea pig plasma (ZAP) or of rhC5a, clearly correlated to the circulating PMN number. The augmentation of local response following the systemic response seemed to be the characteristic feature of the PMN-dependent plasma extravasation. We then revealed the molecular mechanism of the PMN-dependent plasma extravasation. Neither the antihistaminic agent diphenhydramine, nor the bradykinin B2 receptor antagonist, HOE140, affected the ZAP-induced, late-phase extravasation. In contrast to this, pretreatment with an antagonist of cysteinyl leukotriene (cys-LT) 1 receptor, pranlukast, significantly reduced the late-phase extravasation. Similarly, it was reduced by pretreatment with a 5-lipoxygenase inhibitor, MK-886, indicating the participation of cys-LTs in the PMN-dependent plasma extravasation. Histologically, pretreatment with pranlukast or MK-886 did not affect the ZAP-induced PMN infiltration. Consistently, a combined treatment with pranlukast and diphenhydramine completely suppressed the early-phase extravasation. As pranlukast pretreatment did not affect plasma extravasation induced by mast cell degranulation, and depletion of platelets did not influence the pranlukast-inhibitable plasma extravasation induced by rhC5a injection, cys-LTs are most likely produced by transcellular biosynthesis involving PMNs and vascular wall cells.
authors.affiliation: Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan. ktokita@kaiju.medic.kumamoto-u.ac.jp
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Tokita
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uchida
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000276:immunology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology*; D002867:Chromones / Q000494:pharmacology; D015936:Complement C5a / Q000494:pharmacology; D003545:Cysteine / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000633:toxicity; D006168:Guinea Pigs; D006801:Humans; D007155:Immunologic Factors / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007964:Leukocytosis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D020024:Leukotriene Antagonists / Q000494:pharmacology; D015289:Leukotrienes / Q000276:immunology* / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D043782:Receptor, Bradykinin B2 / Q000276:immunology; D011994:Recombinant Proteins; D015054:Zymosan / Q000494:pharmacology; D002722:Chlorobenzenes
chemical_list: D000319:Adrenergic beta-Antagonists; D001094:Arachidonate 5-Lipoxygenase; D001920:Bradykinin; D065094:Bradykinin B2 Receptor Antagonists; D002867:Chromones; D015936:Complement C5a; D003545:Cysteine; D016179:Granulocyte Colony-Stimulating Factor; D007155:Immunologic Factors; D007211:Indoles; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D043782:Receptor, Bradykinin B2; D011994:Recombinant Proteins; D015054:Zymosan; C112381:cysteinyl-leukotriene; C060893:MK-886; D002722:Chlorobenzenes; C065679:icatibant; C047681:pranlukast