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.

Anti-allergic activity of an ethanol extract from Salviae miltiorrhiza

“…Arachidonic acid can also be converted to cysteinyl leukotrienes (LTs) by the action of 5-LOX. The cysteinyl LTs are potent mediators of allergy and inflammation by modulation of the smooth muscle tone and vascular permeability (Kanaoka et al, 2006;Tokita et al, 2006). In addition, they play an important role in asthma and other respiratory diseases (Lewis et al, 1990;McMillan et al, 1992;Henderson, 1994).…”

Pivotal Advance: Interconversion between pure chemotactic ligands and chemoattractant/secretagogue ligands of neutrophil C5a receptor by a single amino acid substitution

“…For the latter function, we examined granule release induction and respiratory burst induction in neutrophils and vascular permeability enhancement in guinea pig skin. In the latter case, the histamine release reaction of cutaneous mast cells and the arachidonate cascade reaction of migrating neutrophils are involved [19,25]. Furthermore, we have revealed that the guinea pig C5a receptor recognizes human C5a [16] as well as E. coli Skp [1].…”

Involvement of regional neutrophil apoptosis promotion by ribosomal protein S19 oligomers in resolution of experimental acute inflammation

“…In contrast to the neutrophil number, the fluid volume did not increase. The neutrophil extravasation associates vascular permeability enhancement via cysteinyl leukotriene generation by the neutrophils and endothels in their corporation . The disassociation between the neutrophil number and the fluid volume suggests that the increased neutrophil number would be mainly due to retardation of the neutrophil clearance once infiltrated.…”