Studies on the mechanisms involved in the inflammatory response in a reversed passive Arthus reaction in guinea‐pig skin: contribution of neutrophils and endogenous mediators

Abstract

1 Mediators of inflammation can increase vascular permeability in at least two different ways: by acting directly on endothelial cells or, indirectly, through an incompletely understood mechanism, dependent on circulating neutrophils. Neutrophil-dependent oedema formation has been described in the skin of rabbits, rats, hamsters, mice and man. In contrast, we presented evidence in a previous study that local oedema formation induced by i.d. injection of chemoattractants in guinea-pig skin was neutrophil-independent. In the present study, we sought evidence of neutrophil-dependent oedema formation in immune-complex-mediated vasculitis, the reversed passive Arthus (RPA) reaction, in guinea-pig skin. We also investigated whether haemorrhage in the RPA reaction was neutrophildependent (as it is in other species) and the role of endogenous mediators of inflammation (prostaglandins, nitric oxide, histamine, PAF and leukotrienes) in contributing to the local inflammatory response. 2 In the RPA reaction, most oedema formation occurred over the first 60 min whereas "'In-neutrophil accumulation was still increasing from 60 to 240 min. The different kinetics of these two events suggested that they may be dissociated.3 Oedema formation was partially inhibited by a long-acting PAF antagonist (UK-74,505) and an HI histamine receptor antagonist (mepyramine) but not by a 5-lipoxygenase inhibitor (ZM 230487). A nitric oxide synthesis inhibitor (NW-nitro-L-arginine methyl ester, L-NAME) suppressed oedema formation by 68% whereas a cyclo-oxygenase inhibitor suppressed oedema by 27%. 4 "'In-neutrophil accumulation in the RPA reaction was partially suppressed by UK-74,505. In contrast, ZM 230487 was without effect at doses which abrogated arachidonic acid-induced "'Inneutrophil accumulation. 5The anti-CD18 monoclonal antibody, (mAb) 6.5E F(ab')2, effectively inhibited "'In-neutrophil accumulation induced by PAF, zymosan-activated plasma (ZAP) and in the RPA reaction. However, oedema formation measured in the same sites was not altered. In contrast, oedema formation in the RPA reaction was partially suppressed by 6.5E whole mAb which was 2.5 times more potent than 6.5E F(ab')2 at inhibiting guinea-pig neutrophil adhesion to protein-coated plastic. Haemorrhage induced by PAF and in the RPA reaction was significantly inhibited by 6.5E F(ab')2 pretreatment. 6 We conclude that in the RPA reaction in guinea-pig skin, oedema formation is partially neutrophildependent as assessed by using an anti-CD18 mAb, whereas ZAP-induced oedema formation is neutrophil-independent. Haemorrhage was also dependent on neutrophil accumulation. In addition, our studies support a role for PAF in mediating both oedema formation and "'In-neutrophil accumulation in the RPA reaction. Endogenous release of histamine also appears to be important in mediating oedema formation suggesting that mast cells play a critical role in increases of vascular permeability in inflammatory reactions in guinea-pig skin. Moreover, our results confirm previous findings which suggest...

P-selectin requirement for neutrophil accumulation and injury in the direct passive Arthus reaction

“…Depletion studies have confirmed the requirements for immune complexes and complement for the full expression of injury [1,6,7]. In addition, neutrophil recruitment is believed to be important in the initiation and mediation of this reaction [7]. Early studies have concentrated on the contribution of complement in recruiting the effector cells of the reaction, neutrophils [1,6].…”

Differential role of neutrophils and monocytes during subcutaneous plasma extravasation

“…21,22 However, our current study using the PMN-depleted animal clearly demonstrated that the ZAP-induced plasma protein extravasation in guinea-pig skin is composed of two different mechanisms, one PMN-dependent and the other PMN-independent. This result is consistent with the previous report using the rabbit skin.…”

“…21,22 So, we examined whether the ZAP-induced PMN-independent plasma extravasation could be suppressed with an antihistaminic agent, triprolidine. To evaluate the effect exclusively on the PMN-independent response, we measured the plasma extravasation for initial 30 min in the PMN-depleted guinea-pigs pretreated with cyclophosphamide.…”

Inhibition of Guinea Pig Skin Allergic Reactions by Nonpeptide Bradykinin B₂ Receptor Antagonist FR173657

“…1). Platelet–activating factor and neutrophils have been shown to play important roles in rat, guinea pig and rabbit Arthus reaction models [36, 37, 38]. Platelet–activating factor antagonists attenuated the cutaneous Arthus reaction including the late VPE in the three animal models [37].…”