Prevention of endogenous leukotriene production during anaphylaxis in the guinea pig by an inhibitor of leukotriene biosynthesis (MK-886) but not by dexamethasone.

Abstract

Leukotriene C4 (LTC4) underwent rapid elimination from the circulating blood and was extensively converted to LTD4 within the vascular space of the guinea pig. To mimic the elimination and metabolism of endogenous LTC4 generated during anaphylaxis, 14,15-3H-labeled LTC4 was infused intravenously over a period of 15 min, leading to a recovery in bile of 85% of the infused LT radioactivity within 2 h. Corresponding to the tracer studies, LTD4 and, to a lesser extent, LTC4 were the predominant endogenous cysteinyl LTs in guinea pig bile. The biliary production rate of endogenous LTD4 increased from 0.3 +/- 0.1 to 6.2 +/- 1.8 pmol x min-1 x kg-1 (p less than 0.001) during anaphylactic shock induced by intravenous injection of OVA (0.2 mg/kg) into sensitized guinea pigs. A novel LT biosynthesis inhibitor (MK-886; 10 mg/kg, i.v., 15 min before antigen challenge) suppressed the antigen-induced cysteinyl LT production by greater than 92% (p less than 0.001). This inhibition of systemic LTC4 formation was associated with a complete protection against lethal anaphylactic shock in animals pretreated in addition with the H1 receptor antagonist pyrilamine. Pretreatment with either the inhibitor of LT synthesis or the histamine receptor antagonist reduced the lethality during anaphylactic shock from 100 to 60 and 78%, respectively. In artificially ventilated, pyrilamine-pretreated animals, the antigen-induced decrease in dynamic lung compliance and the rise in hematocrit were significantly reduced (p less than 0.05) by pretreatment with the inhibitor of LT synthesis. Dexamethasone at high doses (10 mg/kg, i.p., once daily for 7 d, or in a single dose of 10 mg/kg, i.v., 3.5 h before challenge) had no inhibitory effect on LT generation during anaphylaxis in vivo. However, in resident peritoneal macrophages, harvested from these dexamethasone-treated sensitized guinea pigs and stimulated with zymosan, both cysteinyl LT and 6-keto-PGF1 alpha formation were strongly suppressed. These studies indicate an important role of cysteinyl LTs in systemic anaphylaxis in vivo and demonstrate the blockade of anaphylactic LT generation by a novel inhibitor of LT biosynthesis (MK-886) but not by dexamethasone.

Cysteinyl Leukotriene Production in Anaphylactic Reactions

“…The demonstrated results supplement those of earlier re ports on enhanced leukotriene generation in anaphylaxis in laboratory animals [7][8][9][10]. The pathophysiological signif icance of such an increase in humans remains to be estab lished, because specific leukotriene receptor antagonists or leukotriene biosynthesis inhibitors are not at present avail able for use in anaphylaxis patients.…”

“…The pathophysiological signif icance of such an increase in humans remains to be estab lished, because specific leukotriene receptor antagonists or leukotriene biosynthesis inhibitors are not at present avail able for use in anaphylaxis patients. However, leukotriene inhibitors have been shown to be effective in the treatment of bronchial asthma in humans [17,18], and in the mitigation of several symptoms of anaphylaxis in animal models, in cluding coronary vasoconstriction [10], enhanced airway pressure and leukopenia [11], and anaphylaxis-induced le thality [8], Several basic pathophysiologic events observed in anaphylactic reactions, such as smooth muscle contrac tion and microvascular leakage, may be explained by the known actions of leukotrienes [19], Several agents commonly used for the treatment of ana phylaxis have been shown to possess the potential to inhibit leukotriene production. Epinephrine [20] and a number of H|-receptor blockers, including clemastine and azelastine [21], reduce leukotriene production by human leukocytes.…”

“…8]. The specific leuko triene inhibitor MK-886 suppresses this effect and induces complete protection from lethal anaphylactic shock [8]. En hanced leukotriene production has also been demonstrated in pulmonary anaphylaxis induced by tracheal instillation of antigen in rats [9], Considerable amounts o f cysteinyl leukotrienes are released in cardiac anaphylaxis in guinea pig hearts [10], In this model, a 5-lipoxygenase inhibitor markedly attenuates the early phase of anaphylactic in crease in coronary perfusion pressure.…”

Injury-Related Production of Cysteinyl Leukotrienes Contributes to Brain Damage following Experimental Traumatic Brain Injury

“…There is no dose of MK-886 routinely used in the literature at present in rats. Across species the intravenous doses used range from 0.3 to 10 mg=kg (Guhlmann et al, 1989;Provost et al, 1998;Ciceri et al, 2001;Uz et al, 2008). Our 6 mg=kg dose regimen was the median dose represented and the first we tested.…”

Corticosteroids in management of anaphylaxis; a systematic review of evidence

“…The animal models used included guinea pigs (62)(63)(64) and mice (48,53,65,66). One other study was conducted using A549 human adenocarcinoma cell line (52).…”