Endogenous leukotriene D4 formation during anaphylactic shock in the guinea pig.

Abstract

Experiments on the metabolism and excretion of i.v. administered selectively labeled [3H8]1eukotriene C4 in bile duct-cannulated guinea pigs indicated predominantly biliary excretion of tritium. The major leukotriene metabolite in bile was identified as leukotriene D4. By monitoring leukotriene excretion radioimmunochromatographically, it was shown that guinea pigs suffering from anaphylactic shock produce leukotriene D4 endogenously. Immunological challenge of animals sensitized to ovalbumin was accompahied by an increase of biliary leukotriene D4 concentrations from 10 ± 1 to 86 ± 10 nM (mean ± SEM, n = 5, P < 0.001). When considering that bile flow was decreased to abobt half after challenge, the excretion rate of leukotriene D4 in bile increased from 0.88 ± 0.16 before to 3.18 ± 0.38 pmolmin-'-kg-' after challenge (mean ± SEM, n = 5, P < 0.002). It is concluded that systemic anaphylaxis in the guinea pig is associated with endogenous generation of leukotriene C4 (Up to 1 nmol/kg during a 30-min period after the challenge).Leukotriene C4 (LTC4) is a biologically active substance presumed to play major roles as a mediator of allergic and anaphylactic reactions (1, 2). It is formed by basophilic (3) and eosinophilic leukocytes (4), monocytes (5), macrophages (6), and mast cells (7). In cells having IgE receptors, bridging of these receptors by divalent anti-IgE receptor antibodies or by interaction between receptor-bound IgE and anti-IgE will induce LTC4 formation (5-7). Leukotriene formation has also been demonstrated in other in vitro models of immediate hypersensitivity (8-10). The biological actions of LTC4 comprise induction of airway obstruction, constriction of coronary arteries, hypotension, and plasma extravasation (11)(12)(13)(14). Leukotriene formation in vivo may mediate anaphylactic shock symptoms and cause the death of an animal. To prove the presumed mediator role of this substance in anaphylactic reactions, it is necessary to demonstrate its endogenous formation during anaphylaxis. Studies on LTC4 metabolism have revealed rapid catabolism by various transformations of the peptide substituent (15). Three metabolites have been demonstrated to be excreted as end-products: leukotriene E4 (LTE4) (16) in man and N-acetyl-LTE4 plus N-acetyl-11-trans-LTE4 (17) in the rat. By monitoring biliary N-acetyl-LTE4 levels, endogenous leukotriene formation in the rat was demonstrated in vivo after tissue trauma and endotoxin shock (18,19). We now wish to report evidence for endogenous LTC4 production during anaphylactic shock in guinea pigs.

Hepatic uptake and metabolic disposition of leukotriene B4 in rats

“…These differences in hepatic uptake of cysteinyl LTs and LTB4 are in line with the earlier finding that LTB4 does not compete with cysteinyl LTs for hepatocellular uptake [37]. Interestingly, the hepatobiliary excretion of LTB4 and its metabolites exceeded renal elimination (Table 2), as it does with cysteinyl LTs [19,22,31,34,35]. On the other hand, the small extent of hepatic LTB4 extraction ( Fig.…”

“…Elimination and body distribution of LT radioactivity after intravenous injection of 13H8ILTB4 or 13H2ILTE4 Hepatobiliary excretion represents the major route of elimination in vivo of circulating cysteinyl LTs [19,22,31,34,35], including LTE4 (Table 2). In contrast, only about 25 % of LTB4 was extracted from circulation by the hepatobiliary system in rats, of which about 22 % (of the infused dose) was excreted into (Fig.…”

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.…”

Peptide Leukotriene Involvement in Pulmonary Eosinophil Migration upon Antigen Challenge in the Actively Sensitized Guinea Pig

“…The production of peptide LTs, when sensitized guinea pigs are challenged with antigen, has been dem onstrated in a number of systems, including re lease from chopped lung preparations [13], from phar macological modulation of tracheal contractions [11] as well as by the observation that biliary levels of LTs are raised in the intact animal [14] following chal lenge. Such a release has been postulated to be re sponsible for at least a portion of the bronchoconstriction evident; an observation substantiated by the potency of synthetic LTs in smooth muscle prepara tions [15], The present sludy shows that peptide LTs may also participate in pulmonary leukocyte recruit ment processes in the intact animal.…”