Comparative airway and vascular activities of leukotrienes C-1 and D in vivo and in vitro.

Abstract

The pharmacologic activities of leukotrienes C-i and D (LTC-1 and LTD), constituents of slow reacting substance of anaphylaxis (SRS-A), were evaluated in vitro on airway contractile tissues and in vivo on pulmonary mechanical function, mean systemic arterial pressure, and cutaneous microcirculation. In vitro both LTC-Land LTD were potent and selective peripheral airway agonists, being more active than histamine; furthermore, LTD was active on peripheral airways at concentrations 1/100th those of LTC-1. The concentration-effect relationship for LTD and the profile of antagonism by FPL 55712 are consistent with the activity. of this molecule at two separate peripheral airway receptors. Ii vivo, LTC1 and LTD were nearly equally active in their effects on pulmonary mechanics, and the pattern of alterations was consistent with the predominant site of action being in the lung periphery. Furthermore, both agents had a direct systemic arterial hypotensive effect and were vasoactive on the cutaneous microcirculation. Thus, these compounds are likely to be major mediators of the pathologic alterations in immediate type hypersensitivity reactions in which peripheral airway constriction and hypotension are prominent features.Slow reacting substance of anaphylaxis (SRS-A) (1), which is an activity generated during immediate type hypersensitivity reactions (2), has been found to be composed of leukotrienes C-i (LTC-1) and D (LTD) (3). Native SRS-A has a unique profile of contractile activity in vitro in smooth muscle preparations (4). Both partially and highly purified native SRS-A produced by an anaphylactic reaction in the rat peritoneal cavity (SRS-Arat) exhibit a preferential contractile activity for guinea pig pulmonary parenchymal strips compared to musculus trachealis (5), and LTC-1 and LTD exhibit the same differential effect, at concentrations less than 0.1% of those required for histamine to be active (3). Partially purified SRS-Arat augments vascular permeability when injected into guinea pig skin (6). When administered intravenously into the unanesthetized guinea pig, it produces an alteration in pulmonary mechanics consistent with peripheral rather than central airway action (7). We have now demonstrated that intravenous infusion of LTC-1 and LTD alters pulmonary mechanics in unanesthetized and anesthetized guinea pigs in a manner similar to native partially purified SRS-Arat and that, in addition, these newly described products of arachidonate metabolism (8-10) can differ in their actions on the cutaneous microvasculature and on mean systemic arterial pressure.MATERIALS AND METHODS LTC-1 and LTD were prepared as described (3, 10), sealed in ampoules in 10% methanol under argon, and stored frozen until the day of use. Histamine diphosphate was obtained from Sigma. FPL 55712, a specific SRS-A antagonist, was a gift from P. Sheard (Fisons Pharmaceuticals, Ltd., U.K.).Tracheal spirals and parenchymal strips were prepared for recording isometric contractile activity (5) and allowed to relax to baseline tensi...

IL-5 Up-Regulates Cysteinyl Leukotriene 1 Receptor Expression in HL-60 Cells Differentiated into Eosinophils

“…Minimal fluorescence (F min ) was determined by subsequent addition of the chelator EGTA in Tris-HCl buffer (100 mM, pH 9.0) at 125 mM. Stimuli consisted of LTD 4 , LTB 4 , and platelet-activating factor (PAF; Cayman Chemicals, Ann Arbor, MI).…”

“…LTD 4 -induced eosinophil infiltration of the airway could be blocked by the early cysLT antagonist MK-571 (15). More recently, in human studies, blocking the LTD 4 receptor has been shown to reduce airway eosinophil numbers in mildly uncontrolled asthma (16), suggesting it may be a contributing factor in lung eosinophilia in asthma.…”

“…The cysteinyl LTs (cysLTs), LTC 4 , LTD 4 , and LTE 4 (components of the "slow-reacting substance of anaphylaxis"), are potent lipid mediators implicated mainly in acute bronchoconstriction and chronic airway inflammation in asthma. They mimic many of the features of human asthma, including bronchoconstriction, mucus secretion, and bronchial hyperresponsiveness (4 -7).…”

Enhanced peripheral leukocyte leukotriene production and bronchial hyperresponsiveness in asthmatics

“…Cysteinyl LTs (cys-LTs) induce bronchoconstrictor effects [6], increase mucus formation [7], and induce bronchial wall oedema [8]. LTB 4 stimulates neutrophil chemotaxis [9] and activates those cells, leading to the release of mediators and superoxides.…”

Significant Role of Peptide Leukotrienes (p-LTs) in the Antigen-Induced Contractions of Human and Guinea Pig Lung Parenchymas and Bronchi or Tracheas In Vitro.

“…Since the discovery of the slow reacting substance of anaphylaxis (SRS-A), which had been tentatively desig nated as p-LTs until identification of their structures, the p-LTs have been proven to be potent pulmonary tissue constrictors in some species, especially humans and guinea pigs (4)(5)(6)(7). Because human or guinea pig lungs possess a great ability for p-LT formation and their airway smooth muscles markedly respond to p LTs, p-LTs formed intrinsically may be largely re sponsible for the pulmonary tissue contractions during anaphylaxis.…”