Leukotriene D₄‐ and prostaglandin F_2α‐induced airflow obstruction and airway plasma exudation in guinea‐pig: role of thromboxane and its receptor

Abstract

1 We studied the effects of a thromboxane A2 receptor (TP receptor) antagonist, i.v.) and a selective thromboxane (Tx) synthetase inhibitor, OKY-046 (30mgkg-1, i.v.), on airway responses induced by leukotriene D4 (LTD4; 0.2 nmol) or prostaglandin F2a, (PGF2,; 20 nmol) instilled via the airways route to anaesthetized guinea-pigs. For a comparison, airway responses to a TxA2-mimetic, U-46619 (0.02 nmol) were also studied. We measured both lung resistance (RL) to monitor airflow obstruction, and extravasation of Evans Blue dye to quantify airway plasma exudation. 2 Instilled LTD4 into the tracheal lumen induced an immediate peak and subsequently persistent increase in RL and produced a large amount of extravasation of Evans Blue dye at all airway levels. Both 605 and OKY-046 significantly attenuated the persistent increase in RL following the immediate response and reduced LTD4-induced extravasation of Evans Blue dye in the trachea and proximal intrapulmonary airway. Instilled LTD4 produced significant increases in immunoreactive TxB2 in bronchoalveolar lavage fluid obtained 1.5 min after instillation of LTD4.3 Instilled PGF2. into the tracheal lumen induced an immediate increase in RL which peaked at approximately 15 s. We also observed a delayed sustained increase in RL, reaching a second peak at approximately 4 min. PGF2, produced small but significant increases in the amount of Evans Blue dye at all airway levels. As with PGF,, instillation of U-46619 produced a biphasic increase in RL and extravasation of Evans Blue dye. The potency of PGFu, in inducing these airway responses was about 1000 times less than U-46619. 605 abolished both the immediate and the delayed increase in RL after PGF20, and also blocked PGF2,-induced extravasation of Evans Blue dye. However, OKY-046 had no inhibitory effects on these responses. 4 We conclude that airflow obstruction and airway plasma exudation induced by instilled LTD4 is, in part, mediated via TxA2 generation and subsequent activation of TP-receptors. On the other hand, instilled PGF2., while inducing similar responses, does so primarily by direct activation of TP receptors, rather than via TxA2 generation.

Role of thromboxane-A2 and cholinergic mechanisms in bronchoconstriction induced by cigarette smoke in guinea-pigs

“…Intravenous administration of U46619 has been shown to cause marked bronchoconstriction and plasma extravasation in the airways of guinea-pigs [15]. Another study demonstrated that the plasma extravasation induced by intratracheally instilled leukotriene D 4 (LTD 4 ) is partially mediated by Tx generation in guinea-pigs [16]. Our findings on extravasation are inconsistent with those of the previous investigators.…”

“…TxA 2 is known to contract the airway smooth muscle directly by stimulating the specific thromboxane (TP) prostanoid receptor on the muscle [8][9][10], or indirectly by potentiating the neuroeffector transmission of cholinergic contraction [11][12][13][14]. In addition, TxA 2 can produce plasma extravasation in the airways [15,16]. It is, thus, reasonable to hypothesize that TxA 2 may be a key mediator that elicits bronchoconstriction and plasma extravasation induced by cigarette smoke.…”

Leukotriene D4 stimulates collagen production from myofibroblasts transformed by TGF-β

“…Human fetal lung fibroblasts (HFL-1; passage [16][17][18][19][20] were obtained from the American Type Tissue Culture Collection (Rockville, Md). HFL-1 cells were seeded in 12-well tissue-culture plates at a density of 1 3 10 5 cells/mL for procollagen type I carboxyterminal peptide (PIP) enzyme immunoassay and in 96-well tissueculture plates at a density of 2 3 10 4 cells/cm 2 for proliferation assay.…”

“…5 Many studies have shown increased levels of CysLTs in bronchoalveolar lavage fluid and urine samples from patients with asthma. [6][7][8] In addition to acting mainly as smooth muscle contractants, 9,10 CysLTs are associated with mucus hypersecretion, [11][12][13] increased microvascular permeability, 12,14,15 decreased ciliary movement, 16,17 and eosinophil recruitment. [17][18][19][20] Recent studies have shown that CysLTs participate in airway remodeling in animal models of asthma.…”

Inhibitory Effect of a TP-Receptor Antagonist, S-1452, on Antigen-Induced Nasal Plasma Exudation in Guinea Pig Model for Allergic Rhinitis

“…Previous reports have demonstrated that U-46619 could induce plasma exudation in upper (nasal) and lower airways of guinea pigs and rats, and it was significantly inhibited by TP-receptor antagonists [5,18,19]. In addition, plasma exudation in lower airways of guinea pigs and rats caused by leukotriene D 4 , PGF 2· , platelet-activating factor or endothelin-1 was inhibited by a TxA 2 synthase inhibitor or TP-receptor antagonists, but histamine-induced response was not affected by a TP-receptor antagonist [20][21][22]. These findings and our present data indicate that U-46619-induced plasma exudation in upper (nasal) and lower airways is produced via stimulation of the TPreceptor, and TxA 2 is not involved in histamine-induced airway plasma exudation.…”