Leukotriene D4- and prostaglandin F2 alpha-induced airflow obstruction and airway plasma exudation in guinea-pig: role of thromboxane and its receptor

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Leukotriene D4- and prostaglandin F2 alpha-induced airflow obstruction and airway plasma exudation in guinea-pig: role of thromboxane and its receptor. / Arakawa, Hirokazu; Lotvall, Jan; Kawikova, Ivana; Löfdahl, Claes-Göran; Skoogh, Bengt-Eric.

I: British Journal of Pharmacology, Vol. 110, Nr. 1, 1993, s. 127-132.

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T1 - Leukotriene D4- and prostaglandin F2 alpha-induced airflow obstruction and airway plasma exudation in guinea-pig: role of thromboxane and its receptor

AU - Arakawa, Hirokazu

AU - Lotvall, Jan

AU - Kawikova, Ivana

AU - Löfdahl, Claes-Göran

AU - Skoogh, Bengt-Eric

PY - 1993

Y1 - 1993

N2 - 1 We studied the effects of a thromboxane A2 receptor (TP receptor) antagonist, ICI-192,605 (0.5mgkg-', 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 ICI-192,605 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. ICI-192,605 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.

AB - 1 We studied the effects of a thromboxane A2 receptor (TP receptor) antagonist, ICI-192,605 (0.5mgkg-', 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 ICI-192,605 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. ICI-192,605 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.

KW - Asthma

KW - airway oedema

KW - arachidonic acid

KW - vascular permeability

M3 - Article

VL - 110

SP - 127

EP - 132

JO - British Journal of Pharmacology

T2 - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 1476-5381

IS - 1

ER -