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Effects of thromboxane synthase and cyclooxygenase inhibition on PAF-induced changes in lung function and arachidonic
D S Trochtenberg1, P L Lefferts, G A King
1Center For Lung Research, Vanderbilt University School of Medicine, Nashville, TN 37232.
Abstract:
PAF was administered as an intravenous bolus (0.1 micrograms/kg) to eight chronically instrumented awake sheep. The effects of pretreatment with an inhibitor of cyclooxygenase (meclofenamate) on PAF-induced changes in lung function were compared to those observed with a specific inhibitor of thromboxane synthase (DP1904). Each animal was studied four times in varied order: PAF alone, PAF + DP1904, PAF + meclofenamate, and DP1904 alone. Saline alone (control), DP1904 alone, and meclofenamate alone did not cause changes in any of the measured variables. DP1904 and meclofenamate significantly attenuated the PAF-induced fall in lung compliance, elevation in peak pulmonary artery pressure, and increased lung lymph flow. Both drugs abolished the PAF-induced increases in lung lymph thromboxane B2 concentrations. Meclofenamate, but not DP1904, blocked the rise in lymph 6-keto-PGF1 alpha. Although meclofenamate blocked the rise in lymph PGE2, DP1904 resulted in levels 2.7 times higher than PAF alone. We conclude that: (1) inhibition of thromboxane synthase is as effective as inhibition of cyclooxygenase in attenuating PAF-induced changes in lung function, and (2) thromboxane synthase inhibition results in augmented production of PGE2 following PAF administration in vivo.
Insights
Platelet-activating factor (PAF) causes lung dysfunction. Inhibiting thromboxane synthase or cyclooxygenase effectively reduces these PAF-induced lung changes, with thromboxane synthase inhibition boosting PGE2 production.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Inflammation Research
Background:
- Platelet-activating factor (PAF) is a potent mediator implicated in inflammatory responses and cardiovascular effects.
- PAF administration in vivo leads to significant alterations in lung function, including decreased compliance and increased pulmonary artery pressure.
- Understanding the specific pathways involved in PAF-induced lung injury is crucial for developing targeted therapeutic interventions.
Purpose of the Study:
- To investigate the role of thromboxane synthase and cyclooxygenase pathways in PAF-induced lung dysfunction.
- To compare the efficacy of a thromboxane synthase inhibitor (DP1904) versus a cyclooxygenase inhibitor (meclofenamate) in mitigating PAF's effects.
- To examine the impact of these inhibitions on specific pro-inflammatory mediators in lung lymph.
Main Methods:
- Anesthetized sheep underwent chronic instrumentation for physiological measurements.
- Animals received intravenous bolus injections of PAF (0.1 µg/kg) alone or after pretreatment with DP1904 or meclofenamate.
- Lung function parameters (compliance, pulmonary artery pressure, lymph flow) and mediator concentrations (thromboxane B2, 6-keto-PGF1α, PGE2) in lung lymph were measured.
Main Results:
- Both DP1904 and meclofenamate significantly attenuated PAF-induced decreases in lung compliance, increases in pulmonary artery pressure, and elevated lung lymph flow.
- Both inhibitors abolished the PAF-induced rise in thromboxane B2 concentrations in lung lymph.
- Meclofenamate, but not DP1904, inhibited the increase in 6-keto-PGF1α, while DP1904 treatment led to a 2.7-fold increase in PGE2 levels compared to PAF alone.
Conclusions:
- Inhibition of thromboxane synthase is as effective as cyclooxygenase inhibition in attenuating PAF-induced lung dysfunction.
- Thromboxane synthase inhibition results in augmented production of PGE2 following PAF administration in vivo.
- These findings highlight the complex interplay of prostanoid pathways in mediating PAF's pulmonary effects.