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Rolipram and isoproterenol reverse platelet activating factor-induced increases in pulmonary microvascular
P E Noel1, J R Fletcher, W J Thompson
1Department of Surgery, University of South Alabama, College of Medicine, Mobile 36688, USA.
Abstract:
Platelet activating factor (PAF) is an important mediator of pulmonary microvascular endothelial cell (PMVEC) injury in sepsis. Membrane receptors for PAF have been identified on PMVECs and mediate its actions at least in part by protein kinase C activation. Since rolipram, a family IV cyclic AMP phosphodiesterase inhibitor, and isoproterenol, an adenylate cyclase activator, both reverse ischemia-reperfusion-induced lung permeability, we studied the effects of these agents on PAF-induced pulmonary microvascular permeability. The isolated rat lung model was used in which lungs were ventilated and buffer perfused at constant flow while suspended from a force transducer to monitor lung weight along with arterial (P(a)) and venous (Pv) pressures. Control lungs (n = 6) were infused with PAF (40 nmole/kg) via an arterial port and the capillary permeability coefficient (Kf,c) was determined at 0, 15, and 60 min. The remaining lungs were randomized for infusion with either rolipram (n = 4, 20 mumole/kg) or isoproterenol (n = 4, 5 mumole/kg) via an arterial port 30 min after injury with PAF. In the rolipram- and isoproterenol-treated groups, the Kf,c was determined 15 and 60 min postinfusion with these agents. The control group showed significant elevation in the Kf,c and total pulmonary resistance (Rt). At 15 and 60 min, rolipram and isoproterenol reversed PAF injury as shown by the significant improvement in the Kf,c and Rt. These findings support the concept that increased cyclic AMP is an important mediator in the reversal of PAF-increased PMVEC permeability and pulmonary resistance.
Insights
Platelet-activating factor (PAF) causes lung injury by increasing pulmonary microvascular endothelial cell (PMVEC) permeability. Cyclic AMP-elevating agents like rolipram and isoproterenol effectively reversed this PAF-induced lung permeability in rats.
Area of Science:
- Pulmonary medicine
- Cellular biology
- Pharmacology
Background:
- Platelet-activating factor (PAF) is a key mediator of pulmonary microvascular endothelial cell (PMVEC) injury, particularly in sepsis.
- PAF exerts its effects on PMVECs, at least partly through protein kinase C activation.
- Previous studies indicate that agents increasing cyclic AMP levels can reverse lung permeability caused by ischemia-reperfusion injury.
Purpose of the Study:
- To investigate the therapeutic potential of rolipram and isoproterenol in reversing Platelet-activating factor (PAF)-induced pulmonary microvascular permeability.
- To explore the role of cyclic AMP in mitigating PAF-mediated lung injury.
Main Methods:
- Utilized an isolated, ventilated, and perfused rat lung model.
- Measured lung weight changes and pulmonary pressures to assess capillary permeability coefficient (Kf,c) and total pulmonary resistance (Rt).
- Administered PAF to induce injury, followed by treatment with either rolipram or isoproterenol, comparing outcomes to a control group.
Main Results:
- PAF infusion significantly increased Kf,c and Rt, indicating pulmonary microvascular endothelial cell (PMVEC) injury.
- Both rolipram and isoproterenol treatments significantly reversed the PAF-induced elevations in Kf,c and Rt.
- These beneficial effects were observed at 15 and 60 minutes post-treatment.
Conclusions:
- Increased cyclic AMP levels are crucial for reversing Platelet-activating factor (PAF)-induced pulmonary microvascular endothelial cell (PMVEC) permeability.
- Rolipram and isoproterenol demonstrate potential as therapeutic agents for conditions involving PAF-mediated lung injury.