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Pulmonary edema induced by phorbol myristate acetate is attenuated by compounds that increase intracellular cAMP
Abstract:
We have investigated the effect of terbutaline, aminophylline and dibutyryl cyclic AMP (DBcAMP) on phorbol myristate acetate (PMA)-induced acute lung injury in isolated, blood-perfused rabbit lungs. Pulmonary arterial pressure and lung weight were measured for 30 min after a bolus injection of PMA (10 mu g/kg). In the group exposed to PMA alone, the mean pulmonary arterial pressure (PAP) increased from 16.33 + or - 1.28 to 77.30 + or - 6.40 mmHg (P <0.001), and lung weight increased by 70.69 + or - 10.94 g during the 30 min after PMA challenge (P<0.001). Pretreatment with terbutaline, aminophylline or DBcAMP prevented the increases in both PAP and lung weight (P <0.001). Each of the three drugs also prevented the increase in pulmonary vascular permeability induced by PMA: terbutaline, aminophylline, and DBcAMP all significantly reduced the pulmonary capillary filtration coefficient (KfC) as well as the albumin concentration in the lung lavage fluid after PMA exposure. Post-treatment with terbutaline 5 min after PMA administration also had a protective effect. The mechanisms responsible for these protectivp3 effects may all involve an increase in intracellular cAMP, since all three drugs increase cAMP in the lung (though by different mechanisms). Our data further indicate that the inhibition of tumor necrosis factor production may likewise play an important role in the protective effect exerted by these drugs.
Insights
Terbutaline, aminophylline, and dibutyryl cyclic AMP (DBcAMP) protect rabbit lungs from acute lung injury induced by phorbol myristate acetate (PMA). These drugs reduce pulmonary hypertension and vascular permeability, potentially via increased intracellular cyclic AMP (cAMP).
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Cellular Biology
Background:
- Phorbol myristate acetate (PMA) induces acute lung injury (ALI) in isolated rabbit lungs.
- ALI is characterized by increased pulmonary arterial pressure (PAP) and lung weight.
- Pulmonary vascular permeability is a key feature of ALI.
Purpose of the Study:
- To investigate the protective effects of terbutaline, aminophylline, and dibutyryl cyclic AMP (DBcAMP) against PMA-induced ALI.
- To explore the mechanisms underlying the protective effects of these agents.
Main Methods:
- Isolated, blood-perfused rabbit lungs were used.
- PMA was administered to induce ALI.
- PAP and lung weight were measured.
- Pulmonary capillary filtration coefficient (KfC) and albumin concentration in lung lavage fluid were assessed.
- Pretreatment and post-treatment with drugs were evaluated.
Main Results:
- PMA significantly increased PAP and lung weight.
- Terbutaline, aminophylline, and DBcAMP pretreatment prevented these increases.
- These drugs also reduced pulmonary vascular permeability.
- Post-treatment with terbutaline showed a protective effect.
- The protective effects may involve increased intracellular cyclic AMP (cAMP) and inhibition of tumor necrosis factor.
Conclusions:
- Terbutaline, aminophylline, and DBcAMP effectively protect against PMA-induced ALI in rabbit lungs.
- These agents reduce pulmonary hypertension and vascular permeability.
- The protective mechanisms likely involve elevated intracellular cAMP levels and potentially inhibition of tumor necrosis factor production.