Low-dose PGI2 prevents monocrotaline-induced thromboxane production and lung injury.

In animals, monocrotaline induces an acute lung injury secondary to capillary endothelial damage. To date, no reports have appeared dealing with the role of prostaglandins in monocrotaline-induced injury. Our studies, in dogs, revealed that monocrotaline (30 mg/kg iv) caused an acute and persistent thrombocytopenia, lung platelet deposition, pulmonary hypertension, and increased extravascular lung water (EVLW). The pulmonary hypertensive response was biphasic. Thromboxane B2 levels were similarly biphasic, peaking at 5 min and 2 h. The levels of 6-keto-PGF1 alpha peaked at 30 min and returned to base line at 3 h. Pulmonary vascular resistance paralleled thromboxane levels. Infusion of prostacyclin (PGI2) at 50 ng X kg-1 X min-1 effectively prevented the thrombocytopenia, lung platelet deposition, pulmonary hypertension, and increased EVLW; and it decreased excess thromboxane production by 79%. These results suggest that platelet activation and lung sequestration play a role in acute lung injury due to monocrotaline, and that the resultant thromboxane production may contribute to the pulmonary hypertension. PGI2 ameliorates monocrotaline-induced injury, perhaps by preventing platelet activation.

Mechanisms of interaction between oxygen and granulocytes in hyperoxic lung injury.

Hyperoxia and infused granulocytes act synergistically in producing a nonhydrostatic high-permeability lung edema in the isolated perfused rabbit lung within 4 h, which is substantially greater than that seen with hyperoxia alone. We hypothesized that the interaction between hyperoxia and granulocytes was principally due to a direct effect of hyperoxia on the lung itself. Isolated perfused rabbit lungs that were preexposed to 2 h of hyperoxia (95% O2-5% CO2) prior to the infusion of unstimulated granulocytes (under normoxic conditions) developed significant nonhydrostatic lung edema (P = 0.008) within 2 h when compared with lungs that were preexposed to normoxia (15% O2-5% CO2) prior to granulocyte perfusion. The edema in the hyperoxic-preexposed lungs was accompanied by significant increases in bronchoalveolar lavage (BAL) protein, BAL granulocytes, BAL thromboxane and prostacyclin levels, perfusate chemotactic activity, and lung lipid peroxidation. These findings suggest that the synergistic interaction between hyperoxia and granulocytes in producing acute lung injury involves a primary effect of hyperoxia on the lung itself.

Inhibition of indium-111 platelet accretion onto venous thrombi in dogs by prostacyclin.

The known platelet anti-aggregant effects of prostacyclin (epoprostenol) suggest that it may have therapeutic potential in conditions in which the platelet plays a pathophysiological role. The growth of venous thrombi is one such condition. We have attempted to determine, in a canine model of fresh venous thrombosis, whether prostacyclin infusion inhibits platelet accretion in vivo and how this in vivo event related to hemodynamic and in vitro platelet anti-aggregant effects. Gamma camera imaging over thrombi for accretion of indium-111-labeled platelets disclosed that prostacyclin, at an infusion rate of 50 ng/kg per min, inhibited platelet accretion in vivo and resulted in a 95 +/- 4% decrease in in vitro adenosine diphosphate-induced platelet aggregation, and a decrease in mean arterial pressure to 86 +/- 4% of pre-infusion values. Step-wise decrements of prostacyclin infusion demonstrated that platelet accretion occurred in vivo at infusion rates of approximately 10-20 ng/kg per min and correlated with an in vitro adenosine diphosphate-induced aggregation of 54 +/- 13% of control values. Thus, prostacyclin, in a dose that causes only a mild decrease in systemic pressure, can completely inhibit platelet uptake onto fresh venous thrombi in the dog, and this inhibition correlates closely with in vitro adenosine diphosphate-induced platelet aggregation. The potential therapeutic implications of these findings are discussed.

Dissociation between hemodynamic and platelet antiaggregant effects of prostacyclin in dogs determined with a rapid platelet isolation technique.

Prostacyclin, a potent vasodilator and inhibitor of platelet aggregation, is being increasingly used in disease states in which platelets may play a pathophysiologic role. A literature review revealed a variable dissociation between the in vitro platelet antiaggregant activity of prostacyclin and both the in vivo hemodynamic and platelet antiaggregant activities. Because widely variable platelet isolation techniques may have contributed to this variability, we investigated the hemodynamic and platelet antiaggregant effects of prostacyclin infusion in the dog, using in vitro techniques limiting the time from blood sampling to aggregometry to 2 1/2 and 10 1/2 min. Using the short technique, we demonstrate complete inhibition of platelet aggregation at a prostacyclin infusion rate that caused only a mild decrease in arterial pressure. In contrast, the longer technique requires an eightfold higher prostacyclin infusion rate to achieve the same degree of antiaggregant activity. The prostacyclin activity apparent half-life was 3 min. Because interspecies differences exist in both the hemodynamic and antiaggregant effects of prostacyclin and in their relationship to each other, we suggest that a closer approximation of in vivo antiaggregant effects may be obtained with in vitro methods that are rapid, thus taking into account the lability of prostacyclin. We conclude that the variable in vitro platelet antiaggregant effects of prostacyclin reported in the literature are due to the variable and longer techniques.