Quinolines attenuate PAF-induced pulmonary pressor responses and edema formation

In the present study we have investigated the mechanisms of pulmonary edema caused by platelet-activating factor (PAF) in isolated rat lungs as well a s in mice in vivo. In blood-free perfused and ventilated rat lungs, PAF inc reased lung weight by 0.59 +/- 0.18 g. The cyclooxygenase inhibitor aspirin (500 mu M) blocked this response by one-third, and the quinolines quinine (330 mu M), quinidine (100 mu M), and chloroquine (100 mu M) by two-thirds. Lipoxygenase inhibition (10 mu M AA861) alone or in combination with throm boxane receptor antagonism (10 mu M SQ29548) had no effect on PAF-induced w eight gain. In combination with aspirin, quinine or quinidine completely pr evented PAF-induced weight gain and the concomitant increase of the capilla ry filtration coefficient (K-f,K-c). Pretreatment with quinine in vivo prev ented not only PAF-, but also endotoxin-induced edema formation as assessed by Evans Blue extravasation. In addition, in vivo quinine prevented the en dotoxin-induced release of tumor neurosis factor (TNF). Furthermore, in per fused lungs quinine reduced the PAF-induced increases in airway and vascula r resistance, as well as thromboxane release. These findings demonstrate th e following anti-inflammatory properties of quinolines: reduction of thromb oxane and TNF formation; reduction of PAF-induced vasoconstriction and bron choconstriction; and attenuation of PAF- and lipopolysaccharide (LPS)-induc ed edema formation. We conclude that the PAF-induced edema consists of two separate mechanisms, one dependent on an unknown cyclooxygenase metabolite, the other one sensitive to quinolines.