ENDOTHELIN-1 AND THROMBOXANE A(2) INCREASE PULMONARY VASCULAR-RESISTANCE IN GRANULOCYTE-MEDIATED LUNG INJURY

Objective: To examine the pathophysiologic role of vasoactive eicosano ids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature. Design: Prospective experimental study in rabbits. Settin g: Experimental laboratory in a university teaching hospital. Subjects : Thirty adult rabbits. Interventions: The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a c ell- and plasma-free buffer solution. Measurements and Main Results: T he pulmonary arterial pressure and the lung weight gain were continuou sly registered. Intermittently perfused samples were taken to determin e endothelin-1 and thromboxane A(2) concentrations. Six experiments wi thout intervention served as the sham group. The granulocytes in the p ulmonary circulation were stimulated with N-formyl-L-leucin-methionyl- L-phenylalanine (FMLP; 10(-6) M; control, n = 6). To investigate wheth er activated granulocytes influence the pulmonary vasculature via endo thelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6). The potential i nvolvement of thromboxane A(2) in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor dic lofenac (10 mu g/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was f ollowed by a second delayed pressure increase after 60 mins (>14 mm Hg ) and was paralleled by a massive generation of thromboxane A(2) (>250 pg/mL). Fifteen minutes after FMLP-injection, endothelin-1 was detect able in the perfusate. Pretreatment with the selective endothelin-A an tagonist LU135252 significantly (p < .01) reduced the initial pressure response after FMLP stimulation, while diclofenac significantly reduc ed (p <.05) the delayed pressure increase. Using diclofenac (10 mu g/m L) in conjunction with LU135252 (10(-6) M; n = 6) before FMLP injectio n significantly reduced the early and the delayed pressure increase. C onclusions: Activated granulocytes seem to enhance pulmonary vascular resistance via endothelin-1 and thromboxane A(2). The endothelin-1 eff ects are probably mediated via endothelin-A receptors since the endoth elin-A receptor antagonist LU135252 was able to suppress the early pre ssure reaction after FMLP injection, whereas the cyclooxygenase inhibi tor diclofenac was able to reduce the second pressure increase.