Endothelin ETB receptor-mediated mechanisms involved in oleic acid-induced acute lung injury in mice

The receptors underlying the endothelin-dependent component of lung plasma extravasation and leucocyte infiltration induced by oleic acid were assessed in mice. Oleic acid (1 mg.kg(-1) intravenously), but not endothelin-1 (up to 1 nmol kg(-1) intravenously), increased accumulation of Evans blue in the lungs (excluding the trachea and main bronchi) from 11.8+/-3.9 to 98.6+/-10.7 mug 1 h after injection. Bosentan, the antagonist of endothelin receptors (ETA and ETB) or the selective ETB receptor antagonists Ro 46-8443 or A-192621 (administered 1 h before oleic acid at doses of 30, 10 and 30 mg.kg(-1) respectively) reduced the effect of oleic acid by 71%, 58% and 79% respectively. However, the selective ETA receptor antagonist A-127722.5 (10 mg.kg(-1)) was inactive. Oleic acid (2 mg.kg(-1), intravenously) raised the number of total leucocytes, mononuclear cells and neutrophils in broncho-alveolar lavage fluid 4 h after injection. Bosentan and Ro 46-8443 (at doses of 30 and 10 mg.kg(-1) respectively) inhibited the neutrophil infiltration induced by oleic acid by approx. 80%. None of the antagonists modified control (basal) pulmonary microvascular permeability or total and differential cell counts. Thus, endogenous endothelins, acting via ETB receptor-dependent mechanisms, play a major role in oleic acid-induced lung injury in the mouse by promoting infiltration of circulating neutrophils and enhancement of pulmonary microvascular plasma extravasation. These findings suggest that either ETB or mixed ETA/ETB receptor antagonists might be beneficial in the treatment of the adult respiratory distress syndrome.