Promethazine or DPPD pretreatment attenuates oleic acid-induced injury in isolated canine lungs

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Abstract
Oleic acid caused pulmonary edema by increasing capillary endothelial permeability, although the mechanism of this action in uncertain. The hypothesis that the damage is an oxidant injury initiated by oleic acid was tested using isolated blood-perfused canine lung lobes. The lobes were dilated with papaverine and perfused in zone III with a constant airway pressure of 3 cmH2O. Changes in isogravimetric capillary pressure (Pc,i) and capillary filtration coefficient (Kf,C) were used as indices of alterations in microvascular permeability in lungs treated with silicone fluid (n = 3), oleic acid (n = 11), oleic acid after pretreatment with the antioxidants promethazine HCl (n = 11) or N,N''-diphenyl-p-phenylenediamine (DPPD; n = 4) or oleic acid following pretreatment with methylprednisolone (n = 4). Kf,C averaged 0.21 .+-. 0.02 ml .cntdot. min-1 .cntdot. cmH2O-1 .cntdot. 100 g-1 in control and increased to 0.55 .+-. 0.05 and 0.47 .+-. 0.05 when measured 20 and 180 min after the administration of oleic acid. When oleic acid was infused into lungs pretreated with promethazine, Kf,C increased to only 0.38 .+-. 0.05 ml .cntdot. min-1 .cntdot. cmH2O-1 .cntdot. 100 g-1 after 20 min and turned to control levels by 180 min. Pretreatment with DPPD, but not methylprednisolone, similarly attenuated the increase in Kf,C following oleic acid. Silicone fluid had no effect on Kf,C. That oleic acid increases vascular permeabilty was also evidenced by a fall (P < 0.05) in Pc,i from control when measured at 180 min in every group. The fall in Pc,i was attenuated to some extent by promethazine (P = 0.01 vs. oleic acid alone and P < 0.05 vs. steroid-treated lungs) and DPPD (P < 0.05) but not by methylprednisolone. The oleic acid-induced damage of cellular membranes may in part be due to production of some toxic free radical. Among other actions, promethazine and DPPD can act as electron scavengers and may limit oxidative injury due to oleic acid at the endothelial barrier.