Abstract 2617: Inhibition of Secretory Phospholipase A2 Activity Attenuates Acute Cardiogenic Pulmonary Congestion Induced by Isoproterenol Infusion in Mice with Post-Myocardial Infarction
Several types of secretory phospholipase A2 (sPLA2) are expressed in airway epithelial cells and alveolar inflammatory cells, yielding various eicosanoids that might cause pulmonary edema. This study examined whether inhibition of sPLA2 activity attenuates acute cardiogenic pulmonary congestion in mice. Acute cardiogenic pulmonary congestion in 10-week-old male C57BL/6J mice was induced by continuous intravenous infusion of isoproterenol (ISP) (10 mg/kg/hr) at 2 weeks after the creation of myocardial infarction by left coronary artery ligation. Just before ISP infusion, a single intraperitoneal injection of 100 mg/kg of LY374388 (LY), a prodrug of LY329722 that is a specific inhibitor of activity of all sPLA2, or vehicle was administered. Arterial systolic pressure, heart rate, and LV end-diastolic pressure were comparably increased after ISP in both LY-mice and vehicle-mice. Also, lung expression levels of mRNA and protein of group V and X sPLA2 were comparably increased from baseline by 3 ~ 5-fold in both groups of mice. sPLA2 activity in lung tissue after ISP was increased from baseline by 5-fold in vehicle-mice, while the activity was not detected in LY-mice. In isolated neutrophils, incubation with LY329722 inhibited the respiratory burst and migration in response to fMLP or C5a by 40~50%. LY significantly reduced the lung-to-body weight ratio after ISP (71% of vehicle-mice) and attenuated alveolar neutrophil accumulation based on the lung histology (56% of vehicle-mice). Using the Evans Blue extravasation method, pulmonary vascular permeability was suppressed in LY-mice (Evans Blue content in lung; 66% of vehicle-mice). The lung content of thromboxane A2 and leukotriene B4 was increased in both groups, but was lower in LY-mice (71% and 64% of vehicle-mice, respectively). In Kaplan-Meyer analysis, the survival rate during the 12hr ISP infusion was higher in LY-mice than vehicle-mice (p < 0.01, n = 15 mice per group). Similar results were obtained with another inhibitor of sPLA2 activity, para-bromophenacyl bromide. Inhibition of sPLA2 activity suppressed acute cardiogenic pulmonary edema, and sPLA2 inhibition may have therapeutic value in acute cardiogenic pulmonary congestion.