Abstract 2617: Inhibition of Secretory Phospholipase A 2 Activity Attenuates Acute Cardiogenic Pulmonary Congestion Induced by Isoproterenol Infusion in Mice with Post-Myocardial Infarction

Abstract

Several types of secretory phospholipase A 2 (sPLA 2 ) are expressed in airway epithelial cells and alveolar inflammatory cells, yielding various eicosanoids that might cause pulmonary edema. This study examined whether inhibition of sPLA 2 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 sPLA 2 , 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 sPLA 2 were comparably increased from baseline by 3 ~ 5-fold in both groups of mice. sPLA 2 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 A 2 and leukotriene B 4 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 sPLA 2 activity, para -bromophenacyl bromide. Inhibition of sPLA 2 activity suppressed acute cardiogenic pulmonary edema, and sPLA 2 inhibition may have therapeutic value in acute cardiogenic pulmonary congestion.