Inhibition of secretory phospholipase A2 activity attenuates acute cardiogenic pulmonary edema induced by isoproterenol infusion in mice after myocardial infarction.
Several types of secretory phospholipase A2 (sPLA2) are expressed in lung tissue, yielding various eicosanoids that might cause pulmonary edema. This study examined whether inhibition of sPLA2 activity attenuates acute cardiogenic pulmonary edema in mice. Acute cardiogenic pulmonary edema was induced in C57BL/6J male mice by an increase in heart rate with continuous intravenous infusion of isoproterenol (ISP) (10 mg/kg/h) 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 LY374388, a prodrug of LY329722 that inhibits sPLA2 activity, or vehicle was administered. The ISP infusion after myocardial infarction induced interstitial and alveolar edema on lung histology. Furthermore, it increased the lung-to-body weight ratio, pulmonary vascular permeability evaluated by the Evans blue extravasation method, lung activity of sPLA2, and lung content of thromboxane A2 and leukotriene B4. These changes were significantly attenuated by LY374388 treatment. In Kaplan-Meier analysis, the survival rate during the ISP infusion after myocardial infarction was significantly higher in LY374388- than in vehicle-treated mice. Similar results were obtained with another inhibitor of sPLA2 activity, para-bromophenacyl bromide. In conclusion, inhibition of sPLA2 activity suppressed acute cardiogenic pulmonary edema.
Kawabata
Kenichi
K
Department of Internal Medicine II, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
Fujioka
Daisuke
D
Kobayashi
Tsuyoshi
T
Saito
Yukio
Y
Obata
Jun-Ei
JE
Nakamura
Takamitsu
T
Yano
Toshiaki
T
Watanabe
Kazuhiro
K
Watanabe
Yosuke
Y
Mishina
Hideto
H
Kugiyama
Kiyotaka
K
D000818:Animals; D007210:Indoleacetic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007545:Isoproterenol; D007975:Leukotriene B4 / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000150:complications* / Q000503:physiopathology; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors*; D011654:Pulmonary Edema / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D013929:Thromboxane B2 / Q000378:metabolism
C551333:(3-aminooxalyl-1-benzyl-2-ethyl-6-methyl-1H-indol- 4-yloxy)-acetic acid methyl ester; D007210:Indoleacetic Acids; D007975:Leukotriene B4; D013929:Thromboxane B2; D054497:Phospholipases A2, Secretory; D007545:Isoproterenol