Crucial Role of Group IIA Phospholipase A₂ in Oleic Acid–Induced Acute Lung Injury in Rabbits

Abstract

Group IIA secretory phospholipase A(2) (sPLA(2)) has been implicated in a variety of inflammatory diseases including acute lung injury (ALI); however, the role of sPLA(2) in this disorder remains unclear. The aim of the present investigation was to examine the role of this enzyme in a model of ALI induced by oleic acid (OA) in rabbits by testing human group IIA phospholipase A(2) (PLA(2)) inhibitor, S-5920/LY315920Na. Experimental groups consisted of a saline control group (n = 8), an OA control group (n = 10) infused intravenously with OA (0.1 ml/kg/h for 2 h), and three groups given OA + S-5920/LY315920Na (three different doses, n = 8, respectively). Infusion of OA provoked pulmonary hemorrhage and edema formation, protein leakage, and massive neutrophil infiltration, resulting in severe hypoxemia and impaired lung compliance. PLA(2) activity was detected in the bronchoalveolar lavage fluid (BALF), but not plasma, which correlated well with severity of lung injury in this model. Pretreatment with S-5920/LY315920Na diminished the OA-induced PLA(2) activity in the BALF and dose-dependently attenuated the previously described lung injury induced by OA, accompanied by protection against lung surfactant degradation and production of thromboxane A(2) (TXA(2)) and leukotriene B(4) (LTB(4)). S-5920/LY315920Na also inhibited the OA-induced production of interleukin-8 (IL-8), both in plasma and BALF. Thus, sPLA(2) appears to play a key role in OA-induced lung injury, suggesting that the group IIA PLA(2) inhibitor may be a promising agent for patients with acute respiratory distress syndrome (ARDS).

A Study on the Mechanism of Immunomodulating Effects of Moxifloxacin in Oleic Acid-Induced Acute Lung Injury

“…As expected, moxifloxacin was shown to exert a protective effect on OA-induced lung leak and to suppress the accumulation and migration of neutrophils in the lung. The OA is one of the derivatives of fatty acids and is responsible for acute inflammatory injury of the lung in FES, that is, OA induces lung leak, accumulation of neutrophils, and oxidative stress leading to ALI in experimental animals and human beings 21 . Moxifloxacin was effective to suppress lung leak by the decrease of neutrophilic oxidative stress or neutrophil-induced tissue injury evidenced by reducing lung MPO, number of BAL neutrophils, MDA content in the lung of rats given OA.…”

Effect of a Selective Inhibitor of Secretory Phospholipase A2, S-5920/LY315920Na, on Experimental Acute Pancreatitis in Rats

“…In these patients, increased serum catalytic sPLA 2 activity has been implicated in the pathogenesis of remote organ failure such as pulmonary insufficiency (7 -9), and both types of sPLA 2 have been suggested to be involved in clinical acute lung injury such as adult respiratory distress syndrome (28,29), as supported by the effective degradation of lung surfactant phospholipids by both types of sPLA 2 (30,31). In this connection, since S-5920 / LY315920Na showed a beneficial effect on the experimental acute lung injury induced by oleic acid (12) or intestinal ischemia-reperfusion (13), this inhibitor could be useful for preventing not only further destruction of the pancreas but also acute lung injury complicated by necrotizing pancreatitis.…”

“…Recently, highly potent inhibitors of sPLA 2 -IIA have been found by using computer-aided drug design and chemical modification (10). Among them, S-5920 / LY315920Na was most potent and specific for sPLA 2 -IIA (10,11) and has been already found to show efficacy against models of acute lung injury (12,13) and trypsin-taurocholate (TCA)-induced pancreatitis in rats (14). Another sPLA 2 -IIA inhibitor, BM 16.2056, also showed a beneficial effect on taurocholate-induced acute pancreatitis in rats (15), suggesting that sPLA 2 -IIA plays pathophysiological roles in these models.…”

Human group IIA secretory phospholipase A2 potentiates Ca2+ influx through L‐type voltage‐sensitive Ca2+ channels in cultured rat cortical neurons

“…sPLA 2 s have several common characteristics, including a relatively low molecular mass (13-18 kDa), the presence of six to eight disulfide bonds, an absolute catalytic requirement for millimolar concentration of Ca 2+ , and a broad specificity for phospholipids with different polar head groups and fatty acid chains (Tishchfield 1997;Lambeau and Lazdunski 1999). Among sPLA 2 s, group IIA sPLA 2 (sPLA 2 -IIA) is thought to be one of the key enzymes in the pathogenesis of inflammatory disease, because its local and systemic levels are elevated in diseases, such as acute lung injury (Furue et al 1999;Koike et al 2000). An sPLA 2 inhibitor was reported to suppress lung injury induced by oleic acid and intestinal ischemia reperfusion (Furue et al 1999;Koike et al 2000).…”

“…Among sPLA 2 s, group IIA sPLA 2 (sPLA 2 -IIA) is thought to be one of the key enzymes in the pathogenesis of inflammatory disease, because its local and systemic levels are elevated in diseases, such as acute lung injury (Furue et al 1999;Koike et al 2000). An sPLA 2 inhibitor was reported to suppress lung injury induced by oleic acid and intestinal ischemia reperfusion (Furue et al 1999;Koike et al 2000). sPLA 2 -IIA gene expression is induced in the ischemic brain (Lauritzen et al 1994).…”