Dioleylphosphatidylglycerol Inhibits the Expression of Type II Phospholipase A2 in Macrophages

Abstract

We have recently shown that modified natural pulmonary surfactant Curosurf inhibits the synthesis of type II phospholipase A2 (sPLA2-II) by cultured guinea-pig alveolar macrophages (AM). The goal of the present study was to identify the surfactant components and the mechanisms involved in this process. We show that protein-free artificial surfactant (AS) mimicked the inhibitory effect of Curosurf, suggesting that phospholipid components of surfactant play a role in the inhibition of sPLA2-II expression. Among surfactant phospholipids, dioleylphosphatidylglycerol (DOPG) was the most effective in inhibiting the synthesis of sPLA2-II. By contrast, the concentrations of platelet-activating factor (PAF)-acetylhydrolase and lysophospholipase activities remained unchanged, indicating that inhibition of sPLA2-II synthesis was caused by a specific effect of surfactant. The effect of DOPG on sPLA2-II synthesis was concentration-dependent and was accompanied by a rapid and time-dependent uptake of DOPG by AM whereas dipalmitoylphosphatidylcholine (DPPC) was only marginally taken up. Curosurf, AS, and DOPG inhibited tumor necrosis factor-alpha (TNF-alpha) secretion, a key step in the induction of sPLA2-II synthesis by AM, in contrast to DPPC which had only a marginal effect. We conclude that phospholipid components, especially DOPG, play a major role in the inhibition of sPLA2-II synthesis by surfactant and that this effect can be explained, at least in part, by an impairment of TNF-alpha secretion.

Role of distinct phospholipases A2 and their modulators in meconium aspiration syndrome in human neonates

“…First, sPLA2-IB might induce other phospholipases through the release of various eicosanoids [5]. Second, we found significant amounts of meconial TNFa, which upregulate sPLA2 expression [28,31]. TNFa has already been described in meconium together with other proinflammatory cytokines [3,32] and, amongst these, IL1b might be a third factor boosting the lung's sPLA2-IIA production [33].…”

Inhibition by unsaturated fatty acids of type II secretory phospholipase A2 synthesis in guinea‐pig alveolar macrophages

“…In our previous study, we reported that guinea‐pig AM cultured in the presence of serum synthesize and release sPLA 2 ‐II after prolonged in vitro incubation [7]. This synthesis is induced by adherence of AM to plastic dishes and/or by the removal of inhibitory factors present in the lung [7,30]. We have recently shown that the COX‐derived AA metabolite, prostaglandin E 2 , inhibits sPLA 2 ‐II synthesis by AM [17].…”

“…Measurement of sPLA 2 activity was carried out using the fluorimetric assay as described by Radvanyi and co‐workers [28] and shown to be selective for the secreted PLA 2 type [7]. Furthermore, sPLA 2 activity measured in the cell lysates of AM was shown to be blocked totally by the type II sPLA 2 inhibitor LY311727 at 10 µ m [29], indicating that sPLA 2 activity measured in AM corresponds to a type II sPLA 2 activity [18–30]. Briefly, the fluorescent phospholipid was dried under nitrogen and suspended in ethanol at a concentration of 0.2 m m .…”

Secretory phospholipase A2 pathway in various types of lung injury in neonates and infants: a multicentre translational study

“…sPLA2 interferes with the surfactant activity and so reduces compliance [ 4 - 6 ]. sPLA2 starts a vicious cycle in which it damages the surfactant; since some surfactant components have their own inhibitory effect on sPLA2 activity and expression [ 7 , 8 ], the sPLA2-induced surfactant damage reduces this inhibition and thus the enzyme is able to further catabolize the surfactant phospholipids [ 4 ]. Thus, sPLA2 facilitates the action of other injurious agents against the lung epithelium, leading to further surfactant damage, alveolar collapse and respiratory impairment [ 4 ].…”