The role of astrocytes in glutamate toxicity has been controversial. Here, we show that astrocytes in neuron-astrocyte co-cultures increased neuronal sensitivity to chronic glutamate exposure but not to acute exposure. Enhanced neuronal toxicity by chronic exposure was dependent on astrocyte cell numbers. A reduced generation of extracellular H2O2 induced by glutamate was observed in co-cultures. Further, neuronal glutamate toxicity was not suppressed by NADPH oxidase (Nox) inhibitors, catalase or Nox4 knockdown in co-cultures, whereas these compounds effectively reduced the toxicity in pure neuron cultures. Instead, the intracellular scavenger of reactive oxygen species, N-acetylcysteine (NAC), reduced neuronal cytotoxicity in co-cultures, whereas catalase worked in pure neuron cultures. Lipoxygenase (LOX) inhibitors attenuated neuronal glutamate toxicity in co-cultures but not in pure neuron cultures. Neuronal 5-LOX activity was increased only in co-cultures, whereas 12-LOX activity was increased in both types of cultures. The cyclooxygenase (COX) inhibitors, indomethacin and NS-398, and the phospholipase A2 (PLA2) inhibitors, LY311727 and MAFP, more effectively reduced neuronal glutamate toxicity in co-cultures than in pure neuron cultures. However, in co-cultures, pre-treating neurons and astrocytes with the same inhibitors generated opposite results. COX inhibitors suppressed neuronal glutamate toxicity in pre-treated neurons rather than astrocytes, whereas PLA2 inhibitors reduced the toxicity in pre-treated astrocytes rather than neurons. Gene-specific knockdown of PLA2 confirmed these results. Knockdown of cPLA2α and/or sPLA2-V in astrocytes rather than in neurons more effectively reduced glutamate toxicity in co-cultures. These findings suggest that astrocytic PLA2 activity increases neuronal sensitivity to chronic glutamate exposure in neuron-astrocyte co-cultures.

15 May 2013·American Journal of Physiology-Lung Cellular and Molecular PhysiologyQ2 · MEDICINE

Mechanical induction of group V phospholipase A₂causes lung inflammation and acute lung injury

Q2 · MEDICINE

Article

Author: Muñoz, Nilda M. ; Meliton, Angelo Y. ; Birukova, Anna A. ; Leff, Alan R. ; Meliton, Lucille N. ; Birukov, Konstantin G.

Ventilation at high tidal volume may cause lung inflammation and barrier dysfunction that culminates in ventilator-induced lung injury (VILI). However, the mechanisms by which mechanical stimulation triggers the inflammatory response have not been fully elucidated. This study tested the hypothesis that onset of VILI is triggered by activation of secretory group V phospholipase A2(gVPLA2) in pulmonary vascular endothelium exposed to excessive mechanical stretch. High-magnitude cyclic stretch (18% CS) increased expression and surface exposure of gVPLA2 in human pulmonary endothelial cells (EC). CS-induced gVPLA2 activation was required for activation of ICAM-1 expression and polymorphonuclear neutrophil (PMN) adhesion to CS-preconditioned EC. By contrast, physiological CS (5% CS) had no effect on gVPLA2 activation or EC-PMN adhesion. CS-induced ICAM-1 expression and EC-PMN adhesion were attenuated by the gVPLA2-blocking antibody (MCL-3G1), general inhibitor of soluble PLA2, LY311727, or siRNA-induced EC gVPLA2 knockdown. In vivo, ventilator-induced lung leukocyte recruitment, cell and protein accumulation in the alveolar space, and total lung myeloperoxidase activity were strongly suppressed in gVPLA2 mouse knockout model or upon administration of MCL-3G1. These results demonstrate a novel role for gVPLA2 as the downstream effector of pathological mechanical stretch leading to an inflammatory response associated with VILI.

01 Feb 2012·The FASEB JournalQ2 · BIOLOGY

Activated platelets contribute to oxidized low‐density lipoproteins and dysfunctional high‐density lipoproteins through a phospholipase A2‐dependent mechanism

Q2 · BIOLOGY

Article

Author: Tietge, Uwe J. F. ; Lagrost, Laurent ; Blache, Denis ; Gautier, Thomas

Plasma activity of secretory phospholipase A2 (sPLA2) increases in patients with cardiovascular disease. The present study investigated whether platelet-released sPLA2 induces low-density lipoprotein (LDL) and high-density lipoprotein (HDL) modifications that translate into changes in lipoprotein function. Activated but not resting platelets induced oxidative modifications of human native LDLs and HDLs, which render these particles dysfunctional. Platelet-incubated LDLs stimulated the incorporation of cholesterol oleate into macrophages, and modified HDLs lost their cholesterol efflux capacity and antioxidant properties. In vitro and ex vivo experiments showed that lysophophatidylcholine accumulated in the platelet-modified LDLs and HDLs of mice expressing sPLA2 (Balb/c and transgenic C57Bl/6 mice expressing human sPLA2) but not in the lipoproteins of naturally sPLA2-deficient mice (C57Bl/6). Unlike C57Bl/6 mice, Balb/c mice injected with leptin (67 μg/mouse, i.p.) as an in vivo prothrombotic agent displayed increased plasma sPLA2 activity, reduced clotting time, higher plasma levels of oxidation products, increased production of nonesterified fatty acids, and more substantial platelet-mediated modification of lipoproteins. These effects were blocked completely by injection of the platelet inhibitor ticlopidine (5 mg/kg, i.p.) or by a sPLA2 inhibitor (LY311727, 3 mg/kg, i.p.). These results demonstrate that stimulated platelets are major contributors to plasma sPLA2 activity in vivo and account to a large extent for the adverse modification of circulating lipoproteins.

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Indication	Highest Phase	Country/Location	Organization	Date
Sepsis	Phase 2	US	Eli Lilly & Co.	01 Oct 2001

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