Subcellular membrane impairment and application of phospholipase A2 inhibitors in endotoxic shock

Song, S.M; Lu, Songmin; Wang, Zi-Zong; Liu, J.C; Guo, Shiyin; Li, Z

doi:10.1016/s0020-1383(98)00178-8

Cited by 10 publications

(6 citation statements)

References 14 publications

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“…Among PLA 2 s, an 85-kd cytoplasmic PLA 2 (cPLA 2 ) is constitutively expressed in all cells (16,17) and known to play a critical role in the pathogenesis and progression of inflammation, including endotoxin shock (18,19). Furthermore, the protective effects of PLA 2 inhibitors in endotoxin shock (20,21) or reduced septic symptoms in PLA 2 -deficient mice (22,23) indicate that PLA 2 is an essential component in the pathogenesis of endotoxin shock.…”

Section: Introductionmentioning

confidence: 99%

Glutamine Inhibits Lipopolysaccharide-Induced Cytoplasmic Phospholipase A2 Activation and Protects Against Endotoxin Shock in Mouse

Kim

Kim³

et al. 2006

Shock

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Glutamine (Gln) supplementation is known to play a beneficial role in a number of settings of critical illness as well as laboratory models of endotoxin shock. We have investigated a molecular mechanism of the protective role of Gln in lipopolysaccharide (LPS)-induced shock using a mouse model. To examine the effectiveness of Gln, Gln was administered before or after LPS injection. Treatment of Gln before, but not after, LPS injection resulted in inhibition of nuclear factor kappaB activation and tumor necrosis factor alpha synthesis. In contrast, protection of animal from LPS-mediated death by Gln was observed when the Gln treatment was performed after LPS injection, suggesting that nuclear factor kappaB/tumor necrosis factor alpha signaling does not play an important role in this process. LPS injection induced phosphorylation of cytoplasmic phospholipase A2 (cPLA2), which was blocked by Gln treatment after LPS injection. Similarly, the LPS-stimulated cPLA2 activity was also inhibited by Gln treatment after LPS injection. Moreover, a cPLA2 inhibitor not only inhibited LPS-induced activation of cPLA2, but also significantly prevented LPS-mediated death. These observations indicate that Gln has a capability to inhibit cPLA2 phosphorylation and activation and suggest that Gln might be of a great therapeutic value for controlling inflammatory diseases in which cPLA2 plays an important role in the pathogenesis of the diseases.

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Section: Introductionmentioning

confidence: 99%

Glutamine Inhibits Lipopolysaccharide-Induced Cytoplasmic Phospholipase A2 Activation and Protects Against Endotoxin Shock in Mouse

Kim

Kim³

et al. 2006

Shock

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“…Among PLA 2 s, a 85-kDa cytoplasmic PLA 2 (cPLA 2 ) is known to play a critical role in the pathogenesis and progression of inflammation, including endotoxic shock. The protective effects of PLA 2 inhibitors in endotoxic shock (10,11), or reduced septic symptoms in PLA 2 -deficient mice (12,13), indicate that PLA 2 is an essential component in the pathogenesis of endotoxic shock. We have previously shown that Gln protects animals from endotoxic shock through its inhibition of cPLA 2 activity (14), and this activity of Gln was also associated with suppression of asthma in mice (15).…”

mentioning

confidence: 99%

Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1

Bang

et al. 2009

The Journal of Immunology

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The nonessential amino acid l-glutamine (Gln) is the most abundant amino acid in plasma. Clinical trials have demonstrated that Gln therapy is safe and improves clinical outcomes in critically ill patients. We have previously shown that Gln protect animals from endotoxic shock through the inhibition of cytosolic phospholipase A2 activity. In this study, we investigated how Gln regulates MAPK activation, as the molecular mechanism underlying Gln-induced cytosolic phospholipase A2 inactivation. Gln rapidly (within 10 min) inactivated p38 and JNK, but not ERK, by dephosphorylating them only when these MAPKs were phosphorylated in response to LPS in vivo as well as in vitro. Western blot analysis revealed that Gln administration resulted in rapid (∼5 min) phosphorylation and protein induction of MAP kinase phosphatase-1 (MKP-1). MKP-1 siRNA abrogated the Gln-mediated 1) inactivation of p38 and JNK, 2) induction of MKP-1, and 3) protection against endotoxic shock. The ERK inhibitor U0126 blocked Gln-induced MKP-1 phosphorylation and protein induction, as well as Gln’s protective activity against endotoxic shock. These data suggest that Gln exerts a beneficial effect on endotoxic shock by inactivating p38 and JNK via a rapid induction of MKP-1 protein in an ERK-dependent way.

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“…Inhibitive effect on PLA 2 of QA may partly contribute to membrane stabilization. This activity was also found with another PLA 2 inhibitor, chlorquine (Song et al, 1999;Luo et al, 2004;Zhao et al, 2005;Farooqui et al, 2006). Reduction of cellular phospholipids metabolism and a decrease of membrane fluidity induced by fog/smoke inhalement could be inhibited by chlorquine injection, and is perhaps the major protective mechanism of this PLA 2 inhibitor against the injury from fog or smoke inhalation (Luo et al, 2004).…”

Section: Chemicals Results Ofmentioning

confidence: 83%

Quinacrine protects neuronal cells against heat‐induced injury

Gao

Shuhong

Yan

et al. 2009

Cell Biology International

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The effects of quinacrine (QA) on heat-induced neuronal injury have been explored, with the intention of understanding the mechanisms of QA protection. Primary cultivated striatum neurons from newborn rats were treated with QA 1h before heat treatment at 43 degrees C which lasted for another 1h, and necrosis and apoptosis were detected by Annexin-V-FITC and propidium iodide (PI) double staining. Neuronal apoptosis was determined using terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL) techniques. Cell membrane fluidity, activity of cytosolic phospholipase A(2) (cPLA(2)) and the level of arachidonic acid (AA) were also examined. Membrane surface ultrastructure of striatum neurons was investigated by atomic force microscopy (AFM). Results showed that heat treatment induced great striatum neurons death, with many dying neurons undergoing necrosis rather than apoptosis. QA alone had little effect on the survival of striatum neurons, while QA pretreatment before heat treatment decreased necrosis. Heat treatment also resulted in decreased membrane fluidity and increased cPLA(2) activity as well as arachidonic acid level; these effects were reversed by QA pretreatment. QA pretreatment also significantly prevented damage to the membrane surface ultrastructure of heat-treated neurons. These results suggest that QA protects striatum neurons against heat-induced neuronal necrosis, and also demonstrate that inhibition of cPLA(2) activity and stabilization of membranes may contribute to protective effect of quinacrine.

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Subcellular membrane impairment and application of phospholipase A2 inhibitors in endotoxic shock

Cited by 10 publications

References 14 publications

Glutamine Inhibits Lipopolysaccharide-Induced Cytoplasmic Phospholipase A2 Activation and Protects Against Endotoxin Shock in Mouse

Glutamine Inhibits Lipopolysaccharide-Induced Cytoplasmic Phospholipase A2 Activation and Protects Against Endotoxin Shock in Mouse

Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1

Quinacrine protects neuronal cells against heat‐induced injury

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