Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure

Abraham, Edward; Naum, Chris; Bandi, Venkata; Gervich, Daniel; Lowry, Stephen F.; Wunderink, Richard G.; Schein, Roland M. H.; Macias, William L.; Skerjanec, Simona; Dmitrienko, Alex; Farid, Nagy A.; Forgue, S. Thomas; Jiang, Fengwei

doi:10.1097/01.ccm.0000053648.42884.89

Cited by 101 publications

(67 citation statements)

References 34 publications

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“…It seems unlikely that simple inhibition of one specific PLA 2 would be of significant benefit to septic patients. Indeed, clinical trials in sepsis targeting two PLA 2 molecules (group IIA sPLA 2 (official gene symbol, PLA2G2A) and secretory PAF acetylhydrolase (official gene symbol, PLA2G7)) failed (81)(82)(83). Still, we believe that lipid mediators are good therapeutic targets in sepsis for two reasons.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Lipid and Protein Mediators of Inflammation by Cytosolic Phospholipase A2α during Experimental Sepsis

Uozumi

Kita

Shimizu

2008

The Journal of Immunology

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Cytosolic phospholipase A2α (cPLA2α) is one of the key enzymes in lipid mediator generation. It preferentially hydrolyzes arachidonoyl-phospholipid in response to cellular stimuli, liberating arachidonic acid, the shared precursor of PGs and leukotrienes. Mice with disruption of the cPLA2α gene exhibit a more than 80% decrease in the generation of these lipid mediators, leading to dramatic phenotypes in various models of inflammatory and allergic disease. In this study, we use the cecal ligation and puncture model of sepsis along with multiplex quantitation systems to explore interactions between eicosanoids and protein mediators. cPLA2α-deficient mice exhibited significantly less weight loss accompanied by decreased generation of PGs, leukotriene B4, IL-6, and CCL2. Despite these differences, genetic ablation of cPLA2α did not provide any survival advantage. Unexpectedly, abundant production of 12-hydroxy-eicosatetraenoic acid, another arachidonic acid-derived lipid mediator, was found to be unaffected by disruption of the cPLA2α gene. Eicosanoid production preceded the production of cytokines. Eicosanoid modulation of IL-6 and CCL2 expression was suggested by scattergram analyses. These results provide in vivo evidence for the rapid generation of eicosanoids, regulatory role(s) for cPLA2α-derived lipid mediators on protein mediator production, and the existence of a robust cPLA2α-independent pathway(s) of eicosanoid generation.

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Section: Discussionmentioning

confidence: 99%

Modulation of Lipid and Protein Mediators of Inflammation by Cytosolic Phospholipase A2α during Experimental Sepsis

Uozumi

Kita

Shimizu

2008

The Journal of Immunology

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“…There are at least 12 isoforms of secreted PLA 2 in mice (27,33,36,38); all of these isoforms are expressed in humans. Among the secreted PLA 2 s, gIIaPLA 2 , gVPLA 2 , and gXPLA 2 have been implicated in a variety of inflammatory lung diseases, e.g., acute lung injury (3,10,21,40), acute respiratory distress syndrome (11,37), sepsis (1,41), and asthma (12,24,30). However, the relative contributions of secretory PLA 2 s in these diseases remain unclear, as disparate findings have been demonstrated (3,12,24,27,30,37,40,41).…”

mentioning

confidence: 99%

Secretory group V phospholipase A₂regulates acute lung injury and neutrophilic inflammation caused by LPS in mice

Muñoz¹,

Meliton²,

Meliton³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Muñ oz NM, Meliton AY, Meliton LN, Dudek SM, Leff AR. Secretory group V phospholipase A2 regulates acute lung injury and neutrophilic inflammation caused by LPS in mice. Am J Physiol Lung Cell Mol Physiol 296: L879 -L887, 2009. First published March 13, 2009 doi:10.1152/ajplung.90580.2008.-We investigated the regulatory role of 14-kDa secretory group V phospholipase A2 (gVPLA2) in the development of acute lung injury (ALI) and neutrophilic inflammation (NI) caused by intratracheal administration of LPS. Experiments were conducted in gVPLA2 knockout (pla2g5 Ϫ/Ϫ ) mice, which lack the gene, and gVPLA2 wild-type littermate control (pla2g5 ϩ/ϩ ) mice. Indices of pulmonary injury were evaluated 24 h after intratracheal administration of LPS. Expression of gVPLA2 in microsections of airways and mRNA content in lung homogenates were increased substantially in pla2g5 ϩ/ϩ mice after LPS-administered compared with saline-treated pla2g5 ϩ/ϩ mice. By contrast, expression of gVPLA2 was neither localized in LPS-nor saline-treated pla2g5 Ϫ/Ϫ mice. LPS also caused 1) reduced transthoracic static compliance, 2) lung edema, 3) neutrophilic infiltration, and 4) increased neutrophil myeloperoxidase activity in pla2g5 ϩ/ϩ mice. These events were attenuated in pla2g5 Ϫ/Ϫ mice exposed to LPS or in pla2g5 ϩ/ϩ mice receiving MCL-3G1, a neutralizing MAb directed against gVPLA2, before LPS administration. Our data demonstrate that gVPLA2 is an inducible protein in pla2g5 ϩ/ϩ mice but not in pla2g5 Ϫ/Ϫ mice within 24 h after LPS treatment. Specific inhibition of gVPLA2 with MCL-3G1 or gene-targeted mice lacking gVPLA 2 blocks ALI and attenuates NI caused by LPS. airway inflammation; chemotaxis; pulmonary compliance SECRETORY PHOSPHOLIPASE A2S (PLA 2 ) are a family of lipolytic enzymes that catalyze the cleavage of fatty acids from the sn-2 position of phospholipids leading to the generation of free fatty acids and lysophospholipids (6,9,20,27,33,36,38). There are at least 12 isoforms of secreted PLA 2 in mice (27,33,36,38

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“…The use of these agents would inhibit the production of several membrane phospholipidderived metabolites that play a role in inflammation, including lysoplasmalogens, PAF, and arachidonic acid and its metabolites. To date, the only designed inhibitors to have advanced into clinical trials are selective for the sPLA 2 enzymes (Tykka et al, 1985;Abraham et al, 2003;Scott et al, 2003). We showed in Fig.…”

Section: Discussionmentioning

confidence: 98%

Neutrophil Adherence to Bladder Microvascular Endothelial Cells following Platelet-Activating Factor Acetylhydrolase Inhibition

Vinson

Rickard²,

Ryerse³

et al. 2005

J Pharmacol Exp Ther

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Interstitial cystitis (IC) is an inflammatory bladder condition of unknown etiology. Tryptase released from elevated numbers of activated mast cells is a proposed mediator of the inflammatory process in IC. We have previously shown that tryptase increases human bladder microvascular endothelial cell (HBMEC) calcium-independent phospholipase A 2 (iPLA 2 ) activity, resulting in the production of multiple biologically active phospholipid metabolites, including platelet-activating factor (PAF), that can mediate inflammation. Because the design of selective PLA 2 inhibitors may provide a useful therapeutic strategy to reduce the inflammatory process in IC, we tested several frequently used PLA 2 inhibitors on PAF production in tryptasestimulated HBMEC. Among the inhibitors tested, methyl arachidonyl fluorophosphonate (MAFP) was found to be a potent inhibitor of PAF-acetylhydrolase activity. Pretreatment of HBMEC with MAFP significantly increased PAF production in both unstimulated and tryptase-stimulated cells. In addition, MAFP pretreatment of tryptase-stimulated HBMEC increased both surface expression of P-selectin and polymorphonuclear leukocyte adherence to the HBMEC monolayer. These effects suggest that MAFP has a proinflammatory effect, irrespective of its ability to inhibit PLA 2 .

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Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure

Cited by 101 publications

References 34 publications

Modulation of Lipid and Protein Mediators of Inflammation by Cytosolic Phospholipase A2α during Experimental Sepsis

Modulation of Lipid and Protein Mediators of Inflammation by Cytosolic Phospholipase A2α during Experimental Sepsis

Secretory group V phospholipase A₂regulates acute lung injury and neutrophilic inflammation caused by LPS in mice

Neutrophil Adherence to Bladder Microvascular Endothelial Cells following Platelet-Activating Factor Acetylhydrolase Inhibition

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Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure

Cited by 101 publications

References 34 publications

Modulation of Lipid and Protein Mediators of Inflammation by Cytosolic Phospholipase A2α during Experimental Sepsis

Modulation of Lipid and Protein Mediators of Inflammation by Cytosolic Phospholipase A2α during Experimental Sepsis

Secretory group V phospholipase A2regulates acute lung injury and neutrophilic inflammation caused by LPS in mice

Neutrophil Adherence to Bladder Microvascular Endothelial Cells following Platelet-Activating Factor Acetylhydrolase Inhibition

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Secretory group V phospholipase A₂regulates acute lung injury and neutrophilic inflammation caused by LPS in mice