Extracellular phospholipase A<sub>2</sub> inhibitors suppress central nervous system inflammation

Pinto, Fausto J.; Brenner, Talma; Dan, Phyllis; Krimsky, Miron; Yedgar, Saul

doi:10.1002/glia.10296

Cited by 46 publications

(39 citation statements)

References 37 publications

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“…store release or CRAC channel activation. In fact, AA generated by PLA 2 has been implicated in the generation of proinflammatory eicosanoids that regulate the production of cytokines, NO, and free radicals involved in the pathogenesis of immune-mediated inflammatory diseases such as multiple sclerosis (24,25). Eicosanoids are also produced by some prokaryotic and eukaryotic pathogens (26) and induce inflammation and host susceptibility to these pathogens (9).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Hypotonicity-Induced Calcium Signaling and Integrin Activation by Arachidonic Acid-Derived Inflammatory Mediators in B Cells

Zhu

Liu

LaBelle

et al. 2005

The Journal of Immunology

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We previously characterized the initial steps in the activation of novel (calcium-permeant) nonselective cation channels (NSCCs) and calcium release-activated calcium channels in primary murine B lymphocytes. Phospholipase C products, namely diacylglycerol and d-myo-inositol 1,4,5-trisphosphate, were identified as proximal intracellular agonists of these respective channels following mechanical stimulation of B cells. However, neither the distal steps in NSCC activation nor the contribution of these channels to sustained mechanical signaling were defined in these previous studies. In this study, single cell measurements of intracellular Ca2+ were used to define the mechanisms of NSCC activation and demonstrate a requirement for arachidonic acid liberated from diacylglycerol. Several arachidonic acid-derived derivatives were identified that trigger Ca2+ entry into B cells, including the lipoxygenase product 5-hydroperoxyeicosatetranenoic acid and the cytochrome P450 hydroxylase product 20-hydroxyeicosatetraenoic; however, the cytochrome P450 epoxygenase product 5,6-epoxyeicosatrienoic acid is primarily responsible for hypotonicity-induced responses. In addition to regulating calcium entry, our data suggest that eicosanoid-activated NSCCs have a separate and direct role in regulating the avidity of integrins on B cells for extracellular matrix proteins, including ICAM-1 and VCAM-1. Thus, in addition to defining a novel osmotically activated signal transduction pathway in B cells, our results have broad implications for understanding how inflammatory mediators dynamically and rapidly regulate B cell adhesion and trafficking.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of Hypotonicity-Induced Calcium Signaling and Integrin Activation by Arachidonic Acid-Derived Inflammatory Mediators in B Cells

Zhu

Liu

LaBelle

et al. 2005

The Journal of Immunology

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“…PGE2 levels were determined in BAL fluid by RIA using specific antibody and a radioligand as previously described by Pinto et al (29). Anti-PGE 2 and standard PGE2 were purchased from Sigma (St. Louis, MO).…”

Section: Methodsmentioning

confidence: 99%

“…The ExPLIs, designed and synthesized in the laboratory of S. Yedgar (42), have been previously found effective in amelioration of inflammatory processes in cell cultures and in animal models. These include inhibition of lipid membrane hydrolysis by diverse types of sPLA 2 (9), inhibition of group V sPLA 2 activation in LPS-stimulated P388D macrophages (3), endotoxin-induced sepsis in rats, as expressed by reduced mortality rate, blood cytokine level (TNF-␣, IL-6), and expression of type IIA sPLA 2 and inducible nitric oxide synthase in liver and kidney of septic rats (4), suppression of sPLA 2 and PGE 2 production by LPS-stimulated cultured rat brain glial cells and experimental allergic encephalomyelitis in rats and mice (29), and trinitrobenzensulfonic acid-induced colitis in rats, expressed by reduced mortality rate, histology, and blood sPLA 2 activity (20). Using the ExPLIs, in the present study we have found that OVA-induced asthma in rats is associated with elevation of sPLA 2 and suppression of cPLA 2 activity and expression in the lung.…”

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confidence: 99%

Negative feedback between secretory and cytosolic phospholipase A₂ and their opposing roles in ovalbumin-induced bronchoconstriction in rats

Offer¹,

Yedgar²,

Schwob³

et al. 2005

American Journal of Physiology-Lung Cellular and Molecular Phys

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Negative feedback between secretory and cytosolic phospholipase A2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats. Am J Physiol Lung Cell Mol Physiol 288: L523-L529, 2005. First published November 19, 2004 doi:10.1152/ajplung.00199.2004.-Phospholipase A2 (PLA2) hydrolyzes cell membrane phospholipids (PL) to produce arachidonic acid and lyso-PL. The PLA 2 enzymes include the secretory (sPLA 2) and cytosolic (cPLA2) isoforms, which are assumed to act synergistically in production of eicosanoids that are involved in inflammatory processes. However, growing evidence raises the possibility that in airways and asthma-related inflammatory cells (eosinophils, basophils), the production of the bronchoconstrictor cysteinyl leukotrienes (CysLT) is linked exclusively to sPLA2, whereas the bronchodilator prostaglandin PGE 2 is produced by cPLA 2. It has been further reported that the capacity of airway epithelial cells to produce CysLT is inversely proportional to PGE 2 production. This seems to suggest that sPLA2 and cPLA2 play opposing roles in asthma pathophysiology and the possibility of a negative feedback between the two isoenzymes. To test this hypothesis, we examined the effect of a cell-impermeable extracellular sPLA2 inhibitor on bronchoconstriction and PLA2 expression in rats with ovalbumin (OVA)-induced asthma. It was found that OVAinduced bronchoconstriction was associated with elevation of lung sPLA2 expression and CysLT production, concomitantly with suppression of cPLA2 expression and PGE2 production. These were reversed by treatment with the sPLA 2 inhibitor, resulting in amelioration of bronchoconstriction and reduced CysLT production and sPLA2 expression, concomitantly with enhanced PGE2 production and cPLA 2 expression. This study demonstrates, for the first time in vivo, a negative feedback between sPLA 2 and cPLA2 and assigns opposing roles for these enzymes in asthma pathophysiology: sPLA 2 activation induces production of the bronchoconstrictor CysLT and suppresses cPLA2 expression and the subsequent production of the bronchodilator PGE 2.

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“…21 Its production has been reported to be linked to PLA 2 produced lipid mediators 22 and was found to be inhibited by ExPLIs in lipopolysaccharide stimulated cells 23 and animals. In line with these findings, we determined the effect of ExPLI on NO production by cultured macrophages collected from BAL fluid of the different groups following their in vivo treatment without further treatment of the cultured cells.…”

Section: Effect Of Hype Inhalation On Biochemical Markersmentioning

confidence: 98%

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2

Shoseyov¹,

Bibi²,

Offer³

et al. 2005

Thorax

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Background: The pathophysiology of asthma involves the action of inflammatory/allergic lipid mediators formed following membrane phospholipid hydrolysis by phospholipase A 2 (PLA 2 ). Cysteinyl leukotrienes are considered potent inducers of bronchoconstriction and airway remodelling. Ovalbumin (OVA) induced bronchoconstriction in rats is associated with increased secretory PLA 2 (sPLA 2 ) activation and cysteinyl leukotriene production, together with suppression of cytosolic PLA 2 and prostaglandin E 2 . These processes are reversed when the animals are pretreated systemically with an extracellular cell impermeable sPLA 2 inhibitor which also suppresses the early allergic reaction to OVA challenge. In this study we examine the capacity of the sPLA 2 inhibitor to ameliorate inflammatory and allergic manifestations (early and late bronchoconstriction) of OVA induced allergic bronchitis in rats when the inhibitor was administered by inhalation to confine it to the airways. Methods: Rats sensitised with OVA were treated with the sPLA 2 inhibitor hyaluronic acid-linked phosphatidyl ethanolamine (HyPE). The rats were divided into four groups (n = 10 per group): (1) naïve controls (no sensitisation/no treatment); (2) positive controls (sensitisation + challenge with OVA inhalation and subcutaneous injection of 1 ml saline before each challenge; (3) sensitisation + challenge with OVA and HyPE inhalation before every challenge; and (4) sensitisation + challenge with OVA and treatment with subcutaneous dexamethasone (300 mg) before each challenge as a conventional reference. Another group received no treatment with HyPE during the sensitisation process but only before or after challenge of already sensitised rats. Pulmonary function was assessed and changes in the histology of the airways, levels of cysteinyl leukotrienes in BAL fluid, and the production of nitric oxide (No) and tumour necrosis factor a (TNFa) by BAL macrophages were determined. Results: Inhalation of HyPE markedly suppressed OVA induced early and late asthmatic reactions as expressed by bronchoconstriction, airway remodelling (histology), cysteinyl leukotriene level in BAL fluid, and production of TNFa and NO by BAL macrophages. OVA induced bronchoconstriction in sensitised non-pretreated rats was also inhibited by inhalation of HyPE either before or after the challenge. Conclusions: These findings confirm the pivotal role of sPLA 2 in the pathophysiology of both the immediate allergic response and the inflammatory asthmatic process. Control of airway sPLA 2 may be a new therapeutic approach to the treatment of asthma.

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Extracellular phospholipase A₂ inhibitors suppress central nervous system inflammation

Cited by 46 publications

References 37 publications

Mechanisms of Hypotonicity-Induced Calcium Signaling and Integrin Activation by Arachidonic Acid-Derived Inflammatory Mediators in B Cells

Mechanisms of Hypotonicity-Induced Calcium Signaling and Integrin Activation by Arachidonic Acid-Derived Inflammatory Mediators in B Cells

Negative feedback between secretory and cytosolic phospholipase A₂ and their opposing roles in ovalbumin-induced bronchoconstriction in rats

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2

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Extracellular phospholipase A2 inhibitors suppress central nervous system inflammation

Cited by 46 publications

References 37 publications

Mechanisms of Hypotonicity-Induced Calcium Signaling and Integrin Activation by Arachidonic Acid-Derived Inflammatory Mediators in B Cells

Mechanisms of Hypotonicity-Induced Calcium Signaling and Integrin Activation by Arachidonic Acid-Derived Inflammatory Mediators in B Cells

Negative feedback between secretory and cytosolic phospholipase A2 and their opposing roles in ovalbumin-induced bronchoconstriction in rats

Treatment of ovalbumin-induced experimental allergic bronchitis in rats by inhaled inhibitor of secretory phospholipase A2

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Extracellular phospholipase A₂ inhibitors suppress central nervous system inflammation

Negative feedback between secretory and cytosolic phospholipase A₂ and their opposing roles in ovalbumin-induced bronchoconstriction in rats