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      mPGES-1 and prostaglandin E 2: vital role in inflammation, hypoxic response, and survival

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          Abstract

          Background:

          Apnea associated with infection and inflammation is a major medical concern in preterm infants. Prostaglandin E 2 (PGE 2) serves as a critical mediator between infection and apnea. We hypothesize that alteration of the microsomal PGE synthase-1 (mPGES-1) PGE 2 pathway influences respiratory control and response to hypoxia.

          Methods:

          Nine-d-old wild-type (WT) mice, mPGES-1 heterozygote (mPGES-1 +/–), and mPGES-1 knockout (mPGES-1 –/–) mice were used. Respiration was investigated in mice using flow plethysmography after the mice received either interleukin-1β (IL-1β) (10 µg/kg) or saline. Mice were subjected to a period of normoxia, subsequent exposure to hyperoxia, and finally either moderate (5 min) or severe hypoxia (until 1 min after last gasp).

          Results:

          IL-1β worsened survival in WT mice but not in mice with reduced or no mPGES-1. Reduced expression of mPGES-1 prolonged gasping duration and increased the number of gasps during hypoxia. Response to intracerebroventricular PGE 2 was not dependent on mPGES-1 expression.

          Conclusion:

          Activation of mPGES-1 is involved in the rapid and vital response to severe hypoxia as well as inflammation. Attenuation of mPGES-1 appears to have no detrimental effects, yet prolongs autoresuscitation efforts and improves survival. Consequently, inhibition of the mPGES-1 pathway may serve as a potential therapeutic target for the treatment of apnea and respiratory disorders.

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          Most cited references32

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          Cytokine-induced sickness behavior: mechanisms and implications.

          Sickness behavior refers to a coordinated set of behavioral changes that develop in sick individuals during the course of an infection. At the molecular level, these changes are due to the brain effects of proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFalpha). Peripherally released cytokines act on the brain via a fast transmission pathway involving primary afferent nerves innervating the bodily site of inflammation and a slow transmission pathway involving cytokines originating from the choroid plexus and circumventricular organs and diffusing into the brain parenchyma by volume transmission. At the behavioral level, sickness behavior appears to be the expression of a central motivational state that reorganizes the organism priorities to cope with infectious pathogens. There is evidence that the sickness motivational state can interact with other motivational states and respond to nonimmune stimuli probably by way of sensitization and/or classical conditioning. However, the mechanisms that are involved in plasticity of the sickness motivational state are not yet understood.
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            Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2.

            Here we report the molecular identification of membrane-bound glutathione (GSH)-dependent prostaglandin (PG) E(2) synthase (mPGES), a terminal enzyme of the cyclooxygenase (COX)-2-mediated PGE(2) biosynthetic pathway. The activity of mPGES was increased markedly in macrophages and osteoblasts following proinflammatory stimuli. cDNA for mouse and rat mPGESs encoded functional proteins that showed high homology with the human ortholog (microsomal glutathione S-transferase-like 1). mPGES expression was markedly induced by proinflammatory stimuli in various tissues and cells and was down-regulated by dexamethasone, accompanied by changes in COX-2 expression and delayed PGE(2) generation. Arg(110), a residue well conserved in the microsomal GSH S-transferase family, was essential for catalytic function. mPGES was functionally coupled with COX-2 in marked preference to COX-1, particularly when the supply of arachidonic acid was limited. Increased supply of arachidonic acid by explosive activation of cytosolic phospholipase A(2) allowed mPGES to be coupled with COX-1. mPGES colocalized with both COX isozymes in the perinuclear envelope. Moreover, cells stably cotransfected with COX-2 and mPGES grew faster, were highly aggregated, and exhibited aberrant morphology. Thus, COX-2 and mPGES are essential components for delayed PGE(2) biosynthesis, which may be linked to inflammation, fever, osteogenesis, and even cancer.
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              Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase.

              Prostaglandin (PG)E2 is a potent mediator of pain and inflammation, and high levels of this lipid mediator are observed in numerous disease states. The inhibition of PGE2 production to control pain and to treat diseases such as rheumatoid arthritis to date has depended on nonsteroidal antiinflammatory agents such as aspirin. However, these agents inhibit the synthesis of all prostanoids. To produce biologically active PGE2, PGE synthases catalyze the isomerization of PGH2 into PGE2. Recently, several PGE synthases have been identified and cloned, but their role in inflammation is not clear. To study the physiological role of the individual PGE synthases, we have generated by targeted homologous recombination a mouse line deficient in microsomal PGE synthase 1 (mPGES1) on the inbred DBA/1lacJ background. mPGES1-deficient (mPGES1-/-) mice are viable and fertile and develop normally compared with wild-type controls. However, mPGES1-/- mice displayed a marked reduction in inflammatory responses compared with mPGES1+/+ mice in multiple assays. Here, we identify mPGES1 as the PGE synthase that contributes to the pathogenesis of collagen-induced arthritis, a disease model of human rheumatoid arthritis. We also show that mPGES1 is responsible for the production of PGE2 that mediates acute pain during an inflammatory response. These findings suggest that mPGES1 provides a target for the treatment of inflammatory diseases and pain associated with inflammatory states.
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                Author and article information

                Journal
                Pediatr Res
                Pediatr. Res
                Pediatric Research
                Nature Publishing Group
                0031-3998
                1530-0447
                November 2012
                27 August 2012
                10 October 2012
                : 72
                : 5
                : 460-467
                Affiliations
                [1 ]Neonatal Research Unit Q2:07, Department of Women's and Children's Health, Astrid Lindgren Children's Hospital , Stockholm, Sweden
                [2 ]Department of Medicine, Karolinska Institutet , Stockholm, Sweden
                Author notes
                Article
                pr2012119
                10.1038/pr.2012.119
                3647218
                22926547
                6da9b3b0-41dd-4a3b-a13b-a643d62de5ba
                Copyright © 2012 International Pediatric Research Foundation, Inc.

                This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 07 November 2011
                : 10 July 2012
                Categories
                Basic Science Investigation

                Pediatrics
                Pediatrics

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