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      Cyclooxygenase-derived mediators regulate the immunological control of Strongyloides venezuelensis infection.

      Fems Immunology and Medical Microbiology

      Animals, Ascitic Fluid, cytology, immunology, Blood, Bronchoalveolar Lavage Fluid, Dinoprostone, metabolism, Duodenum, parasitology, Enzyme Inhibitors, administration & dosage, Eosinophils, Ibuprofen, Indomethacin, Leukocytes, Mononuclear, Lung, Male, Mice, Prostaglandin-Endoperoxide Synthases, Pyrazoles, Rats, Rats, Wistar, Strongyloides, pathogenicity, Strongyloidiasis, pathology, Sulfonamides, Th1 Cells, Th2 Cells

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          Abstract

          The aim of this study was to define the immunoregulatory role of prostaglandins in a mouse model of Strongyloides venezuelensis infection. Strongyloides venezuelensis induced an increase of eosinophils and mononuclear cells in the blood, peritoneal cavity fluid, and bronchoalveolar lavage fluid. Treatment with the dual cyclooxygenase (COX-1/-2) inhibitors indomethacin and ibuprofen, and the COX-2-selective inhibitor celecoxib partially blocked these cellular responses and was associated with enhanced numbers of infective larvae in the lung and adult worms in the duodenum. However, the drugs did not interfere with worm fertility. Cyclooxygenase inhibitors also inhibited the production of the T-helper type 2 (Th2) mediators IL-5, IgG1, and IgE, while indomethacin alone also inhibited IL-4, IL-10, and IgG2a. Cyclooxygenase inhibitors tended to enhance the Th1 mediators IL-12 and IFN-gamma. This shift away from Th2 immunity in cyclooxygenase inhibitor-treated mice correlated with reduced prostaglandin E(2) (PGE(2)) production in infected duodenal tissue. As PGE(2) is a well-characterized driver of Th2 immunity, we speculate that reduced production of this lipid might be involved in the shift toward a Th1 phenotype, favoring parasitism by S. venezuelensis. These findings provide new evidence that cyclooxygenase-derived lipids play a role in regulating host defenses against Strongyloides, and support the exploration of eicosanoid signaling for identifying novel preventive and therapeutic modalities against these infections.

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          Most cited references 47

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          Cyclooxygenases 1 and 2.

           Y Bakhle,  J R Vane,  R Botting (1997)
          Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.
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            Prostaglandin biology in inflammatory bowel disease.

             David Wallace (2001)
            Similar to in the upper gastrointestinal tract, prostaglandins represent one of the most important components of mucosal defense in the small intestine and colon. The effects of prostaglandins in this context are widespread, ranging from maintenance of blood flow to stimulation of mucus secretion to modulation of the mucosal immune system. There is little doubt that the ability of NSAIDs to cause injury throughout the gastrointestinal tract and to exacerbate IBD is due in large part to the ability of these agents to suppress prostaglandin synthesis. With the advent of selective COX-2 inhibitors, it has become possible to dissect further the roles of prostaglandins in mucosal defense. The weight of evidence collected so far suggests that prostaglandins derived from COX-2 are important in promoting the healing of mucosal injury, in protecting against bacterial invasion, and in down-regulating the mucosal immune system. Suppression of COX-2 in a setting of gastrointestinal inflammation and ulceration has been shown in experimental models to result in impairment of healing and exacerbation of inflammation-mediated injury. In the near future, pharmacologic probes will be available that will permit clinicians to identify better the specific prostaglandin receptors that mediate the effects of this group of mediators on the various aspects of mucosal defense. This identification should permit the development of therapeutic agents that specifically can modulate some aspects of mucosal defense without having undesired effects on other aspects of mucosal function. Such agents may permit clinicians to enhance mucosal repair selectively and to block selectively any contribution of prostaglandins to the pain associated with IBD.
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              Prostaglandins in health and disease: an overview.

               Justin Miller (2006)
              Prostaglandins are a group of biologically active compounds that play major roles in human physiology in both health and disease. They function in many different ways and in all major organs. This article reviews the basic physiology of prostaglandins and their application to specific effects on these systems in normal and abnormal clinical states. The critical therapeutic implications of the use of nonsteroidal antiinflammatory drugs in altering organ homeostasis are also examined. References were taken from Medline, Embase, and Index Medicus from 1966 to September 2005. A search was done with keywords, including prostaglandins, nonsteroidal antiinflammatory drugs, inflammation, arachidonic acid, Cox-1 (cyclooxygenase-1), and Cox-2 (cyclooxygenase-2). There was a close correlation and predictability between basic prostaglandin physiology and the anticipated effects of these compounds on the heart, lungs, kidneys, gastrointestinal tract, bones and joints, brain, and male and female reproductive systems. These effects are organ and tissue specific. Despite these findings, unexplained and sometimes paradoxical physiologic responses were identified. A prime example of this is the role of prostaglandins in bone metabolism demonstrating both stimulatory and inhibitory effects. In addition all NSAIDs have the potential to impair the normal physiologic effects of prostaglandins depending primarily on the specific organ and the clinical setting. Prostaglandins are regulatory compounds that play important roles in many physiologic processes in the human body. An understanding of the basic science of prostaglandins is valuable in anticipating the organ-specific biologic effects of these unique compounds in health and disease. However, at selected sites and under different physiologic conditions, unexplained and sometimes paradoxical effects are generated. Impairment of their regulatory functions can lead to significant short- or long-term organ dysfunction.
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                Author and article information

                Journal
                20236322
                10.1111/j.1574-695X.2010.00656.x

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