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      Importance of group X–secreted phospholipase A 2 in allergen-induced airway inflammation and remodeling in a mouse asthma model

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          Abstract

          Arachidonic acid metabolites, the eicosanoids, are key mediators of allergen-induced airway inflammation and remodeling in asthma. The availability of free arachidonate in cells for subsequent eicosanoid biosynthesis is controlled by phospholipase A 2s (PLA 2s), most notably cytosolic PLA 2-α. 10 secreted PLA 2s (sPLA 2s) have also been identified, but their function in eicosanoid generation is poorly understood. We investigated the role of group X sPLA 2 (sPLA 2-X), the sPLA 2 with the highest in vitro cellular phospholipolysis activity, in acute and chronic mouse asthma models in vivo. The lungs of sPLA 2-X −/− mice, compared with those of sPLA 2-X +/+ littermates, had significant reduction in ovalbumin-induced infiltration by CD4 + and CD8 + T cells and eosinophils, goblet cell metaplasia, smooth muscle cell layer thickening, subepithelial fibrosis, and levels of T helper type 2 cell cytokines and eicosanoids. These data direct attention to sPLA 2-X as a novel therapeutic target for asthma.

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          Allergy and allergic diseases. First of two parts.

          A Kay (2001)
          Article 0 comments Cited 147 times – based on 0 reviews     Review now
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            Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2.

            M. Moskowitz, Michael O’Leary, Z. Huang … (1997)
            Phospholipase A2 (PLA2) enzymes are critical regulators of prostaglandin and leukotriene synthesis and can directly modify the composition of cellular membranes. PLA2 enzymes release fatty acids and lysophospholipids, including the precursor of platelet-activating factor, PAF, from phospholipids. Free fatty acids, eicosanoids, lysophospholipids and PAF are potent regulators of inflammation, reproduction and neurotoxicity. The physiological roles of the various forms of PLA2 are not well defined. The cytosolic form, cPLA2, preferentially releases arachidonic acid from phospholipids and is regulated by changes in intracellular calcium concentration. We have now created 'knockout' (cPLA2-/-) mice that lack this enzyme, in order to evaluate its physiological importance. We find that cPLA2-/- mice develop normally, but that the females produce only small litters in which the pups are usually dead. Stimulated peritoneal macrophages from cPLA2-/- animals did not produce prostaglandin E2 or leukotriene B4 or C4. After transient middle cerebral artery occlusion, cPLA2-/- mice had smaller infarcts and developed less brain oedema and fewer neurological deficits. Thus cPLA2 is important for macrophage production of inflammatory mediators, fertility, and in the pathophysiology of neuronal death after transient focal cerebral ischaemia.
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              Heterogeneity of airways mucus: variations in the amounts and glycoforms of the major oligomeric mucins MUC5AC and MUC5B.

              David Knight, D Thornton, Guy P. Richardson … (2002)
              Respiratory mucus contains a mixture of gel-forming mucins but the functional significance of these different mucin species is unknown. To help gain a better understanding of mucus in airways we therefore need to ascertain the concentration of each of the gel-forming mucins within respiratory secretions. Thus the aim of this study was to determine the amounts of specific gel-forming mucins directly from solubilized secretions of the airways and purified mucin preparations. We investigated the feasibility of using direct-binding ELISA employing mucin-specific antisera but were unable to obtain reliable data owing to interference with the immobilization of the mucins on the assay surface by 6 M urea and high levels of non-mucin proteins. We therefore developed an alternative approach based on quantitative Western blotting after agarose-gel electrophoresis, which was not subject to these problems. Here we demonstrate that this procedure provides reliable and reproducible data and have employed it to determine the amounts of the MUC2, MUC5AC and MUC5B mucins in saline-induced sputa from healthy airways and spontaneous sputa from asthmatic airways. Additionally we have used this procedure to analyse these glycoproteins in mucin preparations purified from cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) mucus. Our findings indicate that MUC5AC and MUC5B are the major oligomeric mucins and that airways mucus contains variable amounts of these glycoproteins. By contrast, the MUC2 mucin comprised, at most, only 2.5% of the weight of the gel-forming mucins, indicating that MUC2 is a minor component in sputum. Finally, we show that the amounts and glycosylated variants of the MUC5AC and MUC5B mucins can be altered significantly in diseased airways with, for instance, an increase in the low-charge form of the MUC5B mucin in CF and COPD mucus.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Exp Med
                Title: The Journal of Experimental Medicine
                Publisher: The Rockefeller University Press
                ISSN (Print): 0022-1007
                ISSN (Electronic): 1540-9538
                Publication date (Print): 16 April 2007
                Volume: 204
                Issue: 4
                Pages: 865-877
                Affiliations
                [1 ]Center for Allergy and Inflammation, Department of Medicine, University of Washington, Seattle, WA 98109
                [2 ]Department of Pathology, [3 ]Department of Chemistry, [4 ]Department of Biochemistry, [5 ]Department of Immunology, and [6 ]Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195
                [7 ]Department of Pathology, University of Turku and Turku University Hospital, 20520 Turku, Finland
                Author notes

                CORRESPONDENCE William R. Henderson Jr.: joangb@ 123456u.washington.edu OR Michael H. Gelb: gelb@ 123456chem.washington.edu

                Article
                Publisher ID: 20070029
                DOI: 10.1084/jem.20070029
                PMC ID: 2118555
                PubMed ID: 17403936
                SO-VID: 69ffc45f-fd38-4f03-b9bb-d98b9af43a2a
                Copyright © Copyright © 2007, The Rockefeller University Press
                History
                Date received : 2 January 2007
                Date accepted : 1 March 2007
                Categories
                Subject: Articles
                Subject: Article

                ScienceOpen disciplines: Medicine
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                ScienceOpen disciplines: Medicine

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