Prostaglandin modulation of airway hyperresponsiveness and inflammation in murine models of asthma

摘要: Allergic asthma is an inflammatory disease of the airways and characterised by chronic inflammation, reversible bronchoconstriction airway hyperresponsiveness (AHR). The cyclooxygenases (COXs) are key enzymes in biosynthesis prostaglandins, which have diverse physiological pathological functions, also important modulators responses lung. However, role COX-derived prostanoids AHR inflammation still not fully understood. overall aim this Thesis was to define products allergic experimental mouse models asthma. In present work, lung physiology measured using flexiVent system for direct measurements respiratory mechanics. Inflammation assessed measuring numbers cells bronchoalveolar lavage (BAL) fluid as well levels mediators BAL tissue. Histological analysis tissue performed assess possible structural changes. first part develop improved protocol studies sensitised challenged mice, order optimise delivery route doses allergen antigen challenge. result established that intranasal challenge BALB/c mice caused a dose-dependent increase AHR, whereas cell response augmented same extent all allergen. Intranasal causes more pronounced induction both compared aerosol antigen. second aimed function prostaglandins inflammation. investigated intervention with non-steroidal anti-inflammatory drugs (NSAIDs), genetically modified where synthesis prostaglandin (PG) E2 had been disrupted removal one E synthases (mPGES-1). findings support concept general, COX bronchoprotective airways, i.e. local release PGE2 modulates smooth muscle reactivity protects against excessive narrowing. Furthermore, effects mainly due PGE2, primarily generated mPGES-1. two isoenzymes, COX-1 COX-2, appeared separate whereby predominantly recovered COX-2 activity associated accumulation fluid. It clear, mediated dependent on cellular observations suggest neither mPGES-1 nor involved inhibitory recruitment reaction. Taken together, supports distinct, at least part, uncoupled events. raise awareness predictive surrogate marker AHR. Finally, inhibition has suggested target therapies humans, pro-inflammatory mediator many diseases. it mPGES-1-derived may negative consequences airways. LIST OF PUBLICATIONS This based following publications: I. Linda Swedin, Russ Ellis, Cecilia Kemi, Ake Ryrfeldt, Mark Inman, Sven-Erik Dahlen Mikael Adner Comparison model International Archives Allergy Immunology 2010; 153(3):249-58 II. Theresa Neimert-Andersson, Josephine Hjoberg, Sofia Jonasson, Marianne van Hage, Adner, Dissociation cyclooxygenase European Respiratory Journal 2009(1);34: 200–8 III. Gunnar Nilsson, Prostaglandin modulation sensitized without adjuvant Prostaglandins & Other Lipid Mediators, 2010 Mar, press IV. Susanna Lundstrom, Silvana Lindgren, Craig Wheelock, Deletion microsomal PGE synthase-1 enhances Manuscript