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Cytosolic phospholipase A2alpha mediates Pseudomonas aeruginosa LPS-induced airway constriction of CFTR -/- mice.

Abstract : BACKGROUND: Lungs of cystic fibrosis (CF) patients are chronically infected with Pseudomonas aeruginosa. Increased airway constriction has been reported in CF patients but underplaying mechanisms have not been elucidated. AIM: To examine the effect of P. aeruginosa LPS on airway constriction in CF mice and the implication in this process of cytosolic phospholipase A2alpha (cPLA2alpha), an enzyme involved in arachidonic acid (AA) release. METHODS: Mice were instilled intra-nasally with LPS. Airway constriction was assessed using barometric plethysmograph. MIP-2, prostaglandin E2 (PGE2), leukotrienes and AA concentrations were measured in BALF using standard kits and gas chromatography. RESULTS: LPS induced enhanced airway constriction and AA release in BALF of CF compared to littermate mice. This was accompanied by increased levels of PGE2, but not those of leukotrienes. However, airway neutrophil influx and MIP-2 production remained similar in both mouse strains. The cPLA2alpha inhibitor arachidonyl trifluoro-methyl-ketone (ATK), but not aspirin which inhibit PGE2 synthesis, reduced LPS-induced airway constriction. LPS induced lower airway constriction and PGE2 production in cPLA2alpha -/- mice compared to corresponding littermates. Neither aspirin nor ATK interfered with LPS-induced airway neutrophil influx or MIP-2 production. CONCLUSIONS: CF mice develop enhanced airway constriction through a cPLA2alpha-dependent mechanism. Airway inflammation is dissociated from airway constriction in this model. cPLA2alpha may represent a suitable target for therapeutic intervention in CF. Attenuation of airway constriction by cPLA2alpha inhibitors may help to ameliorate the clinical status of CF patients.
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Submitted on : Thursday, January 5, 2012 - 5:03:38 PM
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yong-Zheng Wu, Mohammad Abolhassani, Mario Ollero, Fariel Dif, Naonori Uozumi, et al.. Cytosolic phospholipase A2alpha mediates Pseudomonas aeruginosa LPS-induced airway constriction of CFTR -/- mice.. Respiratory Research, BioMed Central, 2010, 11 (1), pp.49. ⟨10.1186/1465-9921-11-49⟩. ⟨inserm-00657048⟩



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