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


OBJECTIVE
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.
Wu
Yong-Zheng
YZ
Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France.
Abolhassani
Mohammad
M
Ollero
Mario
M
Dif
Fariel
F
Uozumi
Naonori
N
Lagranderie
Micheline
M
Shimizu
Takao
T
Chignard
Michel
M
Touqui
Lhousseine
L
D000281:Administration, Intranasal; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016084:Bronchoconstriction / Q000187:drug effects*; D054426:Chemokine CXCL2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015289:Leukotrienes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D018181:Mice, Inbred CFTR; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D011014:Pneumonia / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D011550:Pseudomonas aeruginosa / Q000737:chemistry; D013997:Time Factors
D001095:Arachidonic Acids; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D015289:Leukotrienes; D008070:Lipopolysaccharides; C516390:Pla2g4a protein, mouse; C081565:arachidonyltrifluoromethane; D016718:Arachidonic Acid; D054513:Group IV Phospholipases A2; D015232:Dinoprostone; D001241:Aspirin