Targeting cytosolic phospholipase A2 by arachidonyl trifluoromethyl ketone prevents chronic inflammation in mice.
Cytosolic phospholipase A(2) (cPLA(2)) plays a pivotal role in inflammation by catalyzing the release of arachidonic acid, a substrate for lipoxygenase and cyclooxygenase enzymes, from membrane phospholipids. In the present study we examined the role of cPLA(2) in inflammatory responses through the use of a specific inhibitor of the enzyme, cPLA(2), arachidonyl trifluoromethyl ketone (AACOCF3). Interestingly, we observed that AACOCF3 is an inhibitor of chronic but not acute inflammatory responses. Specifically, AACOCF3 inhibited phorbol 12-myristate 13-acetate (PMA)-induced chronic ear edema in mice. Additionally, oral treatment of ovalbumin-sensitized/ovalbumin-challenged BALB/c mice with 20 mg/kg AACOCF3 prevented the development of airway hyper-responsiveness in a model of asthma. Furthermore, AACOCF3 decreased cellular recruitment in the airway lumen and airway inflammation after the ovalbumin challenge. Taken together, these results suggest that a potent and specific chemical inhibitor of cPLA(2) may be useful for the treatment of chronic inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, psoriasis, and asthma.
Malaviya
Ravi
R
Inflammation Research Team, Department of Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ 08869, USA.
Ansell
Justin
J
Hall
LeRoy
L
Fahmy
Mila
M
Argentieri
Rochelle L
RL
Olini
Gilbert C
GC
Pereira
David W
DW
Sur
Runa
R
Cavender
Druie
D
D000485:Allergens / Q000009:adverse effects; D000818:Animals; D001095:Arachidonic Acids / Q000008:administration & dosage*; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002908:Chronic Disease; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D004487:Edema / Q000201:enzymology* / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D054513:Group IV Phospholipases A2; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D007962:Leukocytes / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D054467:Phospholipases A2
D000485:Allergens; D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; C081565:arachidonyltrifluoromethane; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2