Specific physiological roles of cytosolic phospholipase A(2) as defined by gene knockouts.
The cytosolic 85 kDa phospholipase A(2) (cPLA(2)) is a unique member of the phospholipase A(2) (PLA(2)) superfamily. Because PLA(2) activity and eicosanoid production are important in normal and pathophysiological states we and the laboratory of Shimizu created a mouse deficient in cPLA(2) (cPLA(2)(-/-) mouse). cPLA(2)(-/-) mice develop normally but the females have severe reproductive defects. cPLA(2)(-/-) mice suffer smaller infarcts and fewer neurological deficits after transient occlusion of the middle cerebral artery and have less injury after administration of a dopaminergic selective neurotoxin. cPLA(2)(-/-) mice have a more rapid recovery from allergen-induced bronchoconstriction and have no airway hyperresponsiveness. Peritoneal macrophages from cPLA(2)(-/-) mice fail to produce prostaglandins, leukotriene B(4) and cysteinyl leukotrienes after stimulation. Bone marrow-derived mast cells from cPLA(2)(-/-) mice fail to produce eicosanoids in either immediate or delayed phase responses. Thus the cPLA(2) knockout mouse has revealed important roles of cPLA(2) in normal fertility, generation of eicosanoids from inflammatory cells, brain injuries and allergic responses. Furthermore the cPLA(2)(-/-) mouse reveals that the many other forms of PLA(2) cannot replace many functions of cPLA(2). The importance of cPLA(2) in inflammation and tissue injury suggests that pharmacological targeting of this enzyme may have important therapeutic benefits.
Sapirstein
A
A
Department of Anesthesiology and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. sapirste@helix.mgh.harvard.edu
Bonventre
J V
JV
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000403:Airway Resistance / Q000187:drug effects; D000707:Anaphylaxis; D000818:Animals; D001930:Brain Injuries / Q000139:chemically induced / Q000378:metabolism; D002545:Brain Ischemia / Q000209:etiology / Q000473:pathology; D016084:Bronchoconstriction; D003600:Cytosol / Q000201:enzymology*; D005260:Female; D017353:Gene Deletion; D007975:Leukotriene B4 / Q000096:biosynthesis; D017997:Leukotriene C4 / Q000096:biosynthesis; D008070:Lipopolysaccharides; D008098:Litter Size; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D016210:Methacholine Chloride; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020768:Middle Cerebral Artery; D023421:Models, Animal; D010047:Ovalbumin; D010741:Phospholipases A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy
D008070:Lipopolysaccharides; D016210:Methacholine Chloride; D007975:Leukotriene B4; D017997:Leukotriene C4; D010047:Ovalbumin; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D010741:Phospholipases A