Neutrophil protein kinase Cdelta as a mediator of stroke-reperfusion injury.
Thrombolysis is widely used to intervene in acute ischemic stroke, but reestablishment of circulation may paradoxically initiate a reperfusion injury. Here we describe studies with mice lacking protein kinase Cdelta (PKCdelta) showing that absence of this enzyme markedly reduces reperfusion injury following transient ischemia. This was associated with reduced infiltration of peripheral blood neutrophils into infarcted tissue and with impaired neutrophil adhesion, migration, respiratory burst, and degranulation in vitro. Total body irradiation followed by transplantation with bone marrow from PKCdelta-null mice donors reduced infarct size and improved neurological outcome in WT mice, whereas marrow transplantation from WT donors increased infarction and worsened neurological scores in PKCdelta-null mice. These results indicate an important role for neutrophil PKCdelta in reperfusion injury and strongly suggest that PKCdelta inhibitors could prove useful in the treatment of stroke.
Chou
Wen-Hai
WH
Ernest Gallo Clinic and Research Center at the University of California San Francisco, Emeryville, California 94608, USA.
Choi
Doo-Sup
DS
Zhang
Hong
H
Mu
Dezhi
D
McMahon
Tom
T
Kharazia
Viktor N
VN
Lowell
Clifford A
CA
Ferriero
Donna M
DM
Messing
Robert O
RO
D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000473:pathology; D005091:Exons; D002546:Ischemic Attack, Transient / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology*; D011493:Protein Kinase C / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D051745:Protein Kinase C-delta; D011995:Recombination, Genetic; D015427:Reperfusion Injury / Q000097:blood* / Q000201:enzymology
C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta