TY - JOUR
T1 - Acute NADPH oxidase activation potentiates cerebrovascular permeability response to bradykinin in ischemia-reperfusion
AU - Woodfin, Abigail
AU - Hu, De En
AU - Sarker, Mosharraf
AU - Kurokawa, Tsuyoshi
AU - Fraser, Paul
PY - 2011/2/15
Y1 - 2011/2/15
N2 - Free radical generation is a key event in cerebral reperfusion injury. Bradykinin (Bk) and interleukin-1β (IL-1β) have both been implicated in edema formation after stroke, although acute Bk application itself results in only a modest permeability increase. We have investigated the molecular mechanism by assessing the permeability of single pial venules in a stroke model. Increased permeability on reperfusion was dependent on the duration of ischemia and was prevented by applying the B2 receptor antagonist HOE 140. Postreperfusion permeability increases were mimicked by applying Bk (5 μM) for 10 min and blocked by coapplying the IL-1 receptor antagonist with Bk. Furthermore, 10 min pretreatment with IL-1β resulted in a 3 orders of magnitude leftward shift of the acutely applied Bk concentration-response curve. The left shift was abolished by scavenging free radicals with superoxide dismutase and catalase. Apocynin coapplied with IL-1β completely blocked the potentiation, implying that NADPH oxidase assembly is the immediate target of IL-1β. In conclusion, this is first demonstration that bradykinin, released during cerebral ischemia, leads to IL-1β release, which in turn activates NADPH oxidase leading to blood-brain barrier breakdown.
AB - Free radical generation is a key event in cerebral reperfusion injury. Bradykinin (Bk) and interleukin-1β (IL-1β) have both been implicated in edema formation after stroke, although acute Bk application itself results in only a modest permeability increase. We have investigated the molecular mechanism by assessing the permeability of single pial venules in a stroke model. Increased permeability on reperfusion was dependent on the duration of ischemia and was prevented by applying the B2 receptor antagonist HOE 140. Postreperfusion permeability increases were mimicked by applying Bk (5 μM) for 10 min and blocked by coapplying the IL-1 receptor antagonist with Bk. Furthermore, 10 min pretreatment with IL-1β resulted in a 3 orders of magnitude leftward shift of the acutely applied Bk concentration-response curve. The left shift was abolished by scavenging free radicals with superoxide dismutase and catalase. Apocynin coapplied with IL-1β completely blocked the potentiation, implying that NADPH oxidase assembly is the immediate target of IL-1β. In conclusion, this is first demonstration that bradykinin, released during cerebral ischemia, leads to IL-1β release, which in turn activates NADPH oxidase leading to blood-brain barrier breakdown.
UR - http://www.scopus.com/inward/record.url?scp=79251610937&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2010.12.010
DO - 10.1016/j.freeradbiomed.2010.12.010
M3 - Article
C2 - 21167936
AN - SCOPUS:79251610937
SN - 0891-5849
VL - 50
SP - 518
EP - 524
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 4
ER -