TY - JOUR
T1 - Neutrophil elastase and neurovascular injury following focal stroke and reperfusion
AU - Stowe, Ann M.
AU - Adair-Kirk, Tracy L.
AU - Gonzales, Ernesto R.
AU - Perez, Ronald S.
AU - Shah, Aarti R.
AU - Park, Tae S.
AU - Gidday, Jeffrey M.
N1 - Funding Information:
The authors thank Steven S. Shapiro for the breeder pairs of NE−/− mice, and Lena Martensson at AstraZeneca (Wilmington, Delaware) for kindly providing the ZN200355. The authors would like to recognize NIH RO1 NS21045 (TSP), RO1 HL079278 (JMG), PO1 NS032636 (JMG), P01 HL29594 (TLAK), and the Spastic Paralysis Research Foundation of the Illinois-Eastern Iowa District of Kiwanis International (TSP), for funding this research. Ann Stowe is a Hope Center Fellow supported by the Hope Center for Neurological Disorders, Washington University School of Medicine.
PY - 2009/7
Y1 - 2009/7
N2 - Neutrophil elastase (NE) degrades basal lamina and extracellular matrix molecules, and recruits leukocytes during inflammation; however, a basic understanding of the role of NE in stroke pathology is lacking. We measured an increased number of extravascular NE-positive cells, as well as increased levels of tissue elastase protein and activity, following transient middle cerebral artery occlusion (tMCAo). Both pharmacologic inhibition of NE with ZN200355 (ZN), and genetic deletion of NE, significantly reduced infarct volume, blood-brain barrier disruption, vasogenic edema, and leukocyte-endothelial adherence 24 h after tMCAo. ZN also reduced infarct volume in MMP9-null mice following tMCAo. There were, however, no reductions in infarct volume or vasogenic edema in NE-null mice in two models of permanent middle cerebral artery occlusion. Our findings confirm the involvement of NE in neurovascular stroke pathology, when reperfusion allows neutrophils access to vulnerable brain, with pharmacologic or genetic inhibition of NE being both neuro- and vasculo-protective in this setting.
AB - Neutrophil elastase (NE) degrades basal lamina and extracellular matrix molecules, and recruits leukocytes during inflammation; however, a basic understanding of the role of NE in stroke pathology is lacking. We measured an increased number of extravascular NE-positive cells, as well as increased levels of tissue elastase protein and activity, following transient middle cerebral artery occlusion (tMCAo). Both pharmacologic inhibition of NE with ZN200355 (ZN), and genetic deletion of NE, significantly reduced infarct volume, blood-brain barrier disruption, vasogenic edema, and leukocyte-endothelial adherence 24 h after tMCAo. ZN also reduced infarct volume in MMP9-null mice following tMCAo. There were, however, no reductions in infarct volume or vasogenic edema in NE-null mice in two models of permanent middle cerebral artery occlusion. Our findings confirm the involvement of NE in neurovascular stroke pathology, when reperfusion allows neutrophils access to vulnerable brain, with pharmacologic or genetic inhibition of NE being both neuro- and vasculo-protective in this setting.
KW - Blood-brain barrier
KW - Ischemia
KW - Leukocyte-endothelial adherence
KW - Protease
KW - Transient middle cerebral artery occlusion
KW - Vasogenic edema
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U2 - 10.1016/j.nbd.2009.04.006
DO - 10.1016/j.nbd.2009.04.006
M3 - Article
C2 - 19393318
AN - SCOPUS:67349132475
SN - 0969-9961
VL - 35
SP - 82
EP - 90
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1
ER -