Neutrophil elastase and neurovascular injury following focal stroke and reperfusion.
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.
Stowe
Ann M
AM
Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, USA.
Adair-Kirk
Tracy L
TL
Gonzales
Ernesto R
ER
Perez
Ronald S
RS
Shah
Aarti R
AR
Park
Tae S
TS
Gidday
Jeffrey M
JM
D000704:Analysis of Variance; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000235:genetics; D001812:Blood-Brain Barrier / Q000503:physiopathology; D001921:Brain / Q000098:blood supply; D001929:Brain Edema / Q000473:pathology; D020520:Brain Infarction / Q000209:etiology* / Q000517:prevention & control; D002448:Cell Adhesion; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000473:pathology*; D017078:Laser-Doppler Flowmetry / Q000379:methods; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000378:metabolism*; D007962:Leukocytes / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D013778:Tetrazolium Salts
D004791:Enzyme Inhibitors; D013778:Tetrazolium Salts; C009591:triphenyltetrazolium; D019272:Leukocyte Elastase; D020780:Matrix Metalloproteinase 9