Neutrophil elastase and neurovascular injury following focal stroke and reperfusion

Ann M. Stowe; Tracy L. Adair-Kirk; Ernesto R. Gonzales; Ronald S. Perez; Aarti R. Shah; Tae S. Park; Jeffrey M. Gidday

doi:10.1016/j.nbd.2009.04.006

Neutrophil elastase and neurovascular injury following focal stroke and reperfusion

Ann M. Stowe, Tracy L. Adair-Kirk, Ernesto R. Gonzales, Ronald S. Perez, Aarti R. Shah, Tae S. Park, Jeffrey M. Gidday

Research output: Contribution to journal › Article › peer-review

99 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	82-90
Number of pages	9
Journal	Neurobiology of Disease
Volume	35
Issue number	1
DOIs	https://doi.org/10.1016/j.nbd.2009.04.006
State	Published - Jul 2009

Bibliographical note

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.

Funding

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.

Funders	Funder number
Spastic Paralysis Research Foundation of the Illinois-Eastern Iowa District of Kiwanis International
National Institutes of Health (NIH)	P01 HL29594, PO1 NS032636, RO1 HL079278
National Institute of Neurological Disorders and Stroke	R01NS021045
Thailand Science Park

Keywords

Blood-brain barrier
Ischemia
Leukocyte-endothelial adherence
Protease
Transient middle cerebral artery occlusion
Vasogenic edema

ASJC Scopus subject areas

Neurology

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10.1016/j.nbd.2009.04.006

Cite this

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title = "Neutrophil elastase and neurovascular injury following focal stroke and reperfusion",

abstract = "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.",

keywords = "Blood-brain barrier, Ischemia, Leukocyte-endothelial adherence, Protease, Transient middle cerebral artery occlusion, Vasogenic edema",

author = "Stowe, {Ann M.} and Adair-Kirk, {Tracy L.} and Gonzales, {Ernesto R.} and Perez, {Ronald S.} and Shah, {Aarti R.} and Park, {Tae S.} and Gidday, {Jeffrey M.}",

note = "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.",

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language = "English",

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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.

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KW - Ischemia

KW - Leukocyte-endothelial adherence

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Neutrophil elastase and neurovascular injury following focal stroke and reperfusion

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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