Evidence of inflammatory cell involvement in brain arteriovenous malformations.
OBJECTIVE
Brain arteriovenous malformations (AVM) have high matrix metalloproteinase-9, interleukin-6, and myeloperoxidase (MPO) expression, and polymorphic variations in inflammatory genes are associated with an increased risk of hemorrhage. In this study, we characterized the presence of inflammatory cells in AVM lesional tissue specimens.


METHODS
Immunohistochemistry was used to identify and localize neutrophils (MPO as marker), macrophages/microglia (CD68 as marker), T lymphocytes (CD3 as marker), and B lymphocytes (CD20 as marker). Endothelial cell (EC) marker CD31 was used as an index to assess vascular mass (EC mass). Surgical specimens from 20 unruptured, nonembolized AVMs were examined; seven cortical samples from temporal lobectomy were used as controls. Positive signals for inflammatory cell markers were counted and analyzed by normalizing to the area of the tissue section and the amount of endothelial cells (cells/mm/EC mass pixels). Levels of MPO and matrix metalloproteinase 9 were determined by enzyme-linked immunosorbent assay.


RESULTS
Neutrophils and macrophages are all frequently identified in the vascular wall of AVM tissue. In contrast, T and B lymphocytes are rarely observed in AVM tissue. AVM tissue displayed more neutrophil and macrophage/microglia markers than epilepsy control tissue (MPO: 434 +/- 333 versus 5 +/- 4, P = 0.0001; CD68: 454 +/- 404 versus 4 +/- 2, P = 0.0001; cells/mm/EC mass pixels). In ex vivo studies, neutrophil quantity, MPO, and matrix metalloproteinase-9 levels were all colinear (R = 0.98-0.99).


CONCLUSIONS
Our study demonstrates that inflammatory cells are present in AVM tissue. Taken together with previous genetic and cytokine studies, these data are consistent with a novel view that inflammation is associated with AVM disease progression and rupture.
Chen
Yongmei
Y
Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California, USA.
Zhu
Wei
W
Bollen
Andrew W
AW
Lawton
Michael T
MT
Barbaro
Nicholas M
NM
Dowd
Christopher F
CF
Hashimoto
Tomoki
T
Yang
Guo-Yuan
GY
Young
William L
WL
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000378:metabolism* / Q000473:pathology*; D007962:Leukocytes / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009195:Peroxidase / Q000378:metabolism*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009195:Peroxidase; C067980:CD68 antigen, human; D000097382:CD68 Molecule