Alternatively-spliced extra domain A of fibronectin promotes acute inflammation and brain injury after cerebral ischemia in mice.
Stroke
; 43(5): 1376-82, 2012 May.
Article
em En
| MEDLINE
| ID: mdl-22363055
ABSTRACT
BACKGROUND AND PURPOSE:
The fibronectin isoform containing the alternatively spliced extra domain A (EDA(+)-FN) is normally absent from the circulation, but plasma levels of EDA(+)-FN can become markedly elevated in several human pathological conditions associated with inflammation including ischemic stroke. It remains unknown whether EDA(+)-FN contributes to stroke pathogenesis or is simply an associative marker. Several in vitro studies suggest that EDA(+)-FN can activate Toll-like receptor 4, an innate immune receptor that triggers proinflammatory responses. We undertook a genetic approach in mice to investigate the ability of EDA(+)-FN to mediate inflammatory brain damage in a focal cerebral ischemia/reperfusion injury model.METHODS:
We used genetically modified EDA(+/+) mice, which constitutively express EDA(+)-FN. Extent of injury, neurological outcome, and inflammatory mechanisms were assessed after 1-hour cerebral ischemia/23-hour reperfusion injury and compared with wild-type mice.RESULTS:
We found that EDA(+/+) mice developed significantly larger infarcts and severe neurological deficits that were associated with significant increased neutrophil and macrophage infiltration as quantitated by immunohistochemistry. Additionally, we found upregulation of nuclear factor-κB, cyclo-oxygenase-2, and inflammatory cytokines tumor necrosis factor-α, interleukin-1ß, and interleukin-6 in the EDA(+/+) mice compared with wild-type mice. Interestingly, increased brain injury and neurological deficits were largely abrogated in EDA(+/+) mice by treatment with a specific Toll-like receptor 4 inhibitor.CONCLUSIONS:
These findings provide the first evidence that EDA(+)-FN promotes inflammatory brain injury after ischemic stroke and suggest that the elevated levels of plasma EDA(+)-FN observed in chronic inflammatory conditions could worsen injury and outcome in patients after acute stroke.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Lesões Encefálicas
/
Isquemia Encefálica
/
Fibronectinas
/
Estrutura Terciária de Proteína
/
Processamento Alternativo
/
Encefalite
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article