Journal article
Alternatively-spliced extra domain A of fibronectin promotes acute inflammation and brain injury after cerebral ischemia in mice
Stroke (1970), Vol.43(5), pp.1376-1382
05/2012
DOI: 10.1161/STROKEAHA.111.635516
PMCID: PMC3335936
PMID: 22363055
Abstract
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.
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.
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-1β, 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.
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.
Details
- Title: Subtitle
- Alternatively-spliced extra domain A of fibronectin promotes acute inflammation and brain injury after cerebral ischemia in mice
- Creators
- Mohammad Moshahid Khan - University of Iowa, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242, USAChintan GandhiNeelam ChauhanJeff W StevensDavid G MottoSteven R LentzAnil K Chauhan
- Resource Type
- Journal article
- Publication Details
- Stroke (1970), Vol.43(5), pp.1376-1382
- DOI
- 10.1161/STROKEAHA.111.635516
- PMID
- 22363055
- PMCID
- PMC3335936
- ISSN
- 0039-2499
- eISSN
- 1524-4628
- Grant note
- HL063943 / NHLBI NIH HHS K08 HL076539-05 / NHLBI NIH HHS K08 HL076539 / NHLBI NIH HHS P01 NS024621 / NINDS NIH HHS HL076539 / NHLBI NIH HHS R01 HL063943-11 / NHLBI NIH HHS NS024621 / NINDS NIH HHS R01 HL063943 / NHLBI NIH HHS
- Language
- English
- Date published
- 05/2012
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094383002771
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