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Blood-brain barrier damage induces release of alpha2-macroglobulin
Luca Cucullo1, Nicola Marchi, Matteo Marroni
1Department of Neurological Surgery, Cerebrovascular Research Center, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA.
Abstract:
Blood-brain barrier (BBB) failure occurs in many neurological diseases and is caused in part by activation of proinflammatory factors including matrix metalloproteinases. Counterbalancing, "BBB protective" cascades have recently been described, including NO-mediated interleukin 6 release by glia. Interleukin 6 has been shown to trigger production of matrix metalloproteinase inhibitors such as alpha2-macroglobulin (alpha2M). We hypothesized that BBB failure may result in increased alpha(2)M release by perivascular astrocytes. This was initially tested in patients undergoing iatrogenic BBB disruption by hyperosmotic mannitol for intra-arterial chemotherapy of brain tumors. Serum samples revealed significantly increased levels of alpha2M at 4 h after BBB disruption by hyperosmotic mannitol. In parallel in vitro experiments, we observed a similar increase of alpha2M release by astrocytes under conditions mimicking BBB failure and perivascular edema. For both experiments, protein analysis was initially performed by bidimensional gel electrophoresis and mass spectrometry followed by Western blotting immunodetection. We conclude that, in addition to proinflammatory changes, BBB failure may also trigger protective release of alpha2M by perivascular astrocytes as well as peripheral source.
Insights
Blood-brain barrier (BBB) failure triggers increased alpha2-macroglobulin (alpha2M) release from astrocytes. This suggests a protective mechanism against neurological damage, involving both brain and peripheral sources.
Area of Science:
- Neuroscience
- Biochemistry
Background:
- Blood-brain barrier (BBB) dysfunction is implicated in neurological diseases, often driven by inflammation and matrix metalloproteinases.
- Protective mechanisms, like NO-mediated interleukin 6 release, counterbalance BBB damage.
- Interleukin 6 can induce matrix metalloproteinase inhibitors, such as alpha2-macroglobulin (alpha2M).
Purpose of the Study:
- To investigate if BBB failure leads to increased alpha2-macroglobulin (alpha2M) release by perivascular astrocytes.
- To explore potential protective responses to BBB disruption.
Main Methods:
- Analysis of serum samples from patients with iatrogenic BBB disruption using hyperosmotic mannitol.
- In vitro experiments with astrocytes under conditions mimicking BBB failure and perivascular edema.
- Protein analysis via bidimensional gel electrophoresis, mass spectrometry, and Western blotting.
Main Results:
- Significantly elevated alpha2M levels were observed in patient serum 4 hours post-BBB disruption.
- Astrocytes in vitro demonstrated increased alpha2M release under simulated BBB failure conditions.
- These findings were confirmed through advanced protein analysis techniques.
Conclusions:
- BBB failure not only involves proinflammatory factors but also initiates protective cascades.
- Perivascular astrocytes, along with peripheral sources, contribute to alpha2M release in response to BBB compromise.
- Alpha2M may play a role in mitigating neurological damage associated with BBB failure.