期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 40, 期 5, 页码 1090-1102出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X19859465
关键词
Inter-alpha inhibitor proteins; lipopolysaccharide; blood-brain barrier; interleukin 6; inflammation
资金
- NIAAA NIH HHS [R56 AA011431, R01 AA028408] Funding Source: Medline
- NIA NIH HHS [R01 AG046619, T32 AG052354] Funding Source: Medline
- NICHD NIH HHS [R01 HD057100] Funding Source: Medline
- NINDS NIH HHS [R21 NS095130, R21 NS096525, R44 NS084575] Funding Source: Medline
Circulating levels of inter-alpha inhibitor proteins change dramatically in acute inflammatory disorders, which suggest an important contribution to the immunomodulatory system. Human blood-derived inter-alpha inhibitor proteins are neuroprotective and improve survival of neonatal mice exposed to lipopolysaccharide. Lipopolysaccharide augments inflammatory conditions and disrupts the blood-brain barrier. There is a paucity of therapeutic strategies to treat blood-brain barrier dysfunction, and the neuroprotective effects of human blood-derived inter-alpha inhibitor proteins are not fully understood. To examine the therapeutic potential of inter-alpha inhibitor proteins, we administered human blood-derived inter-alpha inhibitor proteins to male and female CD-1 mice after lipopolysaccharide exposure and quantified blood-brain barrier permeability of intravenously injected C-14-sucrose and Tc-99m-albumin. We hypothesized that human blood-derived inter-alpha inhibitor protein treatment would attenuate lipopolysaccharide-induced blood-brain barrier disruption and associated inflammation. Lipopolysaccharide increased blood-brain barrier permeability to both C-14-sucrose and Tc-99m-albumin, but human blood-derived inter-alpha inhibitor protein treatment only attenuated increases in C-14-sucrose blood-brain barrier permeability in male mice. Lipopolysaccharide stimulated a more robust elevation of male serum inter-alpha inhibitor protein concentration compared to the elevation measured in female serum. Lipopolysaccharide administration also increased multiple inflammatory factors in serum and brain tissue, including interleukin 6. Human blood-derived inter-alpha inhibitor protein treatment downregulated serum interleukin 6 levels, which were inversely correlated with serum inter-alpha inhibitor protein concentration. We conclude that inter-alpha inhibitor proteins may be neuroprotective through mechanisms of blood-brain barrier disruption associated with systemic inflammation.
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