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Effects of Immunomodulatory and Organism-Associated Molecules on the Permeability of an in Vitro Blood Brain Barrier Model to Amphotericin B and Fluconazole.

著者 Pyrgos V , Mickiene D , Sein T , Cotton M , Fransesconi A , Mizrahi I , Donoghue M , Bundrant N , Kim SY , Hardwick M , Shoham S , Walsh TJ この記事をPubMed上で見るPubMedで表示
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Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, NIH, Bethesda, MD; Section of Infectious Diseases, Washington Hospital Center, Washington, DC; Department of hematology-Oncology, Children's National Medical Center, Was

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Amphotericin B (AmB) is used to treat fungal infections of the central nervous system (CNS). However, AmB shows poor penetration into the CNS and little is known about factors affecting its blood brain barrier (BBB) permeability. Therefore, we studied immunomodulatory and organism-associated molecules affecting permeability of an in vitro BBB model to AmB. We examined the effects of interleukin 1 beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan (ZYM), dexamethasone (DEX), cyclosporin A and tacrolimus on transendothelial electrical resistance (TEER), endothelial tight junctions, filamentous actin and permeability to deoxycholate AmB (DAmB), liposomal AmB (LAmB) and fluconazole. Pro-inflammatory cytokines and organism associated molecules significantly decreased the mean TEER by 40.7-100% (p</= 0.004). DEX increased mean TEER by 18.2-26.4%(p</=0.04). TNFalpha and LPS increased the permeability to AmB by 8.2-14.5% compared to controls (1.1-2.4%)(p</=0.04). None of the other molecules affected the model's permeability to AmB. By comparison, the BBB model's permeability to fluconazole was >78% in all conditions studied, without significant differences between controls and experimental groups. LPS and TNFalpha decreased tight junction proteins zona occludens 1 (ZO-1) between endothelial cells. In conclusion, IL-1beta, ZYM and LTA increased BBB permeability to small ions but not to AmB. Whereas TNFalpha and LPS, which disrupted the endothelial layer integrity, increased permeability to AmB.
PMID: 19995929 [PubMed - as supplied by publisher]
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