Browsing by Subject "Permeability"

Now showing 1 - 4 of 4
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    Evaluation of chronic lead effects in the blood brain barrier system by DCE-CT
    (Elsevier, 2020-12) Gu, Huiying; Territo, Paul R.; Persohn, Scott A.; Bedwell, Amanda A.; Eldridge, Kierra; Speedy, Rachael; Chen, Zhe; Zheng, Wei; Du, Yansheng; Radiology and Imaging Sciences, School of Medicine
    Background: Lead (Pb) is an environmental factor has been suspected of contributing to the dementia including Alzheimer's disease (AD). Our previous studies have shown that Pb exposure at the subtoxic dose increased brain levels of beta-amyloid (Aβ) and amyloid plaques, a pathological hallmark for AD, in amyloid precursor protein (APP) transgenic mice, and is hypothesized to inhibit Aβ clearance in the blood- cerebrospinal fluid (CSF) barrier. However, it remains unclear how different levels of Pb affect Aβ clearance in the whole blood-brain barrier system. This study was designed to investigate whether chronic exposure of Pb affected the permeability of the blood-brain barrier system by using the Dynamic Contrast-Enhanced Computerized Tomography (DCE-CT) method. Methods: DEC-CT was used to investigate whether chronic exposure of toxic Pb affected the permeability of the real-time blood brain barrier system. Results: Data showed that Pb exposure increased permeability surface area product, and also significantly induced brain perfusion. However, Pb exposure did not alter extracellular volumes or fractional blood volumes of mouse brain. Conclusion: Our data suggest that Pb exposure at subtoxic and toxic levels directly targets the brain vasculature and damages the blood brain barrier system.
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    In Vivo Identification and Manipulation of the Ca2+ Selectivity Filter in the Drosophila Transient Receptor Potential Channel
    (Society for Neuroscience, 2007-01-17) Liu, Che H.; Wang, Tao; Postma, Marten; Obukhov, Alexander G.; Montell, Craig; Hardie, Roger C.; Cellular and Integrative Physiology, School of Medicine
    Null mutations in the transient receptor potential (trp) gene eliminate the major, Ca2+-selective component of the light-sensitive conductance in Drosophila photoreceptors. Although it is the prototypical member of the TRP ion channel superfamily, conclusive evidence that TRP is a pore-forming channel subunit in vivo is lacking. We show here that mutating a specific acidic residue (Asp621) in the putative pore virtually eliminated Ca2+ permeation in vivo and altered other biophysical properties of the native TRP conductance. The results identify Asp621 as a critical residue of the TRP Ca2+ selectivity filter, provide the first rigorous demonstration that a TRP protein is a pore-forming subunit in any native system, and point to the likely location of the pore in mammalian canonical TRP channels. The specific elimination of Ca2+ permeation in TRP also provided a unique opportunity to address the roles of Ca2+ influx in vivo. We found that Asp621 mutations profoundly affected several key aspects of the light response and caused light-dependent retinal degeneration.
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    Oxygen radical-induced microvascular injury in the lung
    (1987) Barnard, Joseph Wade
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    Prostacyclin post-treatment improves LPS-induced acute lung injury and endothelial barrier recovery via Rap1
    (Elsevier, 2015-05) Birukova, Anna A.; Meng, Fanyong; Tian, Yufeng; Meliton, Angelo; Sarich, Nicolene; Quilliam, Lawrence A.; Birukov, Konstantin G.; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Protective effects of prostacyclin (PC) or its stable analog beraprost against agonist-induced lung vascular inflammation have been associated with elevation of intracellular cAMP and Rac GTPase signaling which inhibited the RhoA GTPase-dependent pathway of endothelial barrier dysfunction. This study investigated a distinct mechanism of PC-stimulated lung vascular endothelial (EC) barrier recovery and resolution of LPS-induced inflammation mediated by small GTPase Rap1. Efficient barrier recovery was observed in LPS-challenged pulmonary EC after prostacyclin administration even after 15 h of initial inflammatory insult and was accompanied by the significant attenuation of p38 MAP kinase and NFκB signaling and decreased production of IL-8 and soluble ICAM1. These effects were reproduced in cells post-treated with 8CPT, a small molecule activator of Rap1-specific nucleotide exchange factor Epac. By contrast, pharmacologic Epac inhibitor, Rap1 knockdown, or knockdown of cell junction-associated Rap1 effector afadin attenuated EC recovery caused by PC or 8CPT post-treatment. The key role of Rap1 in lung barrier restoration was further confirmed in the murine model of LPS-induced acute lung injury. Lung injury was monitored by measurements of bronchoalveolar lavage protein content, cell count, and Evans blue extravasation and live imaging of vascular leak over 6 days using a fluorescent tracer. The data showed significant acceleration of lung recovery by PC and 8CPT post-treatment, which was abrogated in Rap1a(-/-) mice. These results suggest that post-treatment with PC triggers the Epac/Rap1/afadin-dependent mechanism of endothelial barrier restoration and downregulation of p38MAPK and NFκB inflammatory cascades, altogether leading to accelerated lung recovery.