| 1. |
- McCrae, Cristopher, et al.
(författare)
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Lanosterol Synthase Regulates Human Rhinovirus Replication in Human Bronchial Epithelial Cells
- 2018
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - 1044-1549. ; 59:6, s. 713-722
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Tidskriftsartikel (refereegranskat)abstract
- Human rhinovirus (RV) infections are a significant risk factor for exacerbations of asthma and chronic obstructive pulmonary disease. Thus, approaches to prevent RV infection in such patients would give significant benefit. Through RNA interference library screening, we identified lanosterol synthase (LSS), a component of the cholesterol biosynthetic pathway, as a novel regulator of RV replication in primary normal human bronchial epithelial cells. Selective knock down of LSS mRNA with short interfering RNA inhibited RV2 replication in normal human bronchial epithelial cells. Small molecule inhibitors of LSS mimicked the effect of LSS mRNA knockdown in a concentration-dependent manner. We further demonstrated that the antiviral effect is not dependent on a reduction in total cellular cholesterol but requires a 24-hour preincubation with the LSS inhibitor. The rank order of antiviral potency of the LSS inhibitors used was consistent with LSS inhibition potency; however, all compounds showed remarkably higher potency against RV compared with the LSS enzyme potency. We showed that LSS inhibition led to an induction of 24(S),25 epoxycholesterol, an important regulator of the sterol pathway. We also demonstrated that LSS inhibition led to a profound increase in expression of the innate antiviral defense protein, IFN-beta. We found LSS to be a novel regulator of RV replication and innate antiviral immunity and identified a potential molecular mechanism for this effect, via induction of 24(S),25 epoxycholesterol. Inhibition of LSS could therefore be a novel therapeutic target for prevention of RV-induced exacerbations.
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| 2. |
- Porra, Liisa, et al.
(författare)
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Synchrotron Imaging Shows Effect of Ventilator Settings on Intrabreath Cyclic Changes in Pulmonary Blood Volume
- 2017
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Ingår i: American Journal of Respiratory Cell and Molecular Biology. - : AMER THORACIC SOC. - 1044-1549 .- 1535-4989. ; 57:4, s. 459-467
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Tidskriftsartikel (refereegranskat)abstract
- Despite the importance of dynamic changes in the regional distributions of gas and blood during the breathing cycle for lung function in the mechanically ventilated patient, no quantitative data on such cyclic changes are currently available. We used a novel gated synchrotron computed tomography imaging to quantitatively image regional lung gas volume (Vg), tissue density, and blood volume (Vb) in six anesthetized, paralyzed, and mechanically ventilated rabbits with normal lungs. Images were repeatedly collected during ventilation and steady-state inhalation of 50% xenon, or iodine infusion. Data were acquired in a dependent and nondependent image level, at zero end-expiratory pressure (ZEEP) and 9 cm H2O (positive end-expiratory pressure), and a tidal volume (V-T) of 6ml/kg(V(T)1) or 9ml/kg(V(T)2) at an Inspiratory: Expiratory ratio of 0.5 or 1.7 by applying an end-inspiratory pause. A video showing dynamic decreases in Vb during inspiration is presented. Vb decreased with positive end-expiratory pressure (P = 0.006; P = 0.036 versus V(T)1-ZEEP and V(T)2-ZEEP, respectively), and showed larger oscillations at the dependent image level, whereas a 45% increase in VT did not have a significant effect. End-inspiratory Vb minima were reduced by an end-inspiratory pause (P = 0.042, P = 0.006 at nondependent and dependent levels, respectively). Normalized regional Vg:Vb ratio increased upon inspiration. Our data demonstrate, for the first time, within-tidal cyclic variations in regional pulmonary Vb. The quantitative matching of regional Vg and Vb improved upon inspiration under ZEEP. Further study is underway to determine whether these phenomena affect intratidal gas exchange.
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