37 research outputs found
Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration
BACKGROUND: The aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH) in rats. METHODS: CD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i) the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii) the anti-remodeling effect of long-term inhalation of tolafentrine (iii) the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated. RESULTS: Monocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks), cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. The upregulation of extracellular matrix regulation and adhesion genes was reduced by nearly 80% by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response. CONCLUSION: In conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses pulmonary hypertension fully developed in response to monocrotaline in rats. This "reverse-remodeling" effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with 60% normalization of hemodynamics
Solonamide B Inhibits Quorum Sensing and Reduces Staphylococcus aureus Mediated Killing of Human Neutrophils
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a serious human pathogen, and particularly the spread of community associated (CA)-MRSA strains such as USA300 is a concern, as these strains can cause severe infections in otherwise healthy adults. Recently, we reported that a cyclodepsipeptide termed Solonamide B isolated from the marine bacterium, Photobacterium halotolerans strongly reduces expression of RNAIII, the effector molecule of the agr quorum sensing system. Here we show that Solonamide B interferes with the binding of S. aureus autoinducing peptides (AIPs) to sensor histidine kinase, AgrC, of the agr two-component system. The hypervirulence of USA300 has been linked to increased expression of central virulence factors like α-hemolysin and the phenol soluble modulins (PSMs). Importantly, in strain USA300 Solonamide B dramatically reduced the activity of α-hemolysin and the transcription of psma encoding PSMs with an 80% reduction in toxicity of supernatants towards human neutrophils and rabbit erythrocytes. To our knowledge this is the first report of a compound produced naturally by a Gram-negative marine bacterium that interferes with agr and affects both RNAIII and AgrA controlled virulence gene expression in S. aureus
Railway-induced ground vibrations – a review of vehicle effects
This paper is a review of the effect of vehicle characteristics on ground- and track borne-vibrations from railways. It combines traditional theory with modern thinking and uses a range of numerical analysis and experimental results to provide a broad analysis of the subject area. First, the effect of different train types on vibration propagation is investigated. Then, despite not being the focus of this work, numerical approaches to vibration propagation modelling within the track and soil are briefly touched upon. Next an in-depth discussion is presented related to the evolution of numerical models, with analysis of the suitability of various modelling approaches for analysing vehicle effects. The differences between quasi-static and dynamic characteristics are also discussed with insights into defects such as wheel/rail irregularities. Additionally, as an appendix, a modest database of train types are presented along with detailed information related to their physical attributes. It is hoped that this information may provide assistance to future researchers attempting to simulate railway vehicle vibrations. It is concluded that train type and the contact conditions at the wheel/rail interface can be influential in the generation of vibration. Therefore, where possible, when using numerical approach, the vehicle should be modelled in detail. Additionally, it was found that there are a wide variety of modelling approaches capable of simulating train types effects. If non-linear behaviour needs to be included in the model, then time domain simulations are preferable, however if the system can be assumed linear then frequency domain simulations are suitable due to their reduced computational demand
Hexamodal Imaging with Porphyrin-Phospholipid-Coated Upconversion Nanoparticles
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