Cigarette smoke exposure up-regulates endothelin receptor B in human pulmonary artery endothelial cells: molecular and functional consequences

BACKGROUND AND PURPOSE

Pulmonary arteries from smokers and chronic obstructive pulmonary disease patients show abnormal endothelium-dependent vascular reactivity. We studied the effect of cigarette smoke extract (CSE) on endothelin receptor B (ET_B) expression in human pulmonary artery endothelial cells (HPAECs) and its role in endothelial dysfunction.

EXPERIMENTAL APPROACH

ET_B receptor expression was measured by real time RT-PCR, Western blot and immunofluorescence. Cell contraction, intracellular Ca²⁺, F/G-actin, RhoA activity, myosin light chain phosphorylation, ET, NO, thromboxane (Tx)A₂ and reactive oxygen species (ROS) were measured by traction microscopy, fluorescence microscopy, phalloidin fluorescence, colorimetric assay, Western blot, elisa and DCFDA fluorescence respectively.

KEY RESULTS

Cigarette smoke extract dose-dependently increased ET_B receptor expression in HPAECs after 24 h incubation. CSE-induced ET_B expression was attenuated by bosentan, the ET_B receptor antagonist BQ788, the Rho kinase antagonist Y27632 and the antioxidant N-acetylcysteine. A monoclonal antibody to ET-1 prevented CSE-induced ET_B receptor overexpression. Twenty-four hour exposure to ET-1 dose-dependently increased ET_B receptor expression, mimicking the effect of CSE. CSE-induced ET_B receptor overexpression caused greater cell contraction; increased intracellular Ca²⁺; increased F/G-actin and RhoA activity; increased myosin light chain phosphorylation; augmented TxA₂ and ROS production; and decreased NO after acute ET-1 (10 nM). These effects were attenuated by bosentan, BQ788, Y27632 and N-acetylcysteine.

CONCLUSIONS AND IMPLICATION

Cigarette smoke extract induced ET_B receptor overexpression by a feed forward mechanism mediated partly by ET release, promoting HPAEC dysfunction and attenuated by ET_B receptor blockade, Rho kinase and ROS inhibition. These results provide support for the use of bosentan in CS-related endothelial dysfunction.     

Diffusion-weighted MR imaging in transient ischaemic attacks

The purpose of this study was to determine frequency and the characteristics of diffusion-weighted imaging (DWI) abnormalities in patients with transient ischaemic attack (TIA). We analysed data of 98 consecutive patients (mean age: 60.6±15.4 years, 56 men) admitted between January 2003 and April 2004 for TIA. Age, gender, symptom type and duration, delay from onset to magnetic resonance imaging (MRI), probable or possible TIA and cause of TIA were compared in patients with (DWI+) and without (DWI−) lesions on DWI. Volume and apparent diffusion coefficient (ADC) values of DWI lesions were computed. DWI revealed ischaemic lesions in 34 patients (34.7%). Lesions were small (mean volume: 1.9 cm³±3.3), and ADC was moderately decreased (mean ADC ratio: 79.5%). The diagnosis of TIA was considered as probable in all DWI+ patients. A multiple logistic regression model demonstrated that TIA duration greater than or equal to 60 min (OR, 7.6; 95% CI, 2.3–25.7), aphasia (OR, 9.2; 95% CI, 2.7–31.4) and motor deficit (OR, 5.1; 95% CI, 1.5–17.8) were independent predictors of DWI lesions. Prolonged TIA duration, aphasia and motor deficits are associated with DWI lesions. More than half of TIA patients with symptoms lasting more than 60 min have DWI lesions.     

Traumatic flap displacement after LASIK

CASE REPORT: We present a case of traumatic displacement of corneal flap in the superior temporal quadrant 13 days after LASIK. The flap was repositioned after gentle irrigation of BSS, cleaned the interface and then drying the flap to verify its stability. In the next day the flap was adhered, clear cornea,smooth and visual acuity without correction was 1.00. DISCUSSION: We should try immediately to reposition the flap after traumatic displacement, as in this case.     

Proliferative ischaemic retinopathy in a case of systemic lupus erythematosus and antiphospholipidic syndrome

PURPOSE/METHODS: We report a 34-year-old woman with sytemic lupus erythematosus (S.L.E.) and antiphospholipidic syndrome which presented severe ischaemic retinopathy and neovascular proliferation. RESULTS/CONCLUSIONS: We achieved no progression of the disease and stabilization of visual acuity with panphotocoagulation. We recommend periodic ophtalmologic exams because of the scarce symptomatology.     

Ventricular arrhythmias following thermal damage of epicardial tissue: possible causes and clinical implications

Epicardial heating may be used for ventricular tachycardia (VT) ablation and transmyocardial revascularization. However, the potential risks of thermal epicardial injury, including arrhythmia, have not been fully explored. This study relates the pathologic and arrhythmic sequellae of epicardial heating when applied with a diode laser at varying doses. Acute pathology and dosimetry were determined in a group of normal dogs using 2-3 W over 30-90 seconds. Another group received a similar dose range before undergoing 24-hour monitoring, and electrophysiological testing was done at 4 weeks. In this group, four dogs each received 12 lesions (90-180 J) according to a randomized block design. Another dog received nine lower dose lesions (30-120 J). Acute lesions measured 2.5-8.0-mm wide by 4-8.5-mm deep. Charring and vaporization were common when 3 W were applied over 45 seconds. Within 24 hours, VT with features of abnormal automaticity occurred in all dogs receiving this dose. The dog in whom lower doses induced coagulation only had no VT. Four weeks later, electrophysiological study induced no VT. At this time fibrosis and granulation tissue were organizing the contraction band necrosis seen acutely, and some lesion borders were becoming calcified. No major vessels had been damaged. Abnormal automaticity and VT may occur if thermal damage of the epicardium exceeds coagulation. This could be related to tissue injury caused by sudden water vaporization, and may have clinical relevance given the growing indications for myocardial heating.     

SEVENTY-TWO HOUR COMPARISON OF METHYLPREDNISOLONE SULEPTANATE AND METHYLPREDNISOLONE SODIUM SUCCINATE IN PATIENTS WITH ACUTE ASTHMA

SUMMARY The efficacy and safety of the methylprednisolone prodrugs methylprednisolone suleptanate and methylprednisolone sodium succinate were evaluated in a multicentre, randomised, double-blind, double-dummy parallel study of 88 patients hospitalised with acute asthma. Each study drug was administered as a bolus intravenous injection of 40mg methylprednisolone equivalents every 6 hours for 48 hours. Methylprednisolone 32mg was administered orally 6 hours after the last dose. Pulmonary function, medical events, and clinical laboratory values were assessed at predefined intervals before and during the 72-hour study. The primary response measure of pulmonary function was per cent predicted forced expiratory volume in one second (FEV₁) at 48 hours. Secondary response measures were peak expiratory flow rate (PEFR) and FEV₁/forced vital capacity (FVC) ratio. Although both drugs demonstrated within-group mean changes from baseline (starting at 6 hours) that were statistically significant for each response, there were no statistically significant differences between the two groups. The mean percent predicted FEV₁ at 48 hours and mean per cent change from baseline were 64% and 13% (p<0.0001) for the methylprednisolone suleptanate group and 67% and 17% (p<0.0001) for the methylprednisolone sodium succinate group, respectively. The mean PEFR and FEV₁/FVC ratio at 48 hours were 5.77 l/s and 73% for the methylprednisolone suleptanate group and 5.78 l/s and 76% for the methylprednisolone sodium succinate group, respectively. There were no clinically or statistically significant between-group differences in any of the safety parameters. In this study, methylprednisolone suleptanate and methylprednisolone sodium succinate have been shown to be therapeutically equivalent in the treatment of patients hospitalized with acute asthma.     

Ultrasonic characterization of aging in skin tissue

The propagation velocity (c) and attenuation coefficient () of ultrasound were measured at room temperature in skin tissues excised from twenty aged (27 months) and eight young (2 months) Bar Harbor strain female mice. Frequencies used were 2.25, 5.0, 7.5 and 10.0 MHz. Both velocity and attenuation data were obtained using a pulse-echo technique. Transit times were measured with a universal counter timer to 10 nsec resolution, and corrected for the “dead time” due to the transducer matching layer.

Aged skin had significantly lower values of c and at all frequencies than did the corresponding young tissues.

This preliminary study suggests that the tissue changes which collectively constitute aging may, in some instances, be predictably associated with measurable changes in the acoustic properties of those tissues.