BackgroundChemokines are emerging as important mediators of CNS inflammation capable of activating leukocyte integrins and directing the migration of leukocyte subsets to sites of antigenic challenge. In this study we investigated the expression, release and binding of CCL2 (MCP-1) and CCL3 (MIP-1α) in an in vitro model of the human blood-brain barrier.MethodsThe kinetics of expression and cytokine upregulation and release of the β-chemokines CCL2 and CCL3 were studied by immunocytochemistry and enzyme-linked immunosorbent assay in primary cultures of human brain microvessel endothelial cells (HBMEC). In addition, the differential binding of these chemokines to the basal and apical endothelial cell surfaces was assessed by immunoelectron microscopy.ResultsUntreated HBMEC synthesize and release low levels of CCL2. CCL3 is minimally expressed, but not released by resting HBMEC. Treatment with TNF-α, IL-1β, LPS and a combination of TNF-α and IFN-γ, but not IFN-γ alone, significantly upregulated the expression and release of both chemokines in a time-dependent manner. The released CCL2 and CCL3 bound to the apical and basal endothelial surfaces, respectively. This distribution was reversed in cytokine-activated HBMEC resulting in a predominantly basal localization of CCL2 and apical distribution of CCL3.ConclusionsSince cerebral endothelial cells are the first resident CNS cells to contact circulating leukocytes, expression, release and presentation of CCL2 and CCL3 on cerebral endothelium suggests an important role for these chemokines in regulating the trafficking of inflammatory cells across the BBB in CNS inflammation.
Background T-peak to T-end interval (Tp-e) is an independent marker of sudden cardiac death. Modulation of Tp-e by sympathetic nerve activation and circulating norepinephrine (NE) is not well understood. The purpose of this study was to characterize endocardial and epicardial dispersion of repolarization (DOR) and its effects on Tp-e with sympathetic activation. Methods and Results In Yorkshire pigs (n=13), a sternotomy was performed and the heart and bilateral stellate ganglia (SG) were exposed. A 56-electrode sock and 64-electrode basket catheter were placed around the epicardium and in the left ventricle (LV), respectively. Activation recovery interval (ARI), dispersion of repolarization (DOR), defined as variance in repolarization time, and Tp-e were assessed before and after left, right, and bilateral SG stimulation and NE infusion. LV endocardial and epicardial ARIs significantly decreased, and LV endocardial and epicardial DOR increased during sympathetic nerve stimulation. There were no LV epicardial vs. endocardial differences in ARI during sympathetic stimulation and regional endocardial ARI patterns were similar to the epicardium. Tp-e prolonged during left (from 40.4±2.2 ms to 92.4±12.4 ms; P<0.01), right (from 47.7±2.6 ms to 80.7±11.5 ms; P<0.01), and bilateral (from 47.5±2.8 ms to 78.1±9.8 ms; P<0.01) stellate stimulation and strongly correlated with whole heart DOR during stimulation (P<0.001, R=0.86). Of note, NE infusion did not increase DOR or Tp-e. Conclusions Regional patterns of LV endocardial sympathetic innervation are similar to that of LV epicardium. Tp-e correlated with whole heart DOR during sympathetic nerve activation. Circulating NE did not affect DOR or Tp-e.
Background Variability in premature ventricular contraction (PVC) coupling interval (CI) increases the risk of cardiomyopathy and sudden death. The autonomic nervous system regulates cardiac electrical and mechanical indices, and its dysregulation plays an important role in cardiac disease pathogenesis. The impact of PVCs on the intrinsic cardiac nervous system (ICNS), a neural network on the heart, remains unknown. The objective was to determine the effect of PVCs and CI on ICNS function in generating cardiac neuronal and electrical instability using a novel cardio-neural mapping approach. Methods and Results In a porcine model (n=8) neuronal activity was recorded from a ventricular ganglion using a microelectrode array, and cardiac electrophysiological mapping was performed. Neurons were functionally classified based on their response to afferent and efferent cardiovascular stimuli, with neurons that responded to both defined as convergent (local reflex processors). Dynamic changes in neuronal activity were then evaluated in response to right ventricular outflow tract PVCs with fixed short, fixed long, and variable CI. PVC delivery elicited a greater neuronal response than all other stimuli (P<0.001). Compared to fixed short and long CI, PVCs with variable CI had a greater impact on neuronal response (P<0.05 versus short CI), particularly on convergent neurons (P<0.05), as well as neurons receiving sympathetic (P<0.05) and parasympathetic input (P<0.05). The greatest cardiac electrical instability was also observed following variable (short) CI PVCs. Conclusions Variable CI PVCs affect critical populations of ICNS neurons and alter cardiac repolarization. These changes may be critical for arrhythmogenesis and remodeling leading to cardiomyopathy.
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