The effects of interleukin 17A on left stellate ganglion remodeling are mediated by neuroimmune communication in normal structural hearts.

BACKGROUND: It is reported interleukin (IL)-17A, a classical proinflammatory cytokine, is implicated in neuroimmune-associated remodeling in neural plasticity and pathological conditions. However, the effect of IL-17A on left stellate ganglion (LSG) remodeling remains unclear. OBJECTIVE: This study was performed to determine whether exogenous IL-17A promotes LSG remodeling and destabilize ventricular electrophysiological properties (EPs) in normal canines. METHODS: 24 beagles were randomly allocated into three groups. In the first group, animals were subjected to 0.1 ml phosphate buffer saline (PBS) microinjection of into LSG (n = 8), an equivalent IL-17A was administrated in the second group (n = 8), and an equivalent anti-IL-17A mAb plus IL-17A was administrated in the third group (n = 8). The ventricular EPs, neural function and activity of the LSG were determined at baseline and 30 min after administration. In the end, LSG tissues were collected. RESULTS: Compared with the control group, the experimental group had a significantly shorter effective refractory period (ERP) and action potential duration (APD)90, an increased ERP, APD90, Smax dispersion, and APD alternans cycle length; and steepened APD restitution curves. In addition, IL-17A enhanced the neural function and activity of the LSG, upregulated the expressions of neuropeptides and proinflammatory cytokines and cells. And all these effects were attenuated by anti-IL-17A mAb. Importantly, IL-17 receptor A (IL-17R-A) was detected in sympathetic neurons in the LSG. CONCLUSION: IL-17A promoted LSG remodeling by regulating the neural inflammation response. It did so by binding to IL-17R-A, resulting in unstable ventricular electrophysiology in normal structural hearts.

Mast cells modulate the pathogenesis of leptin-induced left stellate ganglion activation in canines.

BACKGROUND: Leptin is an adipocytokine predominantly secreted by adipose tissue that participates in immune modulation. Mast cells are important immune cells that are related to altered sympathetic activity. Previous study has shown that leptin promotes activation of the left stellate ganglion (LSG) directly via the leptin receptor. This study aims to investigate whether mast cells play a key role in indirect activation. METHODS: Twenty-eight canines were randomly divided into 3 groups: the control group (saline, n = 8), leptin group (leptin, n = 9), and DSCG group (disodium cromoglycate plus leptin, n = 11). Drugs were locally microinjected into the LSG. The function and neural activity of the LSG were evaluated to investigate LSG activation. Tryptase was adopted to identify activated mast cells in the LSG. RESULTS: Compared with the control group, leptin injection (18 µg) markedly increased the function and neural activity of the LSG. Leptin also upregulated c-fos, nerve growth factor (NGF), and tryptase expression in the LSG. However, these effects of leptin were attenuated by pre-injection of DSCG (25 mg). Additionally, the immunofluorescence analysis revealed that many mast cells were present in the LSG and that those cells were located close to sympathetic neurons. The presence of leptin receptors on the mast cells was verified. CONCLUSIONS: Immune mast cells play an important supplementary role in the pathogenesis of leptin-induced LSG activation.

T-cell-mediated inflammatory activity in the stellate ganglia of patients with ion-channel disease and severe ventricular arrhythmias.

BACKGROUND: Long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) are electric diseases characterized by catecholamine-induced ventricular arrhythmias. Unbalanced autonomic innervation of the heart may trigger arrhythmic events and stellectomy is a treatment option for patients who are resistant to pharmacological drugs. We analyzed left stellectomy specimens of LQTS and CPVT patients for signs of inflammatory activity. METHODS AND RESULTS: Stellate ganglia were retrieved from 12 consecutive patients (8F; 4 mol/L; mean age, 23.4±17 years) with either LQTS (n=8) or CPVT (n=4) and serious arrhythmias. Control stellate ganglia were obtained from 10 accidently deceased patients (6F; 4 mol/L; mean age, 35±17.6 years). Sections were immunostained with antibodies against T cells (CD3, CD4, CD8, CD20, Granzyme B), CD68 (macrophages), and HLA-DR (human leukocyte antigen-DR) antigens (activation marker). Immunopositive cells were quantified as cells/mm2. Polymerase chain reaction (PCR) and reverse transcription PCR were performed to screen for herpes virus DNA. Stellate ganglia of all 12 LQTS/CPVT patients revealed mild but distinct inflammatory infiltrates composed of T lymphocytes and macrophages, which were diffusely spread, but also clustered in small foci opposed to ganglion cells, interpreted as T-cell-mediated ganglionitis. Morphometric analysis showed that CD3+ and CD8+ T cells/mm2 were significantly higher in the ganglia of LQTS/CPVT cases than in healthy controls (P=0.0018 and P=0.0009, respectively). Molecular analyses were negative for neurotropic viruses. CONCLUSIONS: T-cell-mediated cytotoxicity toward ganglion cells may boost adrenergic activity as to trigger or enhance electric instability in LQTS/CPVT patients who are already genetically predisposed to arrhythmias.

Emerging concepts in inflammation and fibrosis.

Hepatic and pancreatic response to several insults commonly includes similar pathways of inflammation, fibrogenesis/regeneration, which may occur simultaneously and without appropriate coordination, resulting in chronic inflammation, scarring, and organ dysfunction. This review highlights the opinion of experts gathered for the Mexican Digestive Disease Week (2001) to analyze these molecular events with emphasis on identifying possible therapeutic opportunities. Inflammatory response encompasses leukocyte infiltration, favored by adhesion molecules of the selectin family, chemokines, integrins, and activated stellate cells (SC). Quiescent SC undergo activation mediated by mechanical stress and expression of cytokines, oxidative stress products, and growth factors and play a significant role in fibrosis and in reparation toward synthesis of extracellular matrix components. Also, hepatocytes and acinar cells contribute to the inflammatory and fibrotic response. Molecules that down-regulate this response are overexpressed. Therapeutic strategies with targeting to such mechanisms underlying chronic hepatic and pancreatic injury are an emerging reality.

Stellate ganglion block modifies the distribution of lymphocyte subsets and natural-killer cell activity.

BACKGROUND: Recent investigations suggest that the sympathetic nervous system affects the immune system. This study examined whether stellate ganglion block (SGB) affects the immune response, specifically the distribution of lymphocyte subsets and natural-killer (NK) cell activity. METHODS: Ten volunteers received three different treatments in random order at 7-day intervals: (1) SGB with 7 ml of 1% lidocaine; (2) an identical volume of normal saline injected at the same site as SGB; and (3) an identical volume of 1% lidocaine injected intramuscularly. Blood samples were drawn before and 30 min after treatment. The distribution of lymphocyte subsets was analyzed, and NK cell activity was measured. Plasma concentrations of epinephrine, norepinephrine, adrenocorticotropic hormone, and cortisol were measured. RESULTS: Any value in the normal saline and intramuscular treatments did not change significantly. After SGB, the plasma concentrations of epinephrine and norepinephrine decreased significantly (P < 0.01), but adrenocorticotropic hormone and cortisol values were unchanged. Increases were observed in the proportion of B cells (from 18.4 +/- 3.0% to 20.0 +/- 3.8%; P < 0.01) and T cells (from 64.2 +/- 4.1% to 67.1 +/- 4.2%; P < 0.01). A decrease in the proportion of NK cells was observed (from 13.4 +/- 2.7% to 9.8 +/- 2.2%; P < 0.01). The proportion of CD4+ cells increased (P < 0.01), and that of CD8+ cells decreased (P < 0.01), so that the CD4+ cell/CD8+ cell ratio increased (P < 0.01). The proportion of CD29+ (helper-inducer T) cells increased (P < 0.05), but that of CD45RA+ (suppressor-inducer T) cells did not change. NK cell activity decreased significantly (from 33.6 +/- 8.3% to 29.1 +/- 7.6%; P < 0.01). CONCLUSIONS: A small but significant alteration in lymphocyte subsets and in NK cell activity by SGB indicates that local sympathetic nerve block may modulate the immune response.