Browsing by Author "Dinh, Viet"
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Item Effect of selective ganglion stimulation on hypertension in systemic lupus erythematosus(2023) Johnson, Keanna; Dinh, Viet; Young-Stubbs, Cassandra M.; Shimoura, Caroline; Chaudhari, Sarika; Mathis, Keisa W.Effect of selective ganglion stimulation on hypertension in systemic lupus erythematosus Keanna K. Johnson1, Viet Dinh2, Cassandra M. Young-Stubbs2, Caroline G. Shimoura2, Sarika Chaudhari2, Keisa W. Mathis2 1School of Public Health,2Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas Purpose: Systemic lupus erythematous (SLE) is a female-dominant autoimmune disease that causes widespread inflammation in various organs. Inflammation precedes the prevalent hypertension in the disease. The cholinergic anti-inflammatory pathway (CAP) is an endogenous neuroimmune pathway that reduces inflammation upon stimulation. We hypothesize that stimulation of the CAP by selective activation of the superior cervical ganglion will halt disease progression and hypertension in SLE. Methods: Female SLE (NZBWF1) and control (NZW) mice received unilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry, a designer receptor exclusively activated by designer drug (DREADD), or pAAV-hSyn-mCherry (vehicle) at the superior cervical ganglion (SCG) at 32 weeks of age. SCG DREADD injections generate muscarinic receptors on SCG neurons that are activated by the designer drug, clozapine N-oxide (CNO), ultimately leading to neuronal stimulation and potentially activation of the CAP. At 33 weeks of age, mice with SCG DREADD received a daily s.c. injection of CNO (3mg/kg) for two weeks. At 35 weeks, mice received a catheter implant in the carotid artery to measure mean arterial pressure (MAP) for two consecutive days followed by euthanasia and tissue collection. Plasma was collected biweekly via retro-orbital bleeding. Plasma samples were used to quantify double-stranded (ds) DNA autoantibodies. Results: dsDNA autoantibodies were higher in SLE than control mice (8.6e5 ± 1.8e5 vs. 5.1e4 ± 1.1e4 U/mL; p=0.0002; n=13). SCG DREADD did not change dsDNA autoantibody levels in SLE mice (1.1e6 ± 2.6e5 U/mL; p=0.1410; n=6) or control mice (5.4e4 ± 1.5e4 U/mL; p=0.6549; n=9). MAP was significantly higher in SLE mice compared to control mice (150 ± 9 vs. 122 ± 3 mmHg; p=0.0009; n=5–9). SCG DREADD did not change MAP in SLE mice (137 ± 2 mmHg; p=0.2572; n=6) or controls (127 ± 3 mmHg; p=0.7678; n=9). Conclusion: These data suggest that selective activation of the CAP at the level of the SCG using DREADD did not significantly alter disease severity or blood pressure in female SLE mice with advanced disease. Future studies will determine the effect of selective ganglion stimulation on inflammatory outcomes. Funding: Research reported in this abstract was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number R25HL125447. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Item Effect of Sigma-1 Receptor Activation on Renal Injury and Hypertension in Female Mice with Lupus(2023) Dinh, Viet; Chaudhari, Sarika; Young-Stubbs, Cassandra M.; Shimoura, Caroline; Tucker, Selina; Essajee, Salman; Warne, Cooper; Luedtke, Robert R.; Mathis, Keisa W.Systemic lupus erythematosus (SLE) is a female-dominant autoimmune disease with prominent renal injury and hypertension, contributing to its morbidity and mortality. Novel therapies to reduce these detrimental outcomes could be beneficial to SLE patients. The sigma-1 receptor (S1R) is a cytoprotective ligand-regulated chaperone protein that decreases protein aggregation, cellular stress, and cell death, thus preventing tissue injury. S1R activation with pharmacological ligands enhances cytoprotection in autoimmune diseases like multiple sclerosis and Huntington’s disease; however, the efficacy of S1R agonists in SLE is unknown. We hypothesize that S1R activation via the agonist LS-1-127 will reduce renal injury and halt the progression of hypertension in SLE mice. Female SLE (NZBWF1) and control (NZW) mice were weighed and urine collected via metabolic cages weekly starting at 30 weeks of age. Albuminuria was measured via dipsticks. At 33 weeks of age, SLE and control mice were treated with LS-1-127 (10 mg/kg IP) or equal volume of vehicle (10% DMSO; IP) three times a week for two weeks. At 35 weeks, mean arterial pressure (MAP) was measured in conscious mice using indwelling carotid catheters for two consecutive days and then mice were euthanized. Wire myography was used to assess potassium chloride (KCl)-induced contraction and acetylcholine (ACh)-induced relaxation in excised aorta. Markers of renal injury – urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and creatinine – as well as plasma double-stranded (ds)DNA autoantibodies were measured by ELISA. Albuminuria was present in 44.4% (4 of 9) of SLE mice and no controls. LS-1-127 did not improve albuminuria in SLE mice (50%; 3 of 6). NGAL:creatinine ratio (ng/mg) was higher in SLE mice compared to controls (327.3 ± 119.8 vs 63.2 ± 4.3 ng/mg; n=9–12; P=0.0007). LS-1-127 did not significantly alter NGAL:creatinine ratio in SLE mice (484.3 ± 209.0; n=6) or controls (71.7 ± 5.2; n=10). KIM1:creatinine ratio (ng/mg) did not differ between groups. dsDNA autoantibodies were higher in SLE mice compared to controls (6.9e5 ± 1.1e5 vs. 1.4e5 ± 3.1e4 U/mL; n=9–10; P<0.0001). LS-1-127 did not significantly alter dsDNA autoantibodies in SLE mice (7.1e5 ± 1.2e5; n=6) or controls (1.5e5 ± 4.0e4; n=10). MAP was higher in SLE mice compared to controls (146 ± 4 vs. 123 ± 3 mmHg; n=9–10; P <0.0001). LS-1-127 did not significantly alter MAP in SLE mice (150 ± 8; n=6) or controls (124 ± 2; n=10). KCl-induced aortic contraction was similar in SLE and controls (21 ± 7 vs. 25 ± 4 mM, n=3–4). Sensitivity to KCl after LS-1-127 treatment was 11 ± 3 and 21 ± 2 mM in SLE and controls (n=2–4). ACh-induced aortic relaxation did not differ between groups. In conclusion, two weeks of S1R activation with LS-1-127 did not significantly alter markers of renal injury, autoimmunity, blood pressure, or vascular reactivity in female SLE mice with advanced disease. Further inquiry into the effect of LS-1-127 on the expression of renal proinflammatory cytokines will be conducted. S1R activation at different stages of SLE disease progression also warrants future investigation.Item Effect of systemic administration of α7-nicotinic acetylcholine receptor ligands on renal inflammation in young mice with systemic lupus erythematosus(2022) Brooks, Calvin D.; Young-Stubbs, Cassandra M.; Shimoura, Caroline; Dinh, Viet; Chaudhari, Sarika; Uteshev, Victor; Mathis, Keisa W.Systemic lupus erythematosus (SLE) is an autoimmune disease where renal inflammation contributes to hypertension. The cholinergic anti-inflammatory pathway is a recently described pathway where stimulating the vagus nerve causes release of acetylcholine from choline acetyltransferase (ChAT)+ T-cells in the spleen. This acetylcholine acts on alpha-7 nicotinic acetylcholine receptors (α7nAChR) of immune cells to hault the production of pro-inflammatory cytokines. Our lab has shown stimulation of this pathway at multiple levels lessens autoimmunity, renal inflammation and hypertension in SLE mice. However, our recent attempts to target the α7nAChR directly with a positive allosteric modulator (PAM) in mice with advanced SLE have not yielded similar results. This may be due to decreased parasympathetic tone in these mice in which the PAM is not able to compensate for. The aim of the current study was to determine if activating the α7nAChR in SLE mice at an earlier age, before dampening of parasympathetic tone, prevents the onset of hypertension and renal inflammation. Twelve week old female NZBWF1 mice, which spontaneously develop SLE, and NZW controls were given a partial agonist of the α7nAChR, GTS-21, a PAM, PNU-120596, or vehicle continuously for two weeks via subcutaneous osmotic mini-pump. Mean arterial pressure (MAP) was measured by carotid artery catheter in conscious, freely moving mice at 14 weeks. Mice were then euthanized and blood, spleen and kidneys harvested to allow measurement of plasma double stranded (ds) DNA autoantibodies via ELISA to assess severity of disease. There was no difference in dsDNA autoantibody activity (U/mL) between SLE mice and controls (all data presented as mean±SEM; 76026.3±38901.4 vs. 19617.4±4092.7; p=0.1141). The treatments had no effect on autoantibody activity in SLE mice [76026.3±38901.4 (SLE vehicle) vs. 36951.7±5962.3 (SLE PNU) vs. 56279.7±31381.0 (SLE GTS)] or controls [19617.4±4092.7 (Con vehicle) vs. 17293.2±3384.1 (Con PNU) vs. 16016.2±3059.6 (Con GTS)]. MAP (mmHg) did not differ significantly between young SLE and control mice (143.53±3.26 vs. 128.8±4.95). Additionally, the treatments had no effect on MAP of SLE mice [143.53±3.26 (SLE vehicle) vs. 128.32±10.92 (SLE PNU) vs. 129.56±19.50 (SLE GTS)] or controls [128.8±4.95 (Con vehicle) vs. 127.60±4.43 (Con PNU), vs. 125.65±5.54 (Con GTS)]. Based on these results, we suspect that the disease process has not progressed enough in 14-week-old mice to see differences due to these treatments. Although the changes in the blood pressure and dsDNA antibodies are not significant, we will continue to evaluate renal damage and cytokine profile to determine the effect of these α7nAChR ligands on pathogenesis of SLE. Future studies will aim to modulate α7nAChRs in SLE mice before the onset of disease (~12 weeks of age) through 35 weeks when mice usually experience terminal disease to determine efficacy of early activation of the cholinergic anti-inflammatory pathway in halting the progression of SLE.Item Pulsatile Perfusion Therapy at 0.1 Hz Improves Survival Following Severe Hemorrhage in Rats(2024-03-21) Dinh, Viet; Farmer, George; Rickards, CarolinePURPOSE: Oscillations in arterial pressure and blood flow at 0.1 Hz are associated with protection of tissue oxygenation during conditions of reduced tissue perfusion. Pulsatile Perfusion Therapy (PPT) is a method we have developed to induce these oscillations, and has been associated with increased tolerance to simulated hemorrhage via lower body negative pressure in humans. However, it is unknown how effective this therapy would be in an actual hemorrhage model. The aim for this study was to test the efficacy of PPT in a rat model of severe hemorrhage. We hypothesized that PPT at 0.1 Hz would protect arterial pressure and cerebral blood flow following severe hemorrhage in rats, subsequently improving survival. METHODS: Eleven adult Sprague-Dawley rats (six female, five male) were anesthetized via isoflurane, then underwent bilateral carotid artery catheterization for assessment of arterial pressure and carotid artery blood flow, while heart rate was assessed via lead II ECG. Following a 15-min baseline period, all animals were hemorrhaged to 50% of their estimated blood volume over 30-min. Rats were then randomly assigned to the PPT group (3 female, 3 male) or the control group (CON; 3 female, 2 male). PPT was administered via inflatable cuffs attached to both hind limbs, oscillating between 0 mmHg and 250 mmHg every 5-s (10-s cycles or 0.1 Hz) for 30-min immediately following hemorrhage. For the CON group, the leg cuffs were also attached but were not inflated for this 30-min period. All animals were then monitored for an additional 150-min recovery period post-hemorrhage, or until death – defined as the absence of ventricular function on the ECG. Survival time and peak mean arterial pressure (MAP), carotid blood flow, and heart rate were assessed to determine the effectiveness of PPT in protecting hemodynamic responses following hemorrhage. RESULTS: PPT increased survival time (P = 0.02), with 3 of 6 (50%) rats in the PPT group and 0 of 5 (0%) rats in the CON group surviving the entire 180-min recovery period following hemorrhage. During recovery, PPT protected MAP (PPT: −46.5 ± 12.9% vs. CON: −72.6 ± 19.5% from baseline; P = 0.07) and carotid blood flow (PPT: −61.5 ± 17.7% vs. CON: −83.7 ± 6.7% from baseline; P = 0.04), but did not affect heart rate (PPT: 0.11 ± 6.58% vs. CON: −18.70 ± 29.34% from baseline, P = 0.20), although responses were highly variable between subjects. CONCLUSIONS: PPT protected arterial pressure and carotid blood flow in rats following severe hemorrhage, subsequently improving survival. These data add further evidence for the use of 0.1 Hz hemodynamic oscillations as a therapeutic intervention for the treatment of hemorrhage.Item Travel-Induced Stress at Varying Ages Modulates the Pathogenesis of Autoimmunity in Female Lupus Mice(2022) Dinh, Viet; Chaudhari, Sarika; Mathis, Keisa W.;Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that causes inflammation throughout the body, notably in the kidneys. Inflammatory flares that occur during the pathogenesis of SLE increase morbidity in humans and are associated with stress and environmental factors. Heat shock proteins (HSPs) are chaperone proteins that are elevated in the stressful conditions, especially HSP90 which is increased in subsets of SLE patients. HSP90 is also correlated with interleukin (IL)-6, a proinflammatory cytokine known to stimulate autoimmune processes in many diseases including SLE. The lupus mice used in our lab travel to our university from Bar Harbor, ME. However, it is not known if this travel period induces stress on these mice that significantly affects the pathogenesis of SLE and renal damage. Likewise, it is unknown if the age at which the mice travel also predicts outcomes of the disease. Based on this, we hypothesize that stressors that occur early in life have a greater impact on the pathogenesis of SLE and renal inflammation than stressors that occur during adulthood in lupus-prone mice. We used female NZBWF1 mice - an established model of SLE - that traveled to our university at 6 weeks of age (pre-pubertal stage) or at 19 weeks of age (mature adult stage) to compare the effects of travel at different ages of life. At 30 weeks of age, they were placed in metabolic cages weekly to collect urine samples. Upon reaching 35 weeks of age, a point at which these mice usually develop severe lupus symptoms, we collected blood samples, euthanized the mice, and collected tissues. Urine, plasma, and homogenized right kidneys were analyzed via ELISA to compare various biomarkers, including double-stranded (ds)DNA autoantibodies (a hallmark of SLE), urinary albumin (a marker of renal injury), IL-6, and HSP90. No differences were found in plasma dsDNA autoantibodies between mice that traveled in younger life vs. in adulthood (Young: 6.0e5 ± 8.4e4 vs. Adults: 5.2e5 ± 7.6e4 U/mL; p=0.6930). Likewise, no differences were found in urinary albumin between these groups (Young: 1.2e7 ± 3.2e6 vs. Adults: 1.0e7 ± 8.4e6 ng/mL; p=0.8208). In mice that traveled as adults, IL-6 was significantly higher in plasma (Young: 195.8 ± 87.4 vs. Adults: 826.7 ± 130.0 pg/mL; p=0.0096) and in kidneys (Young: 177.1 ± 60.6 vs. Adults: 798.1 ± 166.5 pg/mL; p=0.0002). Levels of plasma HSP90 were lower in mice that traveled as adults (Young: 152.1 ± 23.4 vs. Adults: 65.70 ± 8.60 ng/mL; p=0.0302). In conclusion, our data indicate that mice subjected to travel-induced stress as adults developed higher levels of plasma and renal IL-6 and lower levels of plasma HSP90 at 35 weeks of age. We will continue to evaluate these outcomes in more mice and further data will expand on these findings, which will act as an important steppingstone for furthering our understanding of how environmental stressors play a role in the progression of autoimmunity well into adulthood.