Integrative Physiology
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/30815
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Browsing Integrative Physiology by Author "Dinh, Viet"
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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 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.