Integrative Physiology
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21659
Browse
Browsing Integrative Physiology by Author "Mathis, Keisa W."
Now showing 1 - 2 of 2
- Results Per Page
- Sort Options
Item Immunological effects of vagus nerve stimulation in murine systemic lupus erythematosus(2018-03-14) Pham, Grace; Stauss, Harald; Mathis, Keisa W.; Kulp, DennisPurpose: Systemic lupus erythematosus (SLE) is an autoimmune disease that principally affects women and is associated with inflammatory pathogenesis of multiple organs. Of the disseminated features of SLE, classical disease processes such as renal injury with hypertension, as well as autonomic nervous system dysregulation, are prevalent. The autonomic dysfunction in SLE is characterized by increased sympathetic activity and concomitant decreased parasympathetic nervous system (PNS) activity; however, it is unknown if impaired PNS activity promotes hypertension and renal injury in SLE. The cholinergic anti-inflammatory pathway (CAP), is an endogenous neuroimmune reflex that regulates cytokine release from immune cells; briefly, the CAP initiates with stimulation of the parasympathetic vagus nerve and culminates in the inhibition of the secretion of pro-inflammatory cytokines from macrophages and other leukocytes. Although it is known that vagal activity is suppressed in SLE, it remains unclear whether this contributes to a diminished CAP promoting inflammation in the disease. We hypothesized that chronic vagus nerve stimulation (VNS) will decrease the inflammatory cascade in SLE through enhancement of the CAP. Methods: Female SLE (NZBWF1) mice (25 weeks of age) were implanted with electrical vagus nerve stimulators that fit the cervical vagus nerve. Only female mice of this well-characterized strain were used, reflecting the prevalence of lupus in women. The mice were then divided into two groups: VNS (n=10) and sham (n=7). Stimulators targeted the vagus nerve continuously for 2 weeks. Results: Spleen weight was slightly increased in SLE/VNS mice compared to SLE/sham mice (0.14 ± 0.03g vs. 0.11 ± 0.01; P=NS). Flow cytometry showed that SLE/VNS mice had slightly less CD3+/CD4+ bone marrow T cells when compared with SLE/sham mice (27.30 ± 9.41% vs. 40.17 ± 7.01%; P=NS). The percentage of mice with albuminuria, an index of renal injury measured by Albustix, was also decreased in SLE/VNS mice compared to SLE/sham mice (10% vs 29%). Conclusions: These results suggest the efficacy of VNS in reducing the inflammatory profile in SLE mice, and that this protection may reduce end-organ disease. Future work will investigate the role of the CAP in quelling inflammation perpetuated by neuroimmune dysregulations in SLE. Studies supported by the American Heart Association (14SDG18320033) and the National Institutes of Health (1K01HL139859)Item The Effect of Nicotinic Agonist Therapy on Renal Inflammation in Mice with Systemic Lupus Erythematosus(2018-03-14) Pham, Grace; Uteshev, Victor; Mathis, Keisa W.; Williams, EmilyPurpose: Systemic lupus erythematosus (SLE) is an autoimmune disease that causes chronic systemic, and specifically renal, inflammation that results in renal injury and hypertension. Under normal conditions, inflammation may be regulated by a neuroimmune reflex referred to as the cholinergic anti-inflammatory pathway; this pathway is mediated by immune cells responding to acetylcholine via the a7-subunit of nicotinic acetylcholine receptors (nAChRs) and when stimulated results in the reduction of tissue-specific inflammation. These a7nAChRs can be activated nonselectively by nicotine and we have previously shown that nicotine attenuates renal inflammation in female SLE mice. However, because nicotine is toxic and addictive, it would not be available to use as a therapy for SLE. We hypothesized that a selective a7nAChR agonist would similarly reduce renal inflammation and protect against the development of renal injury. Methods: In our pilot studies (n=2-3 mice/group), female SLE (NZBWF1) and control (NZW) mice (33 weeks of age) were surgically implanted with osmotic mini-pumps to subcutaneously administer the nicotinic agonist PNU-120596 (3.8 mg/kg/day), or vehicle (100% DMSO) at a rate of 0.25 mL/hour. At 35 weeks, mice were euthanized and tissues harvested. Results: The gene expression of renal cortical tumor necrosis factor (TNF)-a (measured by qRT-PCR using 2-DDCt method normalized to HPRT) was found to be 3-fold higher in SLE mice as compared to control mice. However, PNU-120596 treatment did not have an effect on TNF-a gene expression in SLE or control mice. Renal cortical interferon (IFN)-a gene expression was similar in SLE and control mice. By contrast, PNU-120596 treatment increased IFN-a gene expression in both SLE mice and controls (18-fold and 3-fold, respectively). Conclusions: Although inflammatory markers were increased in SLE mice, as expected, the effect of this PNU-120596 treatment on TNF-a and IFN-a is inconclusive, because statistical analysis was not performed due to the small sample size. Future studies will increase sample size and agonist dosage to further investigate the potential therapeutic effect of nicotinic agonists on SLE-induced inflammation and renal injury.