Abstract Title

Alteration of Inflammatory Profile following Activation of a Neuroimmune Pathway

RAD Assignment Number

316

Presenter Name

Maitryben Patel

Abstract

Abstract

Hypertension is estimated to cause 7.5 million deaths worldwide and is a major risk factor for stroke, renal failure, and heart failure, all of which may be potentially fatal. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder with a high prevalence of hypertension. Inflammatory cytokines have been shown to promote the development of hypertension in recent studies. Other studies suggest that acute stimulation of an innate, vagally-mediated, neuro-immune pathway (the cholinergic anti-inflammatory pathway) suppresses the production of inflammatory mediators in the spleen. It is unknown whether chronic stimulation of this pathway is capable of reducing inflammation, and ultimately blood pressure during SLE.

Purpose (a):

The purpose of this study was to evaluate the effectiveness of stimulation of the cholinergic anti-inflammatory pathway on reducing inflammation in SLE. We hypothesized that pharmacological stimulation of the vagus nerve with CNI-1493 would suppress splenic cytokine release, thereby reducing systemic inflammation.

Methods (b):

CNI-1493 (8 mg/kg/2swk, IP) or vehicle (saline) was administered twice a week for 4 weeks, starting at 30 weeks of age in female SLE (NZBWF1) and control mice (NZW). At 34 weeks, animals were euthanized and tissues were collected in order to examine splenic and renal inflammation. The spleen and kidney were homogenized using RIPA buffer and the cytokine TNF-a was evaluated using Western blot in these tissues.

Results (c):

TNF-a expression (normalized to b-actin) was increased in the spleen (36.9±8.7 vs. 22.5±2.8; p=0.02) and renal cortex (8.4±0.4 vs. 3.7±0.5; p=0.03) of SLE mice compared to controls. CNI-1493 had no significant effect on spleen TNF (35.9±4.3), however exacerbated renal cortical TNF (12.5±2.2) in SLE mice.

Conclusions (d):

Although the results did not support our hypothesis, the data are preliminary and we suspect additional studies are needed to determine the ability of pharmacological stimulation of the vagus nerve to reduce inflammation in SLE mice. Such therapy could potentially benefit hypertensive SLE patients, since chronic inflammation has recently been linked to the development of the disease.

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Alteration of Inflammatory Profile following Activation of a Neuroimmune Pathway

Abstract

Hypertension is estimated to cause 7.5 million deaths worldwide and is a major risk factor for stroke, renal failure, and heart failure, all of which may be potentially fatal. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disorder with a high prevalence of hypertension. Inflammatory cytokines have been shown to promote the development of hypertension in recent studies. Other studies suggest that acute stimulation of an innate, vagally-mediated, neuro-immune pathway (the cholinergic anti-inflammatory pathway) suppresses the production of inflammatory mediators in the spleen. It is unknown whether chronic stimulation of this pathway is capable of reducing inflammation, and ultimately blood pressure during SLE.

Purpose (a):

The purpose of this study was to evaluate the effectiveness of stimulation of the cholinergic anti-inflammatory pathway on reducing inflammation in SLE. We hypothesized that pharmacological stimulation of the vagus nerve with CNI-1493 would suppress splenic cytokine release, thereby reducing systemic inflammation.

Methods (b):

CNI-1493 (8 mg/kg/2swk, IP) or vehicle (saline) was administered twice a week for 4 weeks, starting at 30 weeks of age in female SLE (NZBWF1) and control mice (NZW). At 34 weeks, animals were euthanized and tissues were collected in order to examine splenic and renal inflammation. The spleen and kidney were homogenized using RIPA buffer and the cytokine TNF-a was evaluated using Western blot in these tissues.

Results (c):

TNF-a expression (normalized to b-actin) was increased in the spleen (36.9±8.7 vs. 22.5±2.8; p=0.02) and renal cortex (8.4±0.4 vs. 3.7±0.5; p=0.03) of SLE mice compared to controls. CNI-1493 had no significant effect on spleen TNF (35.9±4.3), however exacerbated renal cortical TNF (12.5±2.2) in SLE mice.

Conclusions (d):

Although the results did not support our hypothesis, the data are preliminary and we suspect additional studies are needed to determine the ability of pharmacological stimulation of the vagus nerve to reduce inflammation in SLE mice. Such therapy could potentially benefit hypertensive SLE patients, since chronic inflammation has recently been linked to the development of the disease.