Neural reflex regulation of systemic inflammation: potential new targets for sepsis therapy

Fernández, Ricardo; Nardocci, Gino; Navarro, Cristina; Reyes, Edison P.; Acuña-Castillo, Claudio; Côrtes, Paula Pitta de Resende

doi:10.3389/fphys.2014.00489

Cited by 55 publications

(59 citation statements)

References 98 publications

(118 reference statements)

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“…Since the 90's, much effort has been made to better understand this pathway that is known as “cholinergic anti‐inflammatory pathway,” a neural anti‐inflammatory mechanism that is fast and connected through the CNS. This may be attributed to the close or internal location of nerve terminations in the target organs (Bonaz, ; Fernandez et al, ).…”

mentioning

confidence: 99%

The Involvement of Parasympathetic and Sympathetic Nerve in the Inflammatory Reflex

Pereira

Leite

2016

Journal Cellular Physiology

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Production of inflammatory cytokines plays important roles in the response against tissue injury and in host defense. Alterations in the production of inflammatory cytokines may cause local or systemic inflammatory imbalance, culminating in organ failure or lethal systemic inflammation. The cholinergic anti-inflammatory pathway has been implicated as an important mechanism to regulate inflammation of targeted tissue. In this review, we discuss important advances, conflicting and controversial findings regarding the involvement of parasympathetic vagus and sympathetic splenic nerve through acetylcholine (ACh) release and α7 nicotinic acetylcholine receptor (nAChRα7) activation in the spleen. In addition, we address the involvement of cholinergic control of inflammation in other organs innerved by the vagus nerve such as gut, liver, kidney and lung, and independent of parasympathetic innervations such as skin and skeletal muscle. Then, other structures and mechanisms independent of vagus or splenic nerve may be involved in this process, such as local cells and motor neurons producing ACh. Altogether, the convergence of these findings may contribute to current anti-inflammatory strategies involving selective drug-targeting and electrical nerve stimulation. J. Cell. Physiol. 231: 1862-1869, 2016. © 2016 Wiley Periodicals, Inc.

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confidence: 99%

The Involvement of Parasympathetic and Sympathetic Nerve in the Inflammatory Reflex

Pereira

Leite

2016

Journal Cellular Physiology

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“…Finally, we identified several variants in genes associated with neurogenic signaling pathways. The CNS plays a key role in regulating the immune system and cytokine expression, as well as the systemic vascular response observed in sepsis patients 41 .…”

Section: Neuronal Signaling Mechanismsmentioning

confidence: 99%

Identification and Analysis of Shared Risk Factors in Sepsis and High Mortality Risk COVID-19 Patients

Das¹,

Taylor²,

Pearson³

et al. 2020

Preprint

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BACKGROUNDCoronavirus disease 2019 (COVID-19) is a novel coronavirus strain disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease is highly transmissible and severe disease including viral sepsis has been reported in up to 16% of hospitalized cases. The admission characteristics associated with increased odds of hospital mortality among confirmed cases of COVID-19 include severe hypoxia, low platelet count, elevated bilirubin, hypoalbuminemia and reduced glomerular filtration rate. These symptoms correlate highly with severe sepsis cases. The diseases also share similar comorbidity risks including dementia, type 2 diabetes mellitus, coronary heart disease, hypertension and chronic renal failure. Sepsis has been observed in up to 59% of hospitalized COVID-19 patients.It is highly desirable to identify risk factors and novel therapy/drug repurposing avenues for late-stage severe COVID-19 patients. This would enable better protection of at-risk populations and clinical stratification of COVID-19 patients according to their risk for developing life threatening disease. METHODSAs there is currently insufficient data available for confirmed COVID-19 patients correlating their genomic profile, disease severity and outcome, co-morbidities and treatments as well as epidemiological risk factors (such as ethnicity, blood group, smoking, BMI etc.), a direct study of the impact of host genomics on disease severity and outcomes is not yet possible. We therefore ran a study on the UK Biobank sepsis cohort as a surrogate to identify sepsis associated signatures and genes, and correlated these with COVID-19 patients.Sepsis is itself a life-threatening inflammatory health condition with a mortality rate of approximately 20%. Like the initial studies for COVID-19 patients, standard genome wide association studies (GWAS) have previously failed to identify more than a handful of genetic variants that predispose individuals to developing sepsis. RESULTSWe used a combinatorial association approach to analyze a sepsis population derived from UK Biobank. We identified 70 sepsis risk-associated genes, which provide insights into the disease mechanisms underlying sepsis pathogenesis. Many of these targets can be grouped by common mechanisms of action such as endothelial cell dysfunction, PI3K/mTOR pathway signaling, immune response regulation, aberrant GABA and neurogenic signaling. CONCLUSIONThis study has identified 70 sepsis related genes, many of them for the first time, that can reasonably be considered to be potentially relevant to severe COVID-19 patients. We have further identified 59 drug repurposing candidates for 13 of these targets that can be used for the development of novel therapeutic strategies to increase the survival rate of patients who develop sepsis and potentially severe COVID-19.

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“…Whether entrapment of AD-MSCs in peripheral organs might have effects on stroke recovery should be analyzed in future studies. Given the fact that the hypothalamic-pituitary-adrenal axis is a link between the brain and peripheral organs and is known to be involved in immunomodulation [24], it would be interesting to analyze to what extent the peripheral allocation of cells is associated with a modulation of brain inflammation.…”

Section: Ad-msc Therapy In Experimental Animal Models Of Ischemic Strokementioning

confidence: 99%

Adipose tissue-derived mesenchymal stem cells as a strategy to improve recovery after stroke

Gutiérrez-Fernández¹,

Otero-Ortega²,

Ramos‐Cejudo³

et al. 2015

Expert Opinion on Biological Therapy

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Introduction: Based on the positive results observed in experimental animal models, adipose tissue-derived mesenchymal stem cells (AD-MSCs) constitute a promising therapy for stroke treatment. However, several aspects need to be clarified to identify the optimal conditions for successful clinical translation. Areas covered:This review focuses on AD-MSC treatment for ischemic and hemorrhagic stroke in experimental animal models. In addition, we will explore the optimization of treatment conditions including AD-MSC production, administration routes and therapeutic windows for their appropriate use in patients, and we will provide an update on clinical trials on this therapy. Expert opinion:Compared with other cell types, AD-MSCs have been less investigated in stroke studies. Currently, experimental animal models have shown safety and efficacy with this treatment after stroke. Due to several advantages of AD-MSCs, such as their abundance and accessibility, they can be considered a promising strategy for use in patients. However, many questions are still to be resolved regarding their mechanisms of action, immune system modulation and the effects of AD-MSCs on all components of the brain that may be affected after ischemic and hemorrhagic strokes.

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Neural reflex regulation of systemic inflammation: potential new targets for sepsis therapy

Cited by 55 publications

References 98 publications

The Involvement of Parasympathetic and Sympathetic Nerve in the Inflammatory Reflex

The Involvement of Parasympathetic and Sympathetic Nerve in the Inflammatory Reflex

Identification and Analysis of Shared Risk Factors in Sepsis and High Mortality Risk COVID-19 Patients

Adipose tissue-derived mesenchymal stem cells as a strategy to improve recovery after stroke

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