Cholinergic Anti-inflammatory Pathway (CAP) Activation in a Model of Acute Lung Infection
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ABSTRACT:
PROVIDER: PRJNA810441 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR18143600_1.fastq.gz | Fastqsanger.gz | |||
| SRR18143600_2.fastq.gz | Fastqsanger.gz | |||
| SRR18143601_1.fastq.gz | Fastqsanger.gz | |||
| SRR18143601_2.fastq.gz | Fastqsanger.gz | |||
| SRR18143602_1.fastq.gz | Fastqsanger.gz |
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Project description:The cholinergic anti-inflammatory pathway (CAP), has been well-studied and shown to control peripheral cytokine levels and inflammation. This nerve pathway has been activated pharmacologically or by nerve stimulators and studied in animal models and clinical studies. However, these CAP investigations have typically been performed in models or study populations of severe systemic or pathological inflammation. This transcriptomic profiling study was conducted in rats to understand CAP in a model of actue lung infeaction. Splenic ultrasound stimulation was used to activate CAP in both healthy animals and animals with an acute lung infection.
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Project description:The hepatic vagus branches innervate the liver and serve an important role in liver-brain connection. It appears that brain modulates inflammatory responses by activation of vagal efferent fibers. This activation and subsequent acetylcholine releases from vagus nerve terminals leads to inhibition of inflammatory cytokines through α7 nicotinic acetylcholine receptors (α7nAChRs) which located on the surface of different cell types such as liver Kupffer cells. This protective role of vagus-α7nAChR axis in liver diseases has been shown in several experimental studies. On the other hand, accumulated evidence clearly demonstrate that, autonomic dysfunction which is reduced functioning of both vagal and sympathetic nervous system, occurs during chronic liver disease and is well-known complication of patients suffering from cirrhosis. This review describes the impact and significance of cholinergic anti-inflammatory pathway in the liver and discusses about its disease-related dysfunction on the progression of cirrhosis. Considering the fact that sepsis is major cause of death in cirrhotic patients, convergence of these findings, may lead to designing novel therapeutic strategies in the field of chronic liver diseases management involving selective drug targeting and electrical nerve stimulation.
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Project description:The cholinergic anti-inflammatory pathway (CAP) first described by Wang et al, 2003 has contemporary interest arising from the COVID-19 pandemic. While tobacco smoking has been considered an aggravating factor in the severity of COVID-19 infections, it has been suggested by some that the nicotine derived from tobacco could lessen the severity of COVID-19 infections. This spotlight briefly describes the CAP and its potential role as a therapeutic target for the treatment of COVID-19 infections using vagus nerve stimulation or selective alpha7 nicotinic acetylcholine receptor agonists.
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Project description:We tested the hypothesis that cholinergic stimulation (via treatment with carbachol) and cyclic stretch regulate inflammatory gene expression in intact airway smooth muscle by measuring mRNA expression in bovine tracheal smooth muscle. Keywords: response to stress and drug
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Project description:Mesenchymal stromal cells (MSCs) have been considered a promising alternative for treatment of acute respiratory distress syndrome (ARDS). However, there is significant heterogeneity in their therapeutic efficacy, largely owing to the incomplete understanding of the mechanisms underlying the therapeutic activities of MSCs. Here, we hypothesize that the cholinergic anti-inflammatory pathway (CAP), which is recognized as a neuroimmunological pathway, may be involved in the therapeutic mechanisms by which MSCs mitigate ARDS. Using lipopolysaccharide (LPS) and bacterial lung inflammation models, we found that inflammatory cell infiltration and Evans blue leakage were reduced and that the expression levels of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) in lung tissue were significantly increased 6 hours after MSC infusion. When the vagus nerve was blocked or α7 nicotinic acetylcholine (ACh) receptor (α7nAChR)-knockout mice were used, the therapeutic effects of MSCs were significantly reduced, suggesting that the CAP may play an important role in the effects of MSCs in ARDS treatment. Our results further showed that MSC-derived prostaglandin E2 (PGE2) likely promoted ACh synthesis and release. Additionally, based on the efficacy of nAChR and α7nAChR agonists, we found that lobeline, the nicotinic cholinergic receptor excitation stimulant, may attenuate pulmonary inflammation and alleviate respiratory symptoms of ARDS patients in a clinical study (ChiCTR2100047403). In summary, we reveal a previously unrecognized MSC-mediated mechanism of CAP activation as the means by which MSCs alleviate ARDS-like syndrome, providing insight into the clinical translation of MSCs or CAP-related strategies for the treatment of patients with ARDS.
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Project description:Bulk RNA expression profiles were captured from hearts of alpha7 nicotinic acetylcholine receptor (Chrna7) knockout (KO) and wild type (WT) mice that underwent myocardial infarction (MI) or sham (SH) surgery at postnatal day 1 and full ventricle collection at 7 days post-surgery
2021-09-28 | GSE184792 | GEO
Project description:Activation of innate immunity through Toll-like receptors (TLR) can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand). The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant.
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Project description:The magnitude of innate inflammatory immune responses is dependent on interactions between peripheral neural and immune cells. In particular, a cholinergic anti-inflammatory pathway (CAP) has been identified in the spleen whereby noradrenaline (NA) released by splenic nerves binds to ß2-adrenergic receptors (β2-AR) on CD4+ T cells which, in turn, release acetylcholine (ACh). The binding of ACh to α7 acetylcholine receptors (α7-AChR) expressed by splenic macrophages inhibits the production of inflammatory cytokines, including tumor necrosis factor (TNF). However, the role of ACh-secreting CD4+ T-cells in the CAP is still controversial and largely based on the absence of this anti-inflammatory pathway in mice lacking T-cells (nude, FoxN1-/-). Using four conscious, non-lymphopenic transgenic mouse models, we found that, rather than acting on CD4+ T-cells, NA released by splenic nerve terminals acts directly onto β2-AR on splenic myeloid cells to exert this anti-inflammatory effect. We also show that, while larger doses of LPS are needed to trigger CAP in nude mouse strain compared to other strains, TNF production can be inhibited in these animals lacking CD4+ T-cell by stimulating either the vagus or the splenic nerve. We demonstrate that CD4+ T-cells are dispensable for the CAP after antibody-mediated CD4+ T-cell depletion in wild type mice. Furthermore, we found that NA-mediated inhibition of in vitro LPS-induced TNF secretion by human or porcine splenocytes does not require α7-AChR signaling. Altogether our data demonstrate that activation of the CAP by stimulation of vagus or splenic nerves in mice is mainly mediated by direct binding of NA to β2-AR on splenic macrophages, and suggest that the same mechanism is at play in larger species.
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