RESUMEN
The cholinergic anti-inflammatory pathway (CAP) is a classic neuroimmune pathway, consisting of the vagus nerve, acetylcholine (ACh)-the pivotal neurotransmitter of the vagus nerve-and its receptors. This pathway can activate and regulate the activities of immune cells, inhibit cell proliferation and differentiation, as well as suppress cytokine release, thereby playing an anti-inflammatory role, and widely involved in the occurrence and development of various diseases; recent studies have demonstrated that the CAP may be a new target for the treatment of autoimmune rheumatic diseases. In this review, we will summarize the latest progress with the view of figuring out the role of the cholinergic pathway and how it interacts with inflammatory reactions in several autoimmune rheumatic diseases, and many advances are results from a wide range of experiments performed in vitro and in vivo.
Asunto(s)
Enfermedades Autoinmunes/etiología , Enfermedades Reumáticas/etiología , Acetilcolina/inmunología , Animales , Artritis Reumatoide/etiología , Artritis Reumatoide/inmunología , Enfermedades Autoinmunes/inmunología , Humanos , Inflamación/inmunología , Lupus Eritematoso Sistémico/etiología , Lupus Eritematoso Sistémico/inmunología , Neuroinmunomodulación , Osteoartritis/etiología , Osteoartritis/inmunología , Receptores Colinérgicos/inmunología , Enfermedades Reumáticas/inmunología , Esclerodermia Sistémica/etiología , Esclerodermia Sistémica/inmunología , Síndrome de Sjögren/etiología , Síndrome de Sjögren/inmunología , Espondiloartropatías/etiología , Espondiloartropatías/inmunología , Nervio Vago/inmunologíaRESUMEN
The cholinergic system has been proposed as a potential regulator of COVID-19-induced hypercytokinemia. We investigated whole-blood expression of cholinergic system members and correlated it with COVID-19 severity. Patients with confirmed SARS-CoV-2 infection and healthy aged-matched controls were included in this non-interventional study. A whole blood sample was drawn between 9-11 days after symptoms onset, and peripheral leukocyte phenotyping, cytokines measurement, RNA expression and plasma viral load were determined. Additionally, whole-blood expression of native alpha-7 nicotinic subunit and its negative dominant duplicate (CHRFAM7A), choline acetyltransferase and acetylcholine esterase (AchE) were determined. Thirty-seven patients with COVID-19 (10 moderate, 11 severe and 16 with critical disease) and 14 controls were included. Expression of CHRFAM7A was significantly lower in critical COVID-19 patients compared to controls. COVID-19 patients not expressing CHRFAM7A had higher levels of CRP, more extended pulmonary lesions and displayed more pronounced lymphopenia. COVID-19 patients without CHRFAM7A expression also showed increased TNF pathway expression in whole blood. AchE was also expressed in 30 COVID-19 patients and in all controls. COVID-19-induced hypercytokinemia is associated with decreased expression of the pro-inflammatory dominant negative duplicate CHRFAM7A. Expression of this duplicate might be considered before targeting the cholinergic system in COVID-19 with nicotine.
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Acetilcolina/inmunología , COVID-19/inmunología , Inflamación/inmunología , SARS-CoV-2/inmunología , Receptor Nicotínico de Acetilcolina alfa 7/inmunología , Adulto , Anciano , COVID-19/genética , Regulación hacia Abajo , Femenino , Humanos , Inflamación/genética , Masculino , Persona de Mediana Edad , Receptor Nicotínico de Acetilcolina alfa 7/genéticaAsunto(s)
Acetilcolina/inmunología , Hiperreactividad Bronquial/inmunología , Hipersensibilidad/inmunología , Pulmón/efectos de los fármacos , Linfocitos/efectos de los fármacos , Papaína/farmacología , Animales , Hiperreactividad Bronquial/fisiopatología , Líquido del Lavado Bronquioalveolar/citología , Citocinas/inmunología , Hipersensibilidad/fisiopatología , Inmunidad Innata , Pulmón/inmunología , Linfocitos/inmunología , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
OBJECTIVE: To review the latest discoveries regarding the role of tuft cells in the pathogenesis of chronic rhinosinusitis (CRS) with nasal polyposis and asthma. DATA SOURCES: Reviews and primary research manuscripts were identified from PubMed, Google, and bioRxiv using the search words airway epithelium, nasal polyposis, CRS or asthma and chemoreceptor cell, solitary chemosensory cell, brush cell, microvillus cell, and tuft cell. STUDY SELECTIONS: Studies were selected on the basis of novelty and likely relevance to the functions of tuft cells in chronic inflammatory diseases in the upper and lower airways. RESULTS: Tuft cells coordinate a variety of immune responses throughout the body. After the activation of bitter-taste receptors, tuft cells coordinate the secretion of antimicrobial products by adjacent epithelial cells and initiate the calcium-dependent release of acetylcholine resulting in neurogenic inflammation, including mast cell degranulation and plasma extravasation. Tuft cells are also the dominant source of interleukin-25 and a significant source of cysteinyl leukotrienes that play a role in initiating inflammatory processes in the airway. Tuft cells have also been found to seem de novo in the distal airway after a viral infection, implicating these cells in dysplastic remodeling in the distal lung in the pathogenesis of asthma. CONCLUSION: Tuft cells bridge innate and adaptive immunes responses and play an upstream role in initiating type 2 inflammation in the upper and possibly the lower airway. The role of tuft cells in respiratory pathophysiology must be further investigated, because tuft cells are putative high-value therapeutic targets for novel therapeutics in CRS with nasal polyps and asthma.
Asunto(s)
Asma/inmunología , Células Epiteliales/inmunología , Pólipos Nasales/inmunología , Sistema Respiratorio/citología , Rinitis/inmunología , Sinusitis/inmunología , Acetilcolina/inmunología , Animales , Enfermedad Crónica , Eicosanoides/inmunología , Humanos , Interleucina-17/inmunología , Sistema Respiratorio/inmunologíaRESUMEN
Acetylcholine receptor (AChR)-specific CD4+ T cells play a driving role in myasthenia gravis (MG) by regulating the production of autoantibodies. However, the quantitative features of AChR-specific T cells and their clinical significance in MG are unclear. In this study, we adopted standard and cultured enzyme-linked immunosorbent spot (ELISPOT) assays to quantify subpopulations of AChR-specific CD4+ T cells in MG patients, and evaluate their correlation with clinical characteristics. The results showed that Th1- and Th17-AChR-specific CD4+ T cells were detectable by standard and cultured ELISPOT assay respectively, with higher levels observed in MG patients comparing with healthy controls. The number of Th17-AChR-specific CD4+ T cells was positively correlated with anti-AChR antibody titer and quantitative MG score and may have latent capacity to reflect responses to immunosuppressants. These results highlight the differences in quantitative features of AChR-specific CD4+ T cells and imply Th17-AChR-specific CD4+ T cells can serve as a biomarker in MG.
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Acetilcolina/inmunología , Linfocitos T CD4-Positivos/inmunología , Miastenia Gravis/inmunología , Receptores Colinérgicos/inmunología , Adolescente , Adulto , Autoanticuerpos/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células TH1/inmunología , Células Th17/inmunología , Adulto JovenRESUMEN
Mucociliary clearance through coordinated ciliary beating is a major innate defense removing pathogens from the lower airways, but the pathogen sensing and downstream signaling mechanisms remain unclear. We identified virulence-associated formylated bacterial peptides that potently stimulated ciliary-driven transport in the mouse trachea. This innate response was independent of formyl peptide and taste receptors but depended on key taste transduction genes. Tracheal cholinergic chemosensory cells expressed these genes, and genetic ablation of these cells abrogated peptide-driven stimulation of mucociliary clearance. Trpm5-deficient mice were more susceptible to infection with a natural pathogen, and formylated bacterial peptides were detected in patients with chronic obstructive pulmonary disease. Optogenetics and peptide stimulation revealed that ciliary beating was driven by paracrine cholinergic signaling from chemosensory to ciliated cells operating through muscarinic M3 receptors independently of nerves. We provide a cellular and molecular framework that defines how tracheal chemosensory cells integrate chemosensation with innate defense.
Asunto(s)
Acetilcolina/inmunología , Proteínas Bacterianas/farmacología , Cilios/inmunología , Depuración Mucociliar/inmunología , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Canales Catiónicos TRPM/inmunología , Tráquea/inmunología , Acetilcolina/metabolismo , Animales , Proteínas Bacterianas/inmunología , Transporte Biológico , Cilios/efectos de los fármacos , Cilios/metabolismo , Femenino , Formiatos/metabolismo , Expresión Génica , Humanos , Inmunidad Innata , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Optogenética/métodos , Comunicación Paracrina/inmunología , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/patología , Receptor Muscarínico M3/genética , Receptor Muscarínico M3/inmunología , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/inmunología , Canales Catiónicos TRPM/deficiencia , Canales Catiónicos TRPM/genética , Papilas Gustativas/inmunología , Papilas Gustativas/metabolismo , Tráquea/efectos de los fármacos , Tráquea/patología , VirulenciaRESUMEN
INTRODUCTION: Factors predicting remission after thymectomy for myasthenia gravis are not well known. AIM: To analyze the clinical evolution of the patients after this intervention and discuss about predictors of response. PATIENTS AND METHODS: We retrospectively reviewed all clinical data of thymectomies in myasthenia gravis patients performed at our hospital between 2006 from 2016. Using the MGFA-PIS classification, «complete stable remission¼, «pharmacologic remission¼, «minimal manifestations¼ and «improved¼ were defined as «good clinical outcome¼, and «unchanged¼, «worse¼, «exacerbation¼ or «died¼, as «poor clinical outcome¼. RESULTS: In 46 consecutive thymectomies for myasthenia gravis, women comprised 71.7%. Median age was 37 years and 10.9% had concomitant autoimmune disorders associated. Thymoma (23.96%) was more frequent in older patients (53 ± 20 vs 33 ± 24 years) and men (54.5% vs 18.8%). A year after thymectomy, 28.2% of patients were in poor clinical outcome group and 54.3% had good clinical outcome. On univariate analysis, thymomatous myasthenia was associated with poor clinical outcome a year after surgical intervention. After ten years of follow-up, 9.8% reached complete stable remission, a total of 32 patients (78%) had a favourable outcome and thymoma was not correlated. CONCLUSION: Thymectomy is considered an effective treatment for myasthenia gravis but the benefit is not immediate. The presence of thymoma may determine a worse initial clinical response following thymectomy in patients with myasthenia gravis.
TITLE: Timectomía en miastenia grave timomatosa y no timomatosa: análisis de una cohorte de 46 pacientes.Introducción. En la actualidad, los factores predictores de remisión de la enfermedad en la miastenia grave tras una timectomía no están claramente establecidos. Objetivo. Analizar la evolución clínica de los pacientes tras esta intervención y abordar los posibles determinantes pronósticos. Pacientes y métodos. Se analizaron retrospectivamente los registros de pacientes con miastenia grave timectomizados en nuestro centro entre 2006 y 2016. Se utilizó la escala Miasthenya Gravis Foundation of America-Post Intervention Status agrupando las categorías «remisión completa estable¼, «remisión farmacológica¼, «manifestaciones mínimas¼ y «mejoría¼ como «buen resultado clínico¼, y las categorías «sin cambios¼, «empeoramiento¼, «exacerbación¼ y «muerte¼, como «mal resultado clínico¼. Resultados. Se analizaron 46 timectomías de pacientes con miastenia grave, un 71,7% mujeres. La mediana de edad era de 37 años y el 10,9% asociaba enfermedades autoinmunes. El timoma (23,9%) fue más frecuentes en los varones (54,5% frente a 18,8%) y a mayor edad (53 ± 20 frente a 33 ± 24 años). Un año después de la timectomía, el 28,2% se encontraba en el grupo de mal resultado clínico, y un 54,3%, en el de buen resultado clínico. En el análisis univariante, el timoma se asoció a peor resultado clínico al año de la intervención. Tras diez años de seguimiento, 32 pacientes (78%) alcanzaron un buen resultado clínico, un 9,8% en remisión completa estable, y el timoma no se correlacionó como factor de mal pronóstico. Conclusión. La timectomía se considera un tratamiento efectivo, pero sin beneficio inmediato. La presencia de timoma podría determinar una respuesta clínica inicial peor tras la realización de una timectomía en pacientes con miastenia grave.
Asunto(s)
Miastenia Gravis/etiología , Timectomía , Timoma/cirugía , Timo/patología , Neoplasias del Timo/cirugía , Acetilcolina/inmunología , Adolescente , Adulto , Anciano , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/epidemiología , Terapia Combinada , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Hiperplasia , Factores Inmunológicos/uso terapéutico , Masculino , Persona de Mediana Edad , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/inmunología , Miastenia Gravis/cirugía , Prednisona/uso terapéutico , Inducción de Remisión , Estudios Retrospectivos , Timectomía/estadística & datos numéricos , Timoma/complicaciones , Neoplasias del Timo/complicaciones , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Brain ischemia activates the parasympathetic cholinergic pathway in animal models of human disease. However, it remains unknown whether activation of the cholinergic pathway impacts immune defenses and disease outcomes in patients with ischemic stroke. This study investigated a possible association between peripheral cholinergic activity, post-stroke infection, and mortality. METHODS: In this study, we enrolled 458 patients with acute ischemic stroke (< 24 h after onset), 320 patients with ischemic stroke on day 10, and 216 healthy subjects. Peripheral cholinergic activity, reflected by intracellular acetylcholine (ACh) content in human peripheral blood mononuclear cells (PBMCs), was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Expression of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) was measured by quantitative real-time PCR and western blot. Regression analyses were used to assess associations between peripheral cholinergic function and clinical outcomes. RESULTS: Within 24 h after the onset of acute ischemic stroke, there was a rapid increase in peripheral cholinergic activity that correlated with brain infarction volume (r = 0.67, P < 0.01). Specifically, lymphocyte-derived ACh levels were significantly higher in stroke patients with pneumonia (0.21 ± 0.02 ng/106 PBMC versus 0.15 ± 0.01 ng/106 PBMC, P = 0.03). Of note, lymphocytic AChE catalytic activity was significantly lower in these patients. One-year mortality was significantly greater in patients with higher intracellular ACh levels within the first 24 h after acute stroke. CONCLUSIONS: Lymphocytes produced increased amounts of ACh in patients with acute stroke, and pneumonia was a likely result. The association between this enhanced cholinergic activity and increased risk of pneumonia/mortality suggests that increased cholinergic activity may contribute to fatal post-stroke infection.
Asunto(s)
Acetilcolina/metabolismo , Isquemia Encefálica/inmunología , Isquemia Encefálica/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Acetilcolina/inmunología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Gulf War Illness (GWI) is characterized by a constellation of symptoms that includes cognitive dysfunction. While the causes for GWI remain unknown, prophylactic use of the acetylcholinesterase inhibitor pyridostigmine bromide (PB) in combination with the stress of deployment has been proposed to be among the causes of the cognitive dysfunction in GWI. Mechanistically, clinical studies suggest that altered immune function may be an underlying factor in the neurochemical and neurobehavioral complications of GWI. Accordingly, the goal of this study was to determine how responses to an immune challenge (lipopolysaccharide; LPS) or stress impacts inflammation, acetylcholine (ACh) neurochemistry and behavior in an experimental model of GWI. Rats with a history of PB treatment exhibited potentiated increases in C-reactive protein levels in response to a submaximal LPS challenge compared to control rats, indicating that prior treatment with this cholinesterase inhibitor leads to exacerbated inflammatory responses to a subsequent immune challenge. ACh responses to LPS administration were decreased in the hippocampus, but not prefrontal cortex (PFC), in rats with a prior history of PB treatment or stress exposure. Additionally, ACh release in response to acute immobilization stress was attenuated in the PFC and hippocampus in these groups. These attenuated cholinergic responses were accompanied by impairments in contextual and cue-based fear learning. The results of this study suggest that stress and LPS challenges adversely affect central ACh neurochemistry in a rodent model of GWI and support the hypothesis that dysregulated immune responses are mechanistically linked to the neurological complications of GWI.
Asunto(s)
Acetilcolina/inmunología , Inhibidores de la Colinesterasa/administración & dosificación , Inflamación/inmunología , Síndrome del Golfo Pérsico/inmunología , Bromuro de Piridostigmina/administración & dosificación , Estrés Psicológico/inmunología , Animales , Conducta Animal/efectos de los fármacos , Proteína C-Reactiva/inmunología , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Modelos Animales de Enfermedad , Miedo/efectos de los fármacos , Miedo/fisiología , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Inflamación/inducido químicamente , Inflamación/complicaciones , Lipopolisacáridos/administración & dosificación , Masculino , Síndrome del Golfo Pérsico/complicaciones , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/inmunología , Ratas Sprague-Dawley , Estrés Psicológico/inducido químicamente , Estrés Psicológico/complicacionesRESUMEN
The expression of elements of the cholinergic system has been demonstrated in non-neuronal cells, such as immune cells, where acetylcholine modulates innate and adaptive responses. However, the study of the non-neuronal cholinergic system has focused on lymphocyte cholinergic mechanisms, with less attention to its role of innate cells. Considering this background, the aims of this review are 1) to review information regarding the cholinergic components of innate immune system cells; 2) to discuss the effect of cholinergic stimuli on cell functions; 3) and to describe the importance of cholinergic stimuli on host immunocompetence, in order to set the base for the design of intervention strategies in the biomedical field.
Asunto(s)
Acetilcolina/inmunología , Inmunidad Innata/inmunología , Leucocitos/inmunología , Animales , HumanosRESUMEN
OBJECTIVE: Acupuncture has a definite therapeutic effect on chronic obstructive pulmonary disease (COPD), and the cholinergic anti-inflammatory pathway (CAP) has been shown to be involved in regulation of inflammation. In this study, we investigated whether electro-acupuncture (EA) affects the CAP in COPD. METHODS: Sprague-Dawley rats were induced into COPD through exposure to cigarette smoke combined with lipopolysaccharide. EA treatment was applied at Zusanli (ST36) and Feishu (BL13) points for 30â¯min/d for 7â¯d. Seventy-two rats were randomly divided into six study groups, including normal, normalâ¯+â¯EA, normalâ¯+â¯α-bungarotoxin (α-BGT) (the antagonist of the nicotinic acetylcholine receptor α7 subunit (α7nAChR))â¯+â¯EA, COPD, COPDâ¯+â¯EA, and COPDâ¯+â¯α-BGTâ¯+â¯EA. Lung function, pathology and vagus nerve discharge were tested. The levels of acetylcholine (ACh), acetylcholinesterase (AChE), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid (BALF) and lung tissue were measured by enzyme-linked immunosorbent assay. The mRNA and protein expression and immunoreactivity of α7nAChR and its postreceptor inflammation signal pathway, including janus kinase 2 (JAK2), signal transducers and activators of transcription 3 (STAT3), nuclear factor-κB (NF-κB), were observed by quantitative reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. RESULTS: Compared with normal rats, there were a significant decline in lung function and discharge of the vagus nerve (Pâ¯<â¯0.01), a marked sign of lung inflammation and an increase of ACh, AChE, IL-6 and TNF-α level in BALF or lung tissue (Pâ¯<â¯0.05, Pâ¯<â¯0.01) and higher expression of α7nAChR, JAK2, STAT3 and NF-κB (Pâ¯<â¯0.05, Pâ¯<â¯0.01) in the COPD rats. In rats receiving EA, the lung function and vagal discharge were enhanced (Pâ¯<â¯0.01), lung inflammation was improved and the levels of ACh, AChE, IL-6 and TNF-α were decreased (Pâ¯<â¯0.01). Further, the expression of α7nAChR, JAK2, STAT3 and NF-κB was downregulated (Pâ¯<â¯0.05, Pâ¯<â¯0.01). However, the above effects of EA were blocked in rats injected with α-BGT (Pâ¯<â¯0.01). CONCLUSION: EA treatment can reduce the lung inflammatory response and improve lung function in COPD, which may be related to its involvement in the regulation of CAP.
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Acetilcolina/inmunología , Electroacupuntura , Enfermedad Pulmonar Obstructiva Crónica/inmunología , Enfermedad Pulmonar Obstructiva Crónica/terapia , Animales , Modelos Animales de Enfermedad , Humanos , Interleucina-6/genética , Interleucina-6/inmunología , Pulmón/inmunología , Masculino , FN-kappa B/genética , FN-kappa B/inmunología , Enfermedad Pulmonar Obstructiva Crónica/genética , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Regulated antimicrobial peptide expression in the intestinal epithelium is key to defense against infection and to microbiota homeostasis. Understanding the mechanisms that regulate such expression is necessary for understanding immune homeostasis and inflammatory disease and for developing safe and effective therapies. We used Caenorhabditis elegans in a preclinical approach to discover mechanisms of antimicrobial gene expression control in the intestinal epithelium. We found an unexpected role for the cholinergic nervous system. Infection-induced acetylcholine release from neurons stimulated muscarinic signaling in the epithelium, driving downstream induction of Wnt expression in the same tissue. Wnt induction activated the epithelial canonical Wnt pathway, resulting in the expression of C-type lectin and lysozyme genes that enhanced host defense. Furthermore, the muscarinic and Wnt pathways are linked by conserved transcription factors. These results reveal a tight connection between the nervous system and the intestinal epithelium, with important implications for host defense, immune homeostasis, and cancer.
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Acetilcolina/inmunología , Caenorhabditis elegans/inmunología , Mucosa Intestinal/inmunología , Vía de Señalización Wnt/inmunología , Acetilcolina/metabolismo , Animales , Péptidos Catiónicos Antimicrobianos/genética , Péptidos Catiónicos Antimicrobianos/inmunología , Péptidos Catiónicos Antimicrobianos/metabolismo , Bacterias/inmunología , Caenorhabditis elegans/genética , Caenorhabditis elegans/microbiología , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/inmunología , Proteínas de Caenorhabditis elegans/metabolismo , Expresión Génica/inmunología , Homeostasis/genética , Homeostasis/inmunología , Interacciones Huésped-Patógeno/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Neuronas/inmunología , Neuronas/metabolismo , Vía de Señalización Wnt/genéticaRESUMEN
BACKGROUND: The bronchial hyperresponsiveness (BHR) test is useful to diagnose or evaluate effect of therapy in asthmatics, but invasive. On the other hands, the fraction of exhaled nitric oxide (FENO) is a useful noninvasive marker of eosinophilic airway inflammation in asthmatics. And also, the forced oscillation technique (FOT) is a noninvasive method that is used to measure respiratory mechanics, including respiratory resistance and reactance at multiple frequencies. AIM: To evaluate the complementary roles of FENO and FOT to predict bronchial hyperresponsiveness in adult stable asthmatic patients taking inhaled corticosteroids. METHODS: From our outpatient clinic, we recruited 115 stable asthmatics that were being treated with inhaled corticosteroids at the time of the study. For each subject, we measured FENO by using an offline methods (CEIS' method); and we measured resistance at 5Hz (R5), resistance at 20Hz (R20), R5-R20, reactance at 5Hz (X5), frequency of resonance (Fres), and low-frequency reactance area (ALX), by using a MostGraph FOT machine. We also used spirometry to test BHR to acetylcholine (PC20Ach). RESULTS: LogPC20Ach was significantly correlated with FENO, R5, R20, R5-R20 and %FEV1. The ROC curve decided that the cutoff point of FENO was 37.8ppb (AUC=0.647, sensitivity 83.3%, specificity 55.6%, p=0.007) and that of R5 was 3.03cmH2O/L/S (AUC=0.684, sensitivity 72.2%, specificity 52.8%, p=0.001) and that of R20 was 2.77cmH2O/L/S (AUC=0.684, sensitivity 74.5%, specificity 59.4%, p=0.001). When R5 was >3.03 and FENO was >37.8ppb, 25 of 38 subjects (65.7%) had bronchial hyperresponsiveness. If R5 was <3.03 and FENO was <37.8 ppb, only 5 of 29 (17.2%) subjects had. When R20 was >2.77 and FENO was >37.8ppb, 29 of 43 subjects (67.4%) had bronchial hyperresponsiveness. If R20 was <3.03 and FENO was <37.8ppb, only 2 of 18 (11.1%) subjects had. CONCLUSION: Combining R5 or R20 and FENO can predict the level of bronchial hyperresponsiveness in adult stable asthmatics.
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Acetilcolina/inmunología , Asma/fisiopatología , Hiperreactividad Bronquial/fisiopatología , Óxido Nítrico/análisis , Asma/inmunología , Hiperreactividad Bronquial/diagnóstico , Hiperreactividad Bronquial/inmunología , Espiración , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas de Función RespiratoriaRESUMEN
BACKGROUND: The onset of diabetes causes disruption of respiratory epithelial mediators. The present study investigates whether diabetes modifies the epithelium mediated bronchial responses in hyper-reactive airway smooth muscle (ASM) primarily through nitric oxide (NO), cyclooxygenase (COX), and epithelium derived hyperpolarizing factor (EpDHF) pathways. METHODS: Experimental model of guinea pigs having hyper-reactive airways with or without diabetes were developed. The responses of tracheal rings to cumulative concentrations of acetylcholine (ACh) and isoproterenol (IP) in the presence and absence of epithelium and before and after incubation with NO, K+ATP and COX inhibitors, N-(ω)-Nitro-L-arginine methyl ester (L-NAME; 100 µM), glybenclamide (10 µM) and indomethacin (100 µM) were assessed. RESULTS: In diabetic guinea pigs with hyper-reactive airways, a decrease in ACh induced bronchoconstriction was observed after epithelium removal and after incubation with L-NAME/indomethacin, suggesting damage to NO/COX pathways. Hyper-reactivity did not alter the response of trachea to ACh but affected the response to IP which was further reduced in hyper-reactive animals with diabetes. The ASM response to IP after glybenclamide treatment did not alter in hyper-reactive guinea pigs and diabetic guinea pigs with hyper-reactive airways, suggesting damage to the EpDHF pathway. Treatment with indomethacin reduced IP response in the hyper-reactive model, and did not produce any change in diabetic model with hyper-reactive airways, indicating further disruption of the COX pathway. CONCLUSION: EpDHF pathway is damaged in hyper-reactive guinea pigs and in diabetic guinea pigs with hyper-reactive airways. Diabetes further aggravates the NO and COX mediated pathways in diabetic guinea pigs with hyper-reactive airways.
Asunto(s)
Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Complicaciones de la Diabetes/inmunología , Complicaciones de la Diabetes/patología , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/patología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patología , Tráquea/inmunología , Tráquea/patología , Acetilcolina/inmunología , Animales , Antígenos Bacterianos , Proteínas Bacterianas , Broncoconstricción/inmunología , Femenino , Gliburida/farmacología , Cobayas , Humanos , Indometacina/farmacología , Isoproterenol/inmunología , Masculino , Músculo Liso/inmunología , Músculo Liso/patología , Óxido Nítrico , Prostaglandina-Endoperóxido Sintasas , EstreptozocinaRESUMEN
Objective The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca2+) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients. Methods A total of 11 CFS/ME patients (aged 31.82 ± 5.50 years) and 11 non-fatigued controls (aged 33.91 ± 5.06 years) were included. Flow cytometric protocols were used to determine B cell purity, followed by SNP and genotype analysis for 21 mammalian TRP ion channel genes and nine mammalian ACh receptor genes. SNP association and genotyping analysis were performed using ANOVA and PLINK analysis software. Results Seventy-eight SNPs were identified in nicotinic and muscarinic acetylcholine receptor genes in the CFS/ME group, of which 35 were in mAChM3. The remaining SNPs were identified in nAChR delta (n = 12), nAChR alpha 9 (n = 5), TRPV2 (n = 7), TRPM3 (n = 4), TRPM4 (n = 1) mAChRM3 2 (n = 2), and mAChRM5 (n = 3) genes. Nine genotypes were identified from SNPs in TRPM3 (n = 1), TRPC6 (n = 1), mAChRM3 (n = 2), nAChR alpha 4 (n = 1), and nAChR beta 1 (n = 4) genes, and were located in introns and 3' untranslated regions. Odds ratios for these specific genotypes ranged between 7.11 and 26.67 for CFS/ME compared with the non-fatigued control group. Conclusion This preliminary investigation identified a number of SNPs and genotypes in genes encoding TRP ion channels and AChRs from B cells in patients with CFS/ME. These may be involved in B cell functional changes, and suggest a role for Ca2+ dysregulation in AChR and TRP ion channel signalling in the pathomechanism of CFS/ME.
Asunto(s)
Linfocitos B/metabolismo , Señalización del Calcio , Síndrome de Fatiga Crónica/genética , Polimorfismo de Nucleótido Simple , Receptores Colinérgicos/genética , Canales de Potencial de Receptor Transitorio/genética , Acetilcolina/inmunología , Acetilcolina/metabolismo , Adulto , Linfocitos B/inmunología , Linfocitos B/patología , Calcio/inmunología , Calcio/metabolismo , Estudios de Casos y Controles , Síndrome de Fatiga Crónica/inmunología , Síndrome de Fatiga Crónica/metabolismo , Síndrome de Fatiga Crónica/patología , Femenino , Expresión Génica , Genotipo , Humanos , Activación de Linfocitos , Masculino , Cultivo Primario de Células , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , Isoformas de Proteínas/metabolismo , Receptores Colinérgicos/inmunología , Receptores Colinérgicos/metabolismo , Canales de Potencial de Receptor Transitorio/inmunología , Canales de Potencial de Receptor Transitorio/metabolismoRESUMEN
BACKGROUND: Neural-endocrine-immune (NEI) system is a major modulation network among the nervous, endocrine and immune system and weights greatly in maintaining homeostasis of organisms during stress and infection. Some microRNAs are found interacting with NEI system (designated NeurimmiRs), addressing swift modulations on immune system. The oyster Crassostrea gigas, as an intertidal bivalve, has evolved a primary NEI system. However, the knowledge about NeurimmiRs in oysters remains largely unknown. RESULTS: Six small RNA libraries from haemocytes of oysters stimulated with acetylcholine (ACh) and norepinephrine (NE) were sequenced to identify neurotransmitter-responsive miRNAs and survey their immunomodulation roles. A total of 331 miRNAs (132 identified in the present study plus 199 identified previously) were subjected to expression analysis, and twenty-one and sixteen of them were found ACh- or NE-responsive, respectively (FDR < 0.05). Meanwhile, 21 miRNAs exhibited different expression pattern after ACh or NE stimulation. Consequently, 355 genes were predicted as putative targets of these neurotransmitter-responsive miRNAs in oyster. Through gene onthology analysis, multiple genes involved in death, immune system process and response to stimulus were annotated to be modulated by NeurimmiRs. Besides, a significant decrease in haemocyte phagocytosis and late-apoptosis or necrosis rate was observed after ACh and NE stimulation (p < 0.05) while early-apoptosis rate remained unchanged. CONCLUSIONS: A comprehensive immune-related network involving PRRs, intracellular receptors, signaling transducers and immune effectors was proposed to be modulated by ACh- and NE-responsive NeurimmiRs, which would be indispensable for oyster haemocytes to respond against stress and infection. Characterization of the NeurimmiRs would be an essential step to understand the NEI system of invertebrate and the adaptation mechanism of oyster.
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Crassostrea/inmunología , Hemocitos/inmunología , MicroARNs/inmunología , Acetilcolina/inmunología , Animales , Apoptosis , Crassostrea/citología , Inmunomodulación , Norepinefrina/inmunología , Fagocitosis , Receptores de Superficie Celular/inmunologíaRESUMEN
It has been previously shown that acetylcholine (ACh) may affect pro-inflammatory and anti-inflammatory cytokines. The role of the cholinergic system in radiation-induced inflammatory responses and tissue damage remains unclear. Therefore, the present study was designed to determine the radio-protective properties of the cholinergic system in the ileum and the liver of rats. Rats were exposed to 8-Gy single-fraction whole-abdominal irradiation and were then decapitated at either 36 h or 10 d post-irradiation. The rats were treated either with intraperitoneal physiological saline (1 ml/kg), physostigmine (80 µg/kg) or atropine (50 µg/kg) twice daily for 36 h or 10 d. Cardiac blood samples and liver and ileal tissues were obtained in which TNF-α, IL-1ß and IL-10 levels were assayed using ELISA. In the liver and ileal homogenates, caspase-3 immunoblots were performed and myeloperoxidase (MPO) activity was analyzed. Plasma levels of IL-1ß and TNF-α increased significantly following radiation (P < 0.01 and P < 0.001, respectively) as compared with non-irradiated controls, and physostigmine treatment prevented the increase in the pro-inflammatory cytokines (P < 0.01 and P < 0.001, respectively). Plasma IL-10 levels were not found to be significantly changed following radiation, whereas physostigmine augmented IL-10 levels during the late phase (P < 0.01). In the liver and ileum homogenates, IL-1ß and TNF-α levels were also elevated following radiation, and this effect was inhibited by physostigmine treatment but not by atropine. Similarly, physostigmine also reversed the changes in MPO activity and in the caspase-3 levels in the liver and ileum. Histological examination revealed related changes. Physostigmine experiments suggested that ACh has a radio-protective effect not involving the muscarinic receptors.
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Acetilcolina/inmunología , Enfermedades del Íleon/inmunología , Enfermedades del Íleon/prevención & control , Hepatopatías/inmunología , Hepatopatías/prevención & control , Traumatismos por Radiación/inmunología , Traumatismos por Radiación/prevención & control , Animales , Colinérgicos/administración & dosificación , Citocinas/inmunología , Enfermedades del Íleon/patología , Hepatopatías/patología , Dosis de Radiación , Traumatismos por Radiación/patología , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
OBJECTIVE: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes. MATERIALS AND METHODS: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to Porphyromonas gingivalis in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to P. gingivalis lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-bla cell reporter assay. RESULTS: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited P. gingivalis-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to P. gingivalis lipopolysaccharide. CONCLUSION: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes.
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Interleucina-8/inmunología , Queratinocitos/inmunología , Receptor Nicotínico de Acetilcolina alfa 7/inmunología , Acetilcolina/inmunología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Bungarotoxinas/farmacología , Células CHO , Cricetulus , Humanos , Queratinocitos/efectos de los fármacos , Lipopolisacáridos , Mucosa Bucal/citología , Enfermedades Periodontales/genética , Enfermedades Periodontales/inmunología , Porphyromonas gingivalis , Quinuclidinas/farmacología , ARN Mensajero/metabolismo , Factor de Transcripción STAT3/inmunología , Factor de Transcripción ReIA/inmunología , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidores , Receptor Nicotínico de Acetilcolina alfa 7/genéticaRESUMEN
Twenty-five years ago, immunologists and neuroscientists had little science of mutual interest. This is no longer the case. Neuroscientists now know that the first formally defined cytokine, IL-1, activates a discrete population of hypothalamic neurons. This interaction leads to the release of glucocorticoids from the adrenal gland, a hormone that has a long history in immunoregulation. Immunologists have been surprised to learn that lymphoid cells synthesize acetylcholine, the first formally recognized neurotransmitter. This neurotransmitter suppresses the synthesis of TNF. These discoveries blur the distinction of neuroscience and immunology as distinct disciplines. There are now 37 formally recognized cytokines and their receptors, and at least 60 classical neurotransmitters plus over 50 neuroactive peptides. These findings explain why both immunologists and neuroscientists are getting nervous about immunity and highlight a real need to apply integrative physiological approaches in biomedical research.