A role for neurokinin 1 receptor expressing neurons in the paratrigeminal nucleus in bradykinin-evoked cough in guinea pigs.
神经激肽 1 受体在豚鼠缓激肽诱发咳嗽中的作用。
- 作者列表："Driessen AK","McGovern AE","Behrens R","Moe AAK","Farrell MJ","Mazzone SB
KEY POINTS:Airway projecting sensory neurons arising from the jugular vagal ganglia terminate centrally in the brainstem paratrigeminal nucleus, synapsing upon neurons expressing the neurokinin 1 receptor. This study aimed to assess the involvement of paratrigeminal neurokinin 1 receptor neurons in the regulation of cough, breathing and airway defensive responses. Lesioning neurokinin 1 receptor expressing paratrigeminal neurons significantly reduced cough evoked by inhaled bradykinin but not inhaled ATP or tracheal mechanical stimulation. The reduction in bradykinin-evoked cough was not accompanied by changes in baseline or evoked respiratory variables (e.g. frequency, volume or timing), animal avoidance behaviours or the laryngeal apnoea reflex. These findings warrant further investigations into targeting the jugular ganglia and paratrigeminal nucleus as a therapy for treating cough in disease. ABSTRACT:Jugular vagal ganglia sensory neurons innervate the large airways and are thought to mediate cough and associated perceptions of airway irritations to a range of chemical irritants. The central terminals of jugular sensory neurons lie within the brainstem paratrigeminal nucleus, where postsynaptic neurons can be differentiated based on the absence or presence of the neurokinin 1 (NK1) receptor. Therefore, in the present study, we set out to test the hypothesis that NK1 receptor expressing paratrigeminal neurons play a role in cough evoked by inhaled chemical irritants. To test this, we performed selective neurotoxin lesions of NK1 receptor expressing neurons in the paratrigeminal nucleus in guinea pigs using substance P conjugated to saporin (SSP-SAP). Sham lesion control or SSP-SAP lesion guinea pigs received nebulised challenges, with the pan-nociceptor stimulant bradykinin or the nodose ganglia specific stimulant adenosine 5'-triphosphate (ATP), in conscious whole-body plethysmography to study cough and associated behaviours. Laryngeal apnoea reflexes and cough evoked by mechanical stimulation of the trachea were additionally investigated in anaesthetised guinea pigs. SSP-SAP significantly and selectively reduced the number of NK1 receptor expressing neurons in the paratrigeminal nucleus. This was associated with a significant reduction in bradykinin-evoked cough, but not ATP-evoked cough, mechanical cough or laryngeal apnoeic responses. These data provide further evidence for a role of jugular vagal pathways in cough, and additionally suggest an involvement of NK1 receptor expressing neurons in the paratrigeminal nucleus. Therefore, this neural pathway may provide novel therapeutic opportunities to treat conditions of chronic cough. This article is protected by copyright. All rights reserved.
要点: 由颈静脉迷走神经节产生的气道投射感觉神经元在脑干房旁核中心终止，突触在表达神经激肽 1 受体的神经元上。本研究旨在评估房旁神经激肽 1 受体神经元参与咳嗽、呼吸和气道防御反应的调节。表达房旁神经元的毁损神经激肽 1 受体显著减少吸入缓激肽而不吸入 ATP 或气管机械刺激诱发的咳嗽。缓激肽诱发咳嗽的减少不伴有基线或诱发呼吸变量 (如频率、体积或时间) 、动物回避行为或喉呼吸暂停反射的变化。这些发现需要进一步研究靶向颈静脉神经节和房旁核作为治疗疾病咳嗽的疗法。 摘要: 颈静脉迷走神经节感觉神经元支配大气道，被认为介导咳嗽和对一系列化学刺激物的气道刺激的相关感知。颈静脉感觉神经元的中枢末梢位于脑干房旁核内，突触后神经元可以根据神经激肽 1 (NK1) 受体的缺失或存在而分化。因此，在本研究中，我们开始验证表达心房旁神经元的 NK1 受体在吸入化学刺激物诱发的咳嗽中发挥作用的假设。为了测试这一点，我们使用与 saporin (SSP-SAP) 偶联的 p物质对豚鼠心房旁核中表达 NK1 受体的神经元进行选择性神经毒素损伤。假病变对照或 SSP-SAP 病变豚鼠接受雾化激发，使用泛伤害性受体刺激剂缓激肽或 nodose 神经节特异性刺激剂腺苷 5 '-三磷酸 (ATP),在有意识的全身体积描记术中研究咳嗽和相关行为。对麻醉豚鼠进行了气管机械刺激诱发的喉呼吸暂停反射和咳嗽的研究。SSP-SAP 显著选择性地减少了房旁核中 NK1 受体表达神经元的数量。这与缓激肽诱发的咳嗽显著减少有关，但与 ATP 诱发的咳嗽、机械性咳嗽或喉呼吸暂停反应无关。这些数据为颈静脉迷走神经通路在咳嗽中的作用提供了进一步的证据，另外还提示了 NK1 受体表达神经元参与了房旁核。因此，该神经通路可能为治疗慢性咳嗽提供新的治疗机会。本文受版权保护。保留所有权利。
METHODS:INTRODUCTION:Continuous albuterol is a mainstay in management of pediatric status asthmaticus. While the National Heart Lung and Blood Institute Asthma Guidelines suggest 0.5 mg/kg/hr as the recommended dosage, there is a paucity of evidence comparing different weight based rates on hospital outcomes. METHODS:Patients requiring continuous albuterol for asthma exacerbation from January 2015 to December 2016 were identified using ICD codes. The concentration of albuterol (5 mg/h - 20 mg/h) and the duration of treatment were used to determine total albuterol administration. After dividing by patient weight, average weight based doses were divided into equal quintiles. Unadjusted and length of stay adjusted for age, initial asthma severity score, and administration of magnesium were compared among the quintiles. The same multivariate analysis was used for duration of continuous albuterol. RESULTS:533 hospitalizations for asthma were identified of which 289 received continuous albuterol. Weight based dosage quintiles ranged from lowest (0.07 - 0.29 mg/kg/hr) to the highest (>0.76 - 3.2 mg/kg/hr). Baseline characteristics were similar aside from age, race, and magnesium administration. There was no difference in adjusted length of stay or adjusted duration of continuous albuterol therapy among the five quintiles. CONCLUSION:No optimal weight based dose of continuous albuterol was found. Further investigation is needed to see if lower amounts of continuous albuterol may be as efficacious as higher doses. This could improve cost of status asthmaticus management and limit the number of adverse events associated with high exposure to continuous albuterol.
METHODS:Abstract Background We investigated the association between a combination of two markers, peripheral (PEC) and bronchoalveolar lavage (BAL) eosinophil percentage (BEP), and oxygen requirements in patients with acute eosinophilic pneumonia (AEP). Methods We retrospectively reviewed the medical records of patients with AEP treated at the Armed Forces Capital Hospital between May 2012 and May 2017. We used correlation analyses to assess the association between PEC/BEP and clinical outcomes in AEP patients. Receiver operating characteristic (ROC) curve analyses were used to calculate the cut-off value for BEP that categorised patients requiring a significant oxygen supply. The BAL/blood eosinophil (BBE) score was introduced to stratify patients with peripheral eosinophilia and elevated BEP. Clinical characteristics and outcomes were compared between the different groups. Multiple logistic regression was performed for significant oxygen requirements using two different models using age, C-reactive protein (CRP), smoking duration, and BBE score (model 1) and age, CRP, BEP, and PEC (model 2). Results Among the 338 patients, 99.7% were male, and their mean age was 20.4 ± 1.4 years. Only 0.6% of patients were never smokers and the mean number of smoking days was 26.2 ± 25.4. Correlation analyses revealed that both the PaO2/FiO2 ratio and duration of oxygen supply were associated with BEP. ROC curve analyses indicated a cut-off level of 41.5%. Patients with a high BBE score had favourable outcomes in terms of hypoxemia, hospital days, intensive care unit admission, oxygen supply days, and steroid treatment days. Multiple logistic regression revealed that BEP and BBE score tended to be associated with significant oxygen requirements. Conclusions In this study, we revealed that both peripheral and BAL eosinophilia is associated with favourable outcomes in AEP patients.
METHODS:Background. Extensive studies have focused on the diagnosis and treatment of Mycoplasma pneumoniae infection; however, rare studies investigated the posttreatment conditions. We analyzed the carrying status of M. pneumoniae in the respiratory tract of children before and after treatment. Methods. Ninety-two children with M. pneumoniae pneumonia were included in this study. Clinical data were obtained from each patient, and pharyngeal swab sampling was performed at preliminary diagnosis and discharge. Real-time PCR and dilution quantitative culture were utilized to determine the DNA quantification and number of viable M. pneumoniae from samples collected upon preliminary diagnosis and discharge. Results. All the 92 cases showed DNA positivity upon preliminary diagnosis, serum IgM antibody was detected in 80 patients, and positivity of M. pneumoniae culture was observed in 82 cases. Upon discharge, the M. pneumoniae nucleotide and culture positivity were detected in 87 and 49 cases, respectively. The content of viable M. pneumoniae was 10–104 CCU/mL and 10–102 CCU/mL in the preliminary diagnosis samples and discharge samples, respectively. Conclusions. Real-time PCR was rapid and effective for the qualitative diagnosis of M. pneumoniae at the early stage, but it cannot be used to evaluate the prognosis of patients with M. pneumoniae infection. Quantitative analysis for M. pneumoniae DNA could not directly reflex the viable strain content.