Pub Date : 2024-01-17DOI: 10.1016/j.resp.2024.104217
George M.P.R. Souza, Stephen B.G. Abbott
Central respiratory chemoreceptors are cells in the brain that regulate breathing in relation to arterial pH and PCO2. Neurons located at the retrotrapezoid nucleus (RTN) have been hypothesized to be central chemoreceptors and/or to be part of the neural network that drives the central respiratory chemoreflex. The inhibition or ablation of RTN chemoreceptor neurons has offered important insights into the role of these cells on central respiratory chemoreception and the neural control of breathing over almost 60 years since the original identification of acid-sensitive properties of this ventral medullary site. Here, we discuss the current definition of chemoreceptor neurons in the RTN and describe how this definition has evolved over time. We then summarize the results of studies that use loss-of-function approaches to evaluate the effects of disrupting the function of RTN neurons on respiration. These studies offer evidence that RTN neurons are indispensable for the central respiratory chemoreflex in mammals and exert a tonic drive to breathe at rest. Moreover, RTN has an interdependent relationship with oxygen sensing mechanisms for the maintenance of the neural drive to breathe and blood gas homeostasis. Collectively, RTN neurons are a genetically-defined group of putative central respiratory chemoreceptors that generate CO2-dependent drive that supports eupneic breathing and stimulates the hypercapnic ventilatory reflex.
{"title":"Loss-of-function of chemoreceptor neurons in the retrotrapezoid nucleus: What have we learned from it?","authors":"George M.P.R. Souza, Stephen B.G. Abbott","doi":"10.1016/j.resp.2024.104217","DOIUrl":"10.1016/j.resp.2024.104217","url":null,"abstract":"<div><p><span>Central respiratory chemoreceptors<span> are cells in the brain that regulate breathing in relation to arterial pH and PCO</span></span><sub>2</sub><span><span><span>. Neurons located at the retrotrapezoid nucleus (RTN) have been hypothesized to be central chemoreceptors and/or to be part of the </span>neural network<span> that drives the central respiratory chemoreflex. The inhibition or ablation of RTN chemoreceptor neurons has offered important insights into the role of these cells on central respiratory chemoreception and the neural </span></span>control of breathing<span> over almost 60 years since the original identification of acid-sensitive properties of this ventral medullary site. Here, we discuss the current definition of chemoreceptor neurons in the RTN and describe how this definition has evolved over time. We then summarize the results of studies that use loss-of-function approaches to evaluate the effects of disrupting the function of RTN neurons on respiration. These studies offer evidence that RTN neurons are indispensable for the central respiratory chemoreflex in mammals and exert a tonic drive to breathe at rest. Moreover, RTN has an interdependent relationship with oxygen sensing mechanisms for the maintenance of the neural drive to breathe and blood gas homeostasis. Collectively, RTN neurons are a genetically-defined group of putative central respiratory chemoreceptors that generate CO</span></span><sub>2</sub>-dependent drive that supports eupneic breathing and stimulates the hypercapnic ventilatory reflex.</p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139492006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Expiratory neurons in the caudal ventral respiratory group extend descending axons to the lumbar and sacral spinal cord, and they possess axon collaterals, the distribution of which has been well-documented. Likewise, these expiratory neurons extend axons to the thoracic spinal cord and innervate thoracic expiratory motoneurons. These axons also give rise to collaterals, and their distribution may influence the strength of synaptic connectivity between the axons and the thoracic expiratory motoneurons. We investigated the distribution of axon collaterals in the thoracic spinal cord using a microstimulation technique. This study was performed on cats; one cat was used to make an anatomical atlas and six were used in the experiment. Extracellular spikes of expiratory neurons were recorded in artificially ventilated cats. The thoracic spinal gray matter was microstimulated from dorsal to ventral sites at 100-μm intervals using a glass-insulated tungsten microelectrode with a current of 150–250 μA. The stimulation tracks were made at 1 mm intervals along the spinal cord in segments Th9 to Th13, and the effective stimulating sites of antidromic activation in axon collaterals were systematically mapped. The effective stimulating sites in the contralateral thoracic spinal cord with expiratory neurons in the caudal ventral respiratory group (cVRG) occupied 14.4% of the total length of the thoracic spinal cord examined. The mean percentage of effective stimulating tracks per unit was 18.6 ± 4.4%. The distribution of axon collaterals of expiratory neurons in the feline thoracic spinal cord indeed resembled that reported in the upper lumbar spinal cord. We propose that a single medullary expiratory neuron exerts excitatory effects across multiple segments of the thoracic spinal cord via its collaterals.
{"title":"Axonal projection of the medullary expiratory neurons in the feline thoracic spinal cord","authors":"Kenta Kawamura , Kazumasa Sasaki , Sei-Ichi Sasaki , Kazuhide Tomita","doi":"10.1016/j.resp.2024.104218","DOIUrl":"10.1016/j.resp.2024.104218","url":null,"abstract":"<div><p><span><span>Expiratory neurons in the caudal ventral respiratory group extend descending axons to the lumbar and sacral spinal cord, and they possess axon collaterals, the distribution of which has been well-documented. Likewise, these expiratory neurons extend axons to the </span>thoracic spinal cord and innervate thoracic expiratory </span>motoneurons<span><span>. These axons also give rise to collaterals, and their distribution may influence the strength of synaptic connectivity between the axons and the thoracic expiratory motoneurons. We investigated the distribution of axon collaterals in the thoracic spinal cord using a microstimulation<span> technique. This study was performed on cats; one cat was used to make an anatomical atlas and six were used in the experiment. Extracellular spikes of expiratory neurons were recorded in artificially ventilated cats. The thoracic spinal gray matter was microstimulated from dorsal to ventral sites at 100-μm intervals using a glass-insulated tungsten microelectrode<span> with a current of 150–250 μA. The stimulation tracks were made at 1 mm intervals along the spinal cord in segments Th9 to Th13, and the effective stimulating sites of antidromic activation in axon collaterals were systematically mapped. The effective stimulating sites in the </span></span></span>contralateral<span> thoracic spinal cord with expiratory neurons in the caudal ventral respiratory group (cVRG) occupied 14.4% of the total length of the thoracic spinal cord examined. The mean percentage of effective stimulating tracks per unit was 18.6 ± 4.4%. The distribution of axon collaterals of expiratory neurons in the feline thoracic spinal cord indeed resembled that reported in the upper lumbar spinal cord. We propose that a single medullary expiratory neuron exerts excitatory effects across multiple segments of the thoracic spinal cord via its collaterals.</span></span></p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139474686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-09DOI: 10.1016/j.resp.2024.104215
Kai-Jie Liang , Chia-Hsiung Cheng , Chia-Yih Liu , Shih-Chieh Hsu , Andreas von Leupoldt , Valentina Jelinčić , Pei-Ying S. Chan
Individuals with generalized anxiety disorder (GAD) have been shown to have altered neural gating of respiratory sensations (NGRS) using respiratory-related evoked potentials (RREP); however, corresponding neural oscillatory activities remain unexplored. The present study aimed to investigate altered NGRS in individuals with GAD using both time and time-frequency analysis. Nineteen individuals with GAD and 28 healthy controls were recruited. Paired inspiratory occlusions were delivered to elicit cortical neural activations measured from electroencephalography. The GAD group showed smaller N1 amplitudes to the first stimulus (S1), lower evoked gamma and larger evoked beta oscillations compared to controls. Both groups showed larger N1, P3, beta power and theta power in response to S1 compared to S2, suggesting a neural gating phenomenon. These findings suggest that N1, gamma and beta frequency oscillations may be indicators for altered respiratory sensation in GAD populations and that the N1, P3, beta and theta oscillations can reflect the neural gating of respiratory sensations.
{"title":"Neural oscillations underlying the neural gating of respiratory sensations in generalized anxiety disorder","authors":"Kai-Jie Liang , Chia-Hsiung Cheng , Chia-Yih Liu , Shih-Chieh Hsu , Andreas von Leupoldt , Valentina Jelinčić , Pei-Ying S. Chan","doi":"10.1016/j.resp.2024.104215","DOIUrl":"10.1016/j.resp.2024.104215","url":null,"abstract":"<div><p><span>Individuals with generalized anxiety disorder (GAD) have been shown to have altered neural gating of respiratory sensations (NGRS) using respiratory-related </span>evoked potentials<span> (RREP); however, corresponding neural oscillatory activities remain unexplored. The present study aimed to investigate altered NGRS in individuals with GAD using both time and time-frequency analysis. Nineteen individuals with GAD and 28 healthy controls were recruited. Paired inspiratory occlusions were delivered to elicit cortical neural activations measured from electroencephalography. The GAD group showed smaller N1 amplitudes to the first stimulus (S1), lower evoked gamma and larger evoked beta oscillations compared to controls. Both groups showed larger N1, P3, beta power and theta power in response to S1 compared to S2, suggesting a neural gating phenomenon. These findings suggest that N1, gamma and beta frequency oscillations may be indicators for altered respiratory sensation in GAD populations and that the N1, P3, beta and theta oscillations can reflect the neural gating of respiratory sensations.</span></p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139420820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-29DOI: 10.1016/j.resp.2023.104207
Nana Sato Hashizume, Yoichiro Kitajima, Ryoji Ide, Eishi Nakamura, Chikako Saiki
We examined respiratory sinus arrhythmia (RSA) and possible interaction with respiratory frequency (fR) and heart rate (HR) in spontaneously breathing, unanesthetized newborn Wistar rats (2- to 5-day-old; n = 54) and the adult rats (8-week-old; n = 34). Instantaneous heart rate (inst-HR) was calculated as the reciprocal of the inter-beat-interval. For each breath, RSA was determined as the difference between the maximum and minimum inst-HR value. The absolute RSA or RSA% (RSA per HR) were calculated as the average RSA of 10 consecutive breaths. RSA (or RSA%) in the newborn rats was significantly lower than that in the adult rats. Correlation coefficient between RSA (or RSA%) and 1/fR or HR/fR, but not HR, was significant in newborn rats, whereas only that between RSA (or RSA%) and HR was significant in adult rats. The power spectrum density of heartbeat fluctuation was detectable in both age groups. The present findings suggest that RSA exists and could be influenced by fR, rather than HR, in newborn rats.
{"title":"Respiratory sinus arrhythmia in spontaneously breathing, unanesthetized newborn and adult Wistar rats","authors":"Nana Sato Hashizume, Yoichiro Kitajima, Ryoji Ide, Eishi Nakamura, Chikako Saiki","doi":"10.1016/j.resp.2023.104207","DOIUrl":"10.1016/j.resp.2023.104207","url":null,"abstract":"<div><p>We examined respiratory sinus arrhythmia (RSA) and possible interaction with respiratory frequency (<em>f</em><sub>R</sub>) and heart rate (HR) in spontaneously breathing, unanesthetized newborn Wistar rats (2- to 5-day-old; n = 54) and the adult rats (8-week-old; n = 34). Instantaneous heart rate (<em>inst</em>-HR) was calculated as the reciprocal of the inter-beat-interval. For each breath, RSA was determined as the difference between the maximum and minimum <em>inst</em>-HR value. The absolute RSA or RSA% (RSA per HR) were calculated as the average RSA of 10 consecutive breaths. RSA (or RSA%) in the newborn rats was significantly lower than that in the adult rats. Correlation coefficient between RSA (or RSA%) and 1/<em>f</em><sub>R</sub> or HR/<em>f</em><sub>R</sub>, but not HR, was significant in newborn rats, whereas only that between RSA (or RSA%) and HR was significant in adult rats. The power spectrum density of heartbeat fluctuation was detectable in both age groups. The present findings suggest that RSA exists and could be influenced by <em>f</em><sub>R</sub>, rather than HR, in newborn rats.</p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1569904823001957/pdfft?md5=be5f9721538f1393cb872c340643dbba&pid=1-s2.0-S1569904823001957-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139069064","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-21DOI: 10.1016/j.resp.2023.104205
Giovanni Tagliabue , Michael Ji , Danny J. Zuege , Paul A. Easton
Background
There is increasing clinical interest in understanding the contribution of the diaphragm in early expiration, especially during mechanical ventilation. However, current experimental evidence is limited, so essential activity of the diaphragm during expiration and diaphragm segmental differences in expiratory activity, are unknown.
Objectives
To determine if: 1) the diaphragm is normally active into expiration during spontaneous breathing and hypercapnic ventilation, 2) expiratory diaphragmatic activity is distributed equally among the segments of the diaphragm, costal and crural.
Methods
In 30 spontaneously breathing male and female canines, awake without confounding anesthetic, we measured directly both inspiratory and expiratory electrical activity (EMG), and corresponding mechanical shortening, of costal and crural diaphragm, during room air and hypercapnia.
Results
During eupnea, costal and crural diaphragm are active into expiration, showing significant and distinct expiratory activity, with crural expiratory activity greater than costal, for both magnitude and duration. This diaphragm segmental difference diverged further during progressive hypercapnic ventilation: crural expiratory activity progressively increased, while costal expiratory activity disappeared.
Conclusion
The diaphragm is not passive during expiration. During spontaneous breathing, expiratory activity -“braking”- of the diaphragm is expressed routinely, but is not equally distributed. Crural muscle “braking” is greater than costal muscle in magnitude and duration.
With increasing ventilation during hypercapnia, expiratory activity -“braking”- diverges notably. Crural expiratory activity greatly increases, while costal expiratory “braking” decreases in magnitude and duration, and disappears.
Thus, diaphragm expiratory "braking" action represents an inherent, physiological function of the diaphragm, distinct for each segment, expressing differing neural activation.
{"title":"Divergent expiratory braking activity of costal and crural diaphragm","authors":"Giovanni Tagliabue , Michael Ji , Danny J. Zuege , Paul A. Easton","doi":"10.1016/j.resp.2023.104205","DOIUrl":"10.1016/j.resp.2023.104205","url":null,"abstract":"<div><h3>Background</h3><p>There is increasing clinical interest in understanding the contribution of the diaphragm in early expiration, especially during mechanical ventilation. However, current experimental evidence is limited, so essential activity of the diaphragm during expiration and diaphragm segmental differences in expiratory activity, are unknown.</p></div><div><h3>Objectives</h3><p>To determine if: 1) the diaphragm is normally active into expiration during spontaneous breathing and hypercapnic ventilation, 2) expiratory diaphragmatic activity is distributed equally among the segments of the diaphragm, costal and crural.</p></div><div><h3>Methods</h3><p>In 30 spontaneously breathing male and female canines, awake without confounding anesthetic, we measured directly both inspiratory and expiratory electrical activity (EMG), and corresponding mechanical shortening, of costal and crural diaphragm, during room air and hypercapnia.</p></div><div><h3>Results</h3><p>During eupnea, costal and crural diaphragm are active into expiration, showing significant and distinct expiratory activity, with crural expiratory activity greater than costal, for both magnitude and duration. This diaphragm segmental difference diverged further during progressive hypercapnic ventilation: crural expiratory activity progressively increased, while costal expiratory activity disappeared.</p></div><div><h3>Conclusion</h3><p>The diaphragm is not passive during expiration. During spontaneous breathing, expiratory activity -“braking”- of the diaphragm is expressed routinely, but is not equally distributed. Crural muscle “braking” is greater than costal muscle in magnitude and duration.</p><p>With increasing ventilation during hypercapnia, expiratory activity -“braking”- diverges notably. Crural expiratory activity greatly increases, while costal expiratory “braking” decreases in magnitude and duration, and disappears.</p><p>Thus, diaphragm expiratory \"braking\" action represents an inherent, physiological function of the diaphragm, distinct for each segment, expressing differing neural activation.</p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138885983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-21DOI: 10.1016/j.resp.2023.104206
Rachael Herlihy , Leonardo Frasson Dos Reis , Anzor Gvritishvili , Maya Kvizhinadze , Elizabeth Dybas , Atul Malhotra , Victor B. Fenik , Irma Rukhadze
The state-dependent noradrenergic activation of hypoglossal motoneurons plays an important role in the maintenance of upper airway patency and pathophysiology of obstructive sleep apnea (OSA). Chronic intermittent hypoxia (CIH), a major pathogenic factor of OSA, contributes to the risk for developing neurodegenerative disorders in OSA patients. Using anterograde tracer, channelrhodopsin-2, we mapped axonal projections from noradrenergic A7 and SubCoeruleus neurons to hypoglossal nucleus in DBH-cre mice and assessed the effect of CIH on these projections. We found that CIH significantly reduced the number of axonal projections from SubCoeruleus neurons to both dorsal (by 68%) and to ventral (by73%) subregions of the hypoglossal motor nucleus compared to sham-treated animals. The animals’ body weight was also negatively affected by CIH. Both effects, the decrease in axonal projections and body weight, were more pronounced in male than female mice, which was likely caused by less sensitivity of female mice to CIH as compared to males. The A7 neurons appeared to have limited projections to the hypoglossal nucleus. Our findings suggest that CIH-induced reduction of noradrenergic innervation of hypoglossal motoneurons may exacerbate progression of OSA, especially in men.
在维持上气道通畅和阻塞性睡眠呼吸暂停(OSA)的病理生理过程中,下舌运动神经元的状态依赖性去甲肾上腺素能激活起着重要作用。慢性间歇性缺氧(CIH)是 OSA 的主要致病因素,也是导致 OSA 患者罹患神经退行性疾病的风险因素之一。我们利用前向性示踪剂channelrhodopsin-2绘制了DBH-cre小鼠去甲肾上腺素能A7和小叶下神经元到舌下核的轴突投射图,并评估了CIH对这些投射的影响。我们发现,与假治疗动物相比,CIH 明显降低了从小叶下神经元向舌下运动核背侧(68%)和腹侧(73%)亚区的轴突投射数量。动物的体重也受到 CIH 的负面影响。雄性小鼠比雌性小鼠的轴突投射和体重下降更为明显,这可能是因为雌性小鼠对CIH的敏感性低于雄性小鼠。A7神经元对舌下核的投射似乎有限。我们的研究结果表明,CIH 引起的舌下运动神经元去甲肾上腺素能神经支配的减少可能会加剧 OSA 的恶化,尤其是对男性而言。
{"title":"Chronic intermittent hypoxia attenuates noradrenergic innervation of hypoglossal motor nucleus","authors":"Rachael Herlihy , Leonardo Frasson Dos Reis , Anzor Gvritishvili , Maya Kvizhinadze , Elizabeth Dybas , Atul Malhotra , Victor B. Fenik , Irma Rukhadze","doi":"10.1016/j.resp.2023.104206","DOIUrl":"10.1016/j.resp.2023.104206","url":null,"abstract":"<div><p><span>The state-dependent noradrenergic activation of hypoglossal motoneurons<span> plays an important role in the maintenance of upper airway patency<span><span> and pathophysiology of </span>obstructive sleep apnea<span> (OSA). Chronic intermittent hypoxia (CIH), a major pathogenic factor of OSA, contributes to the risk for developing </span></span></span></span>neurodegenerative disorders<span><span> in OSA patients. Using anterograde tracer, channelrhodopsin-2, we mapped axonal projections from noradrenergic A7 and SubCoeruleus neurons to </span>hypoglossal nucleus<span> in DBH-cre mice and assessed the effect of CIH on these projections. We found that CIH significantly reduced the number of axonal projections from SubCoeruleus neurons to both dorsal (by 68%) and to ventral (by73%) subregions of the hypoglossal motor nucleus compared to sham-treated animals. The animals’ body weight was also negatively affected by CIH. Both effects, the decrease in axonal projections and body weight, were more pronounced in male than female mice, which was likely caused by less sensitivity of female mice to CIH as compared to males. The A7 neurons appeared to have limited projections to the hypoglossal nucleus. Our findings suggest that CIH-induced reduction of noradrenergic innervation of hypoglossal motoneurons may exacerbate progression of OSA, especially in men.</span></span></p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139025467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-19DOI: 10.1016/j.resp.2023.104204
Xinyun Jia , Jianxia Sun , Qingya Zhuo , Baosheng Zhao , Yuzhen Liu
Background
Chronic intermittent hypoxia (CIH) increases the hypoxic ventilation response (HVR). The downstream cytokine IL-1β of the NLRP3 inflammasome regulates respiration by acting on the carotid body (CB) and neurons in the respiratory center, but the effect of the NLRP3 inflammasome on HVR induced by CIH remains unclear.
Objective
To investigate the effect of NLRP3 on the increased HVR and spontaneous apnea events and duration induced by CIH, the expression and localization of NLRP3 in the respiratory regulatory center of the rostral ventrolateral medulla (RVLM), and the effect of CIH on the activation of the NLRP3 inflammasome in the RVLM.
Methods
Eighteen male, 7-week-old C57BL/6 N mice and eighteen male, 7-week-old C57BL/6 N NLRP3 knockout mice were randomly divided into CON-WT, CON-NLRP3-/-, CIH-WT and CIH-NLRP3-/- groups. Respiratory changes in mice were continuously detected using whole-body plethysmography. The expression and localization of the NLRP3 protein and the formation of apoptosis-associated speck-like protein containing CARD (ASC) specks were detected using immunofluorescence staining.
Results
NLRP3 knockout reduced the increased HVR and the incidence and duration of spontaneous apnea events associated with CIH. The increase in HVR caused by CIH partially recovered after reoxygenation. After CIH, NLRP3 inflammasome activation in the RVLM, which is related to respiratory regulation after hypoxia, increased, which was consistent with the trend of the ventilation response.
Conclusion
The NLRP3 inflammasome may be involved in the increase in the HVR and the incidence and duration of spontaneous apnea induced by CIH. NLRP3 inhibitors may help reduce the increase in the HVR after CIH, which is important for ensuring sleep quality at night in patients with obstructive sleep apnea.
背景 慢性间歇性缺氧(CIH)会增加缺氧通气反应(HVR)。NLRP3 炎性体的下游细胞因子 IL-1β 通过作用于颈动脉体(CB)和呼吸中枢的神经元来调节呼吸,但 NLRP3 炎性体对 CIH 诱导的 HVR 的影响仍不清楚。目的 研究NLRP3对CIH诱导的HVR增加和自发性呼吸暂停事件及持续时间的影响、NLRP3在喙腹外侧延髓(RVLM)呼吸调节中枢的表达和定位以及CIH对RVLM中NLRP3炎性体激活的影响。方法将18只7周大的雄性C57BL/6 N小鼠和18只7周大的雄性C57BL/6 N NLRP3基因敲除小鼠随机分为CON-WT组、CON-NLRP3-/-组、CIH-WT组和CIH-NLRP3-/-组。小鼠的呼吸变化通过全身胸透进行连续检测。结果NLRP3基因敲除降低了与CIH相关的HVR升高以及自发性呼吸暂停事件的发生率和持续时间。CIH 导致的 HVR 增加在复氧后部分恢复。结论 NLRP3 炎性体可能与 CIH 引起的 HVR 增加、自发性呼吸暂停的发生率和持续时间有关。NLRP3 抑制剂可能有助于减少 CIH 后 HVR 的增加,这对确保阻塞性睡眠呼吸暂停患者的夜间睡眠质量非常重要。
{"title":"Effect of the NLRP3 inflammasome on increased hypoxic ventilation response after CIH exposure in mice","authors":"Xinyun Jia , Jianxia Sun , Qingya Zhuo , Baosheng Zhao , Yuzhen Liu","doi":"10.1016/j.resp.2023.104204","DOIUrl":"10.1016/j.resp.2023.104204","url":null,"abstract":"<div><h3>Background</h3><p><span>Chronic intermittent hypoxia<span> (CIH) increases the hypoxic ventilation response (HVR). The downstream cytokine IL-1β of the NLRP3 inflammasome regulates respiration by acting on the </span></span>carotid body<span> (CB) and neurons in the respiratory center, but the effect of the NLRP3 inflammasome on HVR induced by CIH remains unclear.</span></p></div><div><h3>Objective</h3><p>To investigate the effect of NLRP3 on the increased HVR and spontaneous apnea events and duration induced by CIH, the expression and localization of NLRP3 in the respiratory regulatory center of the rostral ventrolateral medulla (RVLM), and the effect of CIH on the activation of the NLRP3 inflammasome in the RVLM.</p></div><div><h3>Methods</h3><p><span>Eighteen male, 7-week-old C57BL/6 N mice and eighteen male, 7-week-old C57BL/6 N NLRP3 knockout mice were randomly divided into CON-WT, CON-NLRP3</span><sup>-/-</sup>, CIH-WT and CIH-NLRP3<sup>-/-</sup><span><span> groups. Respiratory changes in mice were continuously detected using whole-body plethysmography. The expression and localization of the NLRP3 protein and the formation of apoptosis-associated speck-like protein containing CARD (ASC) specks were detected using immunofluorescence </span>staining.</span></p></div><div><h3>Results</h3><p><span>NLRP3 knockout reduced the increased HVR and the incidence and duration of spontaneous apnea events associated with CIH. The increase in HVR caused by CIH partially recovered after reoxygenation. After CIH, NLRP3 inflammasome activation in the RVLM, which is related to </span>respiratory regulation after hypoxia, increased, which was consistent with the trend of the ventilation response.</p></div><div><h3>Conclusion</h3><p>The NLRP3 inflammasome may be involved in the increase in the HVR and the incidence and duration of spontaneous apnea induced by CIH. NLRP3 inhibitors may help reduce the increase in the HVR after CIH, which is important for ensuring sleep quality at night in patients<span> with obstructive sleep apnea.</span></p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138745075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-14DOI: 10.1016/j.resp.2023.104203
Xuxin Chen , Fan Wang , Jian Tang , Jiguang Meng, Zhihai Han
Background
Acute lung injury (ALI) involves severe lung damage and respiratory failure, which are accompanied by alveolar macrophage (AM) activation. The aim of this article is to verify the influence of paralemmin-3 (PALM3) on alveolar macrophage (AM) polarization in ALI and the underlying mechanism of action.
Methods
An ALI rat model was established by successive lipopolysaccharide (LPS) inhalations. The influence of PALM3 on the survival rate, severity of lung injury, and macrophage polarization was analyzed. Furthermore, we explored the underlying mechanism of PALM3 in regulating macrophage polarization.
Results
PALM3 overexpression increased mortality of ALI rats, augmented lung pathological damage, and promoted AM polarization toward M1 cells. Conversely, PALM3 knockdown had the opposite effects. Mechanistically, PALM3 might promote M1 polarization by acting as an adaptor to facilitate transduction of Notch signaling.
Conclusion
PALM3 aggravates lung injury and induces macrophage polarization toward M1 cells by activating the Notch signaling pathway in LPS-induced ALI, which may shed light on ALI/ARDS treatments.
背景急性肺损伤(ALI)包括严重的肺损伤和呼吸衰竭,并伴随着肺泡巨噬细胞(AM)的活化。方法通过连续吸入脂多糖(LPS)建立 ALI 大鼠模型。分析了 PALM3 对大鼠存活率、肺损伤严重程度和巨噬细胞极化的影响。结果PALM3过表达会增加ALI大鼠的死亡率,加重肺部病理损伤,并促进AM向M1细胞极化。相反,PALM3 基因敲除则会产生相反的效果。结论在LPS诱导的ALI中,PALM3通过激活Notch信号通路加重肺损伤并诱导巨噬细胞向M1细胞极化,这可能对ALI/ARDS的治疗有所启示。
{"title":"Paralemmin-3 augments lipopolysaccharide-induced acute lung injury with M1 macrophage polarization via the notch signaling pathway","authors":"Xuxin Chen , Fan Wang , Jian Tang , Jiguang Meng, Zhihai Han","doi":"10.1016/j.resp.2023.104203","DOIUrl":"https://doi.org/10.1016/j.resp.2023.104203","url":null,"abstract":"<div><h3>Background</h3><p>Acute lung injury (ALI) involves severe lung damage and respiratory failure, which are accompanied by alveolar macrophage (AM) activation. The aim of this article is to verify the influence of paralemmin-3 (PALM3) on alveolar macrophage (AM) polarization in ALI and the underlying mechanism of action.</p></div><div><h3>Methods</h3><p>An ALI rat model was established by successive lipopolysaccharide (LPS) inhalations. The influence of PALM3 on the survival rate, severity of lung injury, and macrophage polarization was analyzed. Furthermore, we explored the underlying mechanism of PALM3 in regulating macrophage polarization.</p></div><div><h3>Results</h3><p>PALM3 overexpression increased mortality of ALI rats, augmented lung pathological damage, and promoted AM polarization toward M1 cells. Conversely, PALM3 knockdown had the opposite effects. Mechanistically, PALM3 might promote M1 polarization by acting as an adaptor to facilitate transduction of Notch signaling.</p></div><div><h3>Conclusion</h3><p>PALM3 aggravates lung injury and induces macrophage polarization toward M1 cells by activating the Notch signaling pathway in LPS-induced ALI, which may shed light on ALI/ARDS treatments.</p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S156990482300191X/pdfft?md5=116d5dd81d3a59b0c50605f74dbb0cea&pid=1-s2.0-S156990482300191X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138769764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-02DOI: 10.1016/j.resp.2023.104202
Rishi R. Dhingra , Werner I. Furuya , Yi Kee Yoong , Mathias Dutschmann
The mammalian three-phase respiratory motor pattern of inspiration, post-inspiration and expiration is expressed in spinal and cranial motor nerve discharge and is generated by a distributed ponto-medullary respiratory pattern generating network. Respiratory motor pattern generation depends on a rhythmogenic kernel located within the pre-Bötzinger complex (pre-BötC). In the present study, we tested the effect of unilateral and bilateral inactivation of the pre-BötC after local microinjection of the GABAA receptor agonist isoguvacine (10 mM, 50 nl) on phrenic (PNA), hypoglossal (HNA) and vagal nerve (VNA) respiratory motor activities in an in situ perfused brainstem preparation of rats. Bilateral inactivation of the pre-BötC triggered cessation of phrenic (PNA), hypoglossal (HNA) and vagal (VNA) nerve activities for 15–20 min. Ipsilateral isoguvacine injections into the pre-BötC triggered transient (6–8 min) cessation of inspiratory and post-inspiratory VNA (p < 0.001) and suppressed inspiratory HNA by − 70 ± 15% (p < 0.01), while inspiratory PNA burst frequency increased by 46 ± 30% (p < 0.01). Taken together, these observations confirm the role of the pre-BötC as the rhythmogenic kernel of the mammalian respiratory network in situ and highlight a significant role for the pre-BötC in the transmission of vagal inspiratory and post-inspiratory pre-motor drive to the nucleus ambiguus.
{"title":"The pre-Bötzinger complex is necessary for the expression of inspiratory and post-inspiratory motor discharge of the vagus","authors":"Rishi R. Dhingra , Werner I. Furuya , Yi Kee Yoong , Mathias Dutschmann","doi":"10.1016/j.resp.2023.104202","DOIUrl":"10.1016/j.resp.2023.104202","url":null,"abstract":"<div><p><span>The mammalian three-phase respiratory motor pattern of inspiration, post-inspiration and expiration is expressed in spinal and cranial motor nerve discharge and is generated by a distributed ponto-medullary respiratory pattern<span> generating network. Respiratory motor pattern generation depends on a rhythmogenic kernel located within the pre-Bötzinger complex (pre-BötC). In the present study, we tested the effect of unilateral and bilateral inactivation of the pre-BötC after local microinjection of the GABA</span></span><sub>A</sub><span><span> receptor agonist isoguvacine<span> (10 mM, 50 nl) on phrenic (PNA), hypoglossal (HNA) and vagal nerve (VNA) respiratory motor activities in an in situ perfused brainstem preparation of rats. Bilateral inactivation of the pre-BötC triggered cessation of phrenic (PNA), hypoglossal (HNA) and vagal (VNA) </span></span>nerve activities<span> for 15–20 min. Ipsilateral isoguvacine injections into the pre-BötC triggered transient (6–8 min) cessation of inspiratory and post-inspiratory VNA (p < 0.001) and suppressed inspiratory HNA by − 70 ± 15% (p < 0.01), while inspiratory PNA burst frequency increased by 46 ± 30% (p < 0.01). Taken together, these observations confirm the role of the pre-BötC as the rhythmogenic kernel of the mammalian respiratory network in situ and highlight a significant role for the pre-BötC in the transmission of vagal inspiratory and post-inspiratory pre-motor drive to the nucleus ambiguus.</span></span></p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138482911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-01DOI: 10.1016/j.resp.2023.104201
Luiz M. Oliveira , Thiago S. Moreira , Ana C. Takakura
Respiration is regulated by various types of neurons located in the pontine-medullary regions. The Kölliker-Fuse (KF)/A7 noradrenergic neurons play a role in modulating the inspiratory cycle by influencing the respiratory output. These neurons are interconnected and may also project to brainstem and spinal cord, potentially involved in regulating the post-inspiratory phase. In the present study, we hypothesize that the parafacial (pF) neurons, in conjunction with adrenergic mechanisms originating from the KF/A7 region, may provide the neurophysiological basis for breathing modulation. We conducted experiments using urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats. Injection of L-glutamate into the KF/A7 region resulted in inhibition of inspiratory activity, and a prolonged and high-amplitude genioglossal activity (GGEMG). Blockade of the α1 adrenergic receptors (α1-AR) or the ionotropic glutamatergic receptors in the pF region decrease the activity of the GGEMG without affecting inspiratory cessation. In contrast, blockade of α2-AR in the pF region extended the duration of GG activity. Notably, the inspiratory and GGEMG activities induced by KF/A7 stimulation were completely blocked by bilateral blockade of glutamatergic receptors in the Bötzinger complex (BötC). While our study found a limited role for α1 and α2 adrenergic receptors at the pF level in modulating the breathing response to KF/A7 stimulation, it became evident that BötC neurons are responsible for the respiratory effects induced by KF/A7 stimulation.
{"title":"Interaction between Kölliker-Fuse/A7 and the parafacial respiratory region on the control of respiratory regulation","authors":"Luiz M. Oliveira , Thiago S. Moreira , Ana C. Takakura","doi":"10.1016/j.resp.2023.104201","DOIUrl":"10.1016/j.resp.2023.104201","url":null,"abstract":"<div><p><span>Respiration is regulated by various types of neurons located in the pontine-medullary regions. The Kölliker-Fuse (KF)/A7 noradrenergic neurons play a role in modulating the inspiratory cycle by influencing the respiratory output. These neurons are interconnected and may also project to brainstem<span> and spinal cord, potentially involved in regulating the post-inspiratory phase. In the present study, we hypothesize that the parafacial (pF) neurons, in conjunction with adrenergic mechanisms originating from the KF/A7 region, may provide the neurophysiological basis for breathing modulation. We conducted experiments using urethane-anesthetized, vagotomized, and artificially ventilated male Wistar rats. Injection of L-glutamate into the KF/A7 region resulted in inhibition of inspiratory activity, and a prolonged and high-amplitude genioglossal activity (GG</span></span><sub>EMG</sub>). Blockade of the α<sub>1</sub><span> adrenergic receptors (α</span><sub>1</sub><span>-AR) or the ionotropic glutamatergic receptors in the pF region decrease the activity of the GG</span><sub>EMG</sub> without affecting inspiratory cessation. In contrast, blockade of α<sub>2</sub>-AR in the pF region extended the duration of GG activity. Notably, the inspiratory and GG<sub>EMG</sub> activities induced by KF/A7 stimulation were completely blocked by bilateral blockade of glutamatergic receptors in the Bötzinger complex (BötC). While our study found a limited role for α<sub>1</sub> and α<sub>2</sub><span> adrenergic receptors at the pF level in modulating the breathing response to KF/A7 stimulation, it became evident that BötC neurons are responsible for the respiratory effects induced by KF/A7 stimulation.</span></p></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}