Respiratory Physiology & Neurobiology最新文献_第2页

Dynamics analysis of neonatal CPAP devices neopuff and inspire rPAP: Investigating pressure stability and work of breathing in anatomically realistic airway models 新生儿CPAP装置的动力学分析：在解剖真实的气道模型中研究压力稳定性和呼吸功

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-04-01 Epub Date: 2025-12-22 DOI: 10.1016/j.resp.2025.104530

M. Berger , E. Leusmann , T. Senfter , A.-S. Käferböck , M. Wald , M. Pillei

Continuous positive airway pressure (CPAP) technology is crucial in the initial respiratory support of newborns with insufficient spontaneous breathing. Although two neonatal CPAP systems, the Neopuff T-piece and the Inspire rPAP, use constant flow technology, clinical observations reveal significant differences in pressure stability during ventilation of newborn children. The Neopuff T-piece device exhibits stronger pressure fluctuations compared to the Inspire rPAP, which maintains more stable airway pressures. This study investigates the root causes of these instabilities using computational fluid dynamics (CFD) simulations in anatomically realistic neonatal airway models, focusing on how device geometry and flow behavior influence pressure stability and imposed work of breathing (iWOB). Digital models of the devices were created using CAD software, and neonatal airway geometries were segmented from MRI data. Steady-state 3D CFD simulations, employing the k-ω-SST turbulence model, were conducted for three respiratory scenarios: resting, inhalation, and exhalation. Both CPAP devices were simulated under identical boundary conditions for direct comparison. The Inspire rPAP demonstrated higher static pressures, flow velocities, and turbulent kinetic energy (TKE) but maintained superior pressure stability, with fluctuations limited to 6.28 %, compared to 46.12 % for the Neopuff. The Neopuff’s T-piece geometry generated vortices and flow resistance, particularly during exhalation, increasing iWOB. In contrast, the Inspire rPAP’s narrower, multi-channel design effectively shielded the patient interface from high-energy flows, reducing interaction with expiratory streams. These findings highlight the critical role of internal flow-guiding geometry in pressure regulation and iWOB. The study underscores the value of CFD modeling in optimizing neonatal CPAP systems to improve respiratory support and reduce the burden on preterm infants.

持续气道正压通气（CPAP）技术在新生儿自主呼吸不足的初始呼吸支持中至关重要。尽管两种新生儿CPAP系统（Neopuff T-piece和Inspire rPAP）采用恒流量技术，但临床观察显示新生儿通气时压力稳定性存在显著差异。与Inspire rPAP相比，Neopuff t型装置表现出更强的压力波动，后者保持更稳定的气道压力。本研究利用计算流体动力学（CFD）模拟解剖学上真实的新生儿气道模型，探讨了这些不稳定性的根本原因，重点研究了设备的几何形状和流动行为如何影响压力稳定性和呼吸功（iWOB）。使用CAD软件创建设备的数字模型，并从MRI数据中分割新生儿气道几何形状。采用k-ω-SST湍流模型，对静息、吸气和呼气三种呼吸情景进行了稳态三维CFD模拟。两种CPAP装置在相同的边界条件下进行模拟，以进行直接比较。Inspire rPAP显示出更高的静压力、流速和湍流动能（TKE），但保持了出色的压力稳定性，其波动限制在6.28 %，而Neopuff的波动限制在46.12 %。Neopuff的t型几何结构产生了涡流和流动阻力，特别是在呼气时，提高了iWOB。相比之下，Inspire rPAP更窄的多通道设计有效地保护了患者界面免受高能气流的影响，减少了与呼气气流的相互作用。这些发现强调了内部导流几何结构在压力调节和iWOB中的关键作用。该研究强调了CFD建模在优化新生儿CPAP系统以改善呼吸支持和减轻早产儿负担方面的价值。

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引用次数: 0

Metabolism and respiration in skin burn injury in rats: Corrective effects of melatonin 大鼠皮肤烧伤的代谢和呼吸：褪黑素的纠正作用。

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-04-01 Epub Date: 2025-12-22 DOI: 10.1016/j.resp.2025.104531

Volodymyr Portnichenko , Roman Yanko , Petro Tsapenko , Mikhail Levashov , Iryna Litovka , Mykola Zavhorodnii , Mieczyslaw Pokorski

Burn disease, which is a sequel of skin burn injuries, is a common cause of complications and the development of associated pathologies. This study aimed to assess the effects of burn disease on the lungs and their correction with melatonin. We used a standard skin 14-day burn model in Wistar rats. During burn progression, phase changes in metabolism were noted from a hypometabolic phase in the first 4 days to a hypermetabolic phase starting on Day 5. By Day 14, the energy metabolism had normalized to the control level. In experimental melatonin burn treatment, a hypermetabolic response was noted during the first 3 days. By Day 10, the ventilatory response decreased below the baseline level, and by Day 14, it did not significantly differ from that in the control group. Morphological changes in the lungs of rats with burn injuries were characterized by structural alterations, such as reduced functional activity, decreased air permeability, and suppression of gas exchange processes. In rats receiving melatonin alongside burn injury, most morphological lung indicators remained at control levels. We conclude that melatonin treatment accelerates healing and reduces complications associated with burn injuries.

烧伤疾病是皮肤烧伤的后遗症，是并发症和相关病理发展的常见原因。本研究旨在评估烧伤疾病对肺部的影响以及褪黑素对其的纠正。我们采用Wistar大鼠14天标准皮肤烧伤模型。在烧伤进展过程中，代谢的阶段变化从最初4天的低代谢阶段到第5天开始的高代谢阶段。到第14天，能量代谢恢复到正常水平。在实验性褪黑素烧伤治疗中，前3天出现了高代谢反应。到第10天，通气反应下降到基线水平以下，到第14天，与对照组相比没有显著差异。烧伤大鼠肺的形态学变化表现为结构改变，如功能活性降低、透气性降低和气体交换过程抑制。在烧伤同时接受褪黑素的大鼠中，大多数形态学指标保持在控制水平。我们得出结论，褪黑素治疗加速愈合和减少并发症相关的烧伤。

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引用次数: 0

Developmental nicotine exposure eliminates the ventilatory response to a brief episode of severe hypoxia, independently of sex 发育性尼古丁暴露消除了短暂严重缺氧发作的通气反应，与性别无关。

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-04-01 Epub Date: 2025-12-17 DOI: 10.1016/j.resp.2025.104529

Michael L. Frazure , Emily G. Flanigan , Ralph F. Fregosi

We tested the hypothesis that developmental nicotine exposure (DNE) disrupts the cardiorespiratory response to brief, severe hypoxia by measuring ventilatory and heart rate during a 15 s epoch of N₂ breathing in one-to-six-day-old Sprague Dawley rat pups. Data were analyzed with a 3-way ANOVA, with inspired O₂ concentration, treatment group and sex the main factors. As expected, N₂ breathing significantly increased the inspired pulmonary ventilation rate (

\dot{V}

) in control pups of both sexes, driven by an increase of tidal volume. In contrast, neither male nor female DNE pups increased

\dot{V}

during the N₂ challenge. There was no effect of hypoxia on heart rate in any group. These findings reveal a selective vulnerability: DNE specifically compromises the respiratory system’s ability to increase ventilation in response to brief severe hypoxia. This dissociation between ventilatory and heart rate responses to severe hypoxia provides fresh insight into the impact of DNE on cardiorespiratory function during a critical developmental stage.

我们通过测量1 - 6天大的Sprague Dawley幼鼠15秒N2呼吸期的通气率和心率，验证了发育性尼古丁暴露（DNE）会破坏心肺对短暂严重缺氧的反应这一假设。数据采用3-way方差分析，主要影响因素为吸入氧浓度、治疗组和性别。正如预期的那样，在潮气量增加的驱动下，N2呼吸显著提高了雌雄对照幼崽的吸气肺通气量(V)。相比之下，雄性和雌性DNE幼崽在N2刺激期间都没有增加V值。各组均无缺氧对心率的影响。这些发现揭示了一种选择性的脆弱性：DNE特别损害了呼吸系统增加通气的能力，以应对短暂的严重缺氧。这种严重缺氧时通气和心率反应之间的分离为DNE在关键发育阶段对心肺功能的影响提供了新的见解。

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引用次数: 0

Neurophysiologic tongue protrusion characteristics$ in obstructive sleep apnea: A comparative study 阻塞性睡眠呼吸暂停患者舌突神经生理特征的比较研究。

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-04-01 Epub Date: 2026-01-13 DOI: 10.1016/j.resp.2026.104544

Ron Oliven , Arie Oliven , Mostafa Somri , Emilia Hardak , Naveh Tov

The essential role of upper airway muscles in maintaining patency has led to the hypothesis that alterations in tongue muscle properties may contribute to the development of obstructive sleep apnea (OSA). Prior studies comparing the mechanical characteristics of tongue muscles in OSA patients and healthy controls have yielded inconsistent results. In this study, we evaluated tongue muscle mechanics using an objective, non-volitional method: surface electrical stimulation of the genioglossus (GG) muscle. Tongue protrusion force, whether generated volitionally or by electrical stimulation, was significantly lower in OSA patients. Stimulated force was consistently lower than volitional force across all participants; however, the two measures were strongly correlated (r = 0.62, p < 0.001). Tongue muscle fatigability in OSA patients did not differ significantly from controls during volitional testing or low-frequency stimulation but was increased during high-frequency stimulation. Twitch contraction and half-relaxation times, as well as high-to-low frequency force curves, were comparable between OSA and control subjects. These findings indicate that although tongue muscle fiber composition appears similar in OSA and control groups, maximal tongue protrusion force is reduced in OSA. Given the inconsistent results of prior studies, we suggest that the methodology of force assessment may be critical: different testing modes likely recruit distinct patterns of tongue muscle coordination and may uncover coordination deficits in OSA. Furthermore, the increased fatigability observed during high-frequency stimulation is consistent with the presence of tongue muscle neuropathy in this population.

上气道肌肉在维持气道通畅方面的重要作用使得舌肌特性的改变可能导致阻塞性睡眠呼吸暂停（OSA）的发生。先前的研究比较了OSA患者和健康对照者舌肌的力学特性，结果并不一致。在这项研究中，我们评估舌肌力学使用客观的，非意志的方法：颏舌肌（GG）的表面电刺激。在OSA患者中，无论是自愿还是电刺激产生的舌突力都明显降低。在所有参与者中，受刺激的力量始终低于意志力量；然而，这两种测量结果是强相关的（r = 0.62, p < 0.001）。在意志测试或低频刺激时，OSA患者的舌肌疲劳与对照组无显著差异，但在高频刺激时，舌肌疲劳有所增加。抽搐收缩和半松弛时间以及高低频力曲线在OSA和对照组之间具有可比性。这些发现表明，尽管OSA组和对照组的舌肌纤维组成相似，但OSA组的最大舌突力有所降低。鉴于之前的研究结果不一致，我们认为力评估的方法可能是至关重要的：不同的测试模式可能会招募不同的舌肌协调模式，并可能发现OSA的协调缺陷。此外，在高频刺激期间观察到的疲劳增加与该人群中舌肌神经病变的存在是一致的。

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引用次数: 0

Diethelm Richter (1943-2025); a life in Respiratory Neurobiology. Diethelm Richter (1943-2025)；呼吸神经生物学的生活。

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-02-21 DOI: 10.1016/j.resp.2026.104560

K Michael Spyer, Julian F R Paton

引用次数: 0

Description of automatic-voluntary dissociation of breathing in multiple sclerosis 多发性硬化症患者呼吸自动-自主分离的描述。

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-02-01 Epub Date: 2025-11-20 DOI: 10.1016/j.resp.2025.104523

Alicia Garcia Alvarez , Djamel Bensmail , Caroline Hélie , Manon Tamiatto , Isabelle Bossard , Jonathan Levy , Hélène Prigent

Background

Respiratory dysfunction in people with multiple sclerosis (PwMS) is often attributed to respiratory pump failure, yet central respiratory drive and automatic breathing control remain underexplored. We assessed the prevalence of breathing automatic-voluntary dissociation (AVD) in PwMS.

Methods

We analyzed prospectively collected data from a tertiary care rehabilitation center observational cohort. All adult PwMS, who underwent pulmonary function testing, including a CO₂ ventilatory response test, while relapse-free for ≥ 3 months, between January 2018 and December 2024 were screened. AVD was defined by maximal tidal volume (VTmax) during CO₂ response test higher than vital capacity (VC)(VTmax/VC>1), reflecting discordance between voluntary and automatic respiratory response. Univariate analysis and multivariate logistic regression were performed to identify variables associated with AVD.

Results

Fifty-five PwMS were included (age 59 ±7 years, disease duration 23 ± 11 years, women 64 %, median EDSS 8[7,5;8,5]). Restrictive ventilatory pattern was observed in 65 %, 32 % being severely impaired, and with cough impairment in 64 %. Eighteen (33 %) presented AVD. It was associated with significantly lower VC, inspiratory capacity, peak cough flow (p < 0.001), higher EDSS scores and greater use of respiratory support devices (CPAP/NIV, p = 0.002; mechanical in-exsufflation, p = 0.002).

Conclusion

Breathing AVD is frequent in PwMs with severe disease, underscoring the relevance of thorough respiratory assessment to individualize respiratory care.

背景：多发性硬化症（PwMS）患者的呼吸功能障碍通常归因于呼吸泵衰竭，但对中枢呼吸驱动和自动呼吸控制的研究尚不充分。我们评估了呼吸自动-自愿分离（AVD）在PwMS中的患病率。方法：我们对来自三级康复中心观察队列的前瞻性数据进行分析。筛查2018年1月至2024年12月期间接受肺功能测试（包括CO₂通气反应测试）且无复发≥3个月的所有成年PwMS。AVD的定义为CO₂反应试验时最大潮气量（VTmax）高于肺活量（VTmax/VC>1），反映自主呼吸反应与自动呼吸反应之间的不一致。采用单因素分析和多因素logistic回归来确定与AVD相关的变量。结果：纳入55例PwMS患者（年龄59岁 ±7岁，病程23±11年，女性64%，中位EDSS 8[7,5;8,5]）。65%的患者存在限制性通气模式，32%的患者存在严重通气障碍，64%的患者存在咳嗽障碍。18例（33%）出现AVD。结论：呼吸性AVD在病情严重的PwMs患者中较为常见，需要进行全面的呼吸评估以进行个性化的呼吸护理。

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引用次数: 0

Sex differences in the cardiovascular and ventilatory responses to arm or leg mechanoreflex activation 对手臂或腿部机械反射激活的心血管和通气反应的性别差异。

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-02-01 Epub Date: 2025-12-10 DOI: 10.1016/j.resp.2025.104527

T.J. Pereira , H. Edgell

The mechanoreflex mediates the initial cardiorespiratory response during dynamic exercise, via input from the mechanical deformation of the exercising muscle. In response to passive movement (PM), engaging a greater number of limbs elicits a higher heart rate response. Additionally, males have larger pressor responses to arm PM; however, no sex differences exist in the pressor response to leg PM. Considering that the legs are a larger muscle mass and the pressor response to leg PM was not different between sexes, this may suggest inherent limb-dependant differences. This study aimed to determine sex differences and the role of limb volume and muscle strength on the cardiorespiratory responses to arm and leg PM. Females were smaller (i.e., stature, limb volume), less fit and had weaker handgrip strength compared to males (all p < 0.05); although, both sexes had similar plantarflexion strength (p = 0.3). During arm PM, only males experienced an increased MAP response to arm PM (p < 0.001), compared to females (p < 0.05); however, this sex difference was eliminated when accounting for disparities in forearm volume. Males and females had similar cardiorespiratory responses to leg PM (all p > 0.05). Further, greater plantarflexion strength enhanced the ventilatory response to leg PM in both sexes (p = 0.024). Based on covariate analysis, differences in limb volume and muscle strength contributed almost half of the variability in the cardiorespiratory responses to arm or leg PM. Contrary to our hypotheses, the results of the current study suggest that the previously observed sex and limb-dependant differences were influenced by disparities in limb characteristics (i.e., volume or strength).

机械反射通过运动肌肉的机械变形输入，介导动态运动时的初始心肺反应。在被动运动（PM）的反应中，参与更多的肢体会引起更高的心率反应。此外，男性对手臂PM有更大的升压反应；然而，腿部PM的升压反应不存在性别差异。考虑到腿部的肌肉量更大，腿部PM的加压反应在性别之间没有差异，这可能表明存在固有的肢体依赖性差异。本研究旨在确定性别差异以及肢体体积和肌肉力量对手臂和腿部PM心肺反应的作用。与男性相比，女性更小（即身高、肢体体积）、更不适合、握力更弱（均p0.05）。此外，更大的跖屈强度增强了两性对腿部PM的通气反应（p=0.024）。基于协变量分析，肢体体积和肌肉力量的差异贡献了手臂或腿部PM心肺反应变异性的近一半。与我们的假设相反，目前的研究结果表明，先前观察到的性别和肢体依赖差异受到肢体特征差异（即体积或力量）的影响。

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引用次数: 0

Fixed-point spirometry biases the evaluation of posturo-respiratory coupling: A comparison with optoelectronic plethysmography 定点肺活量测定偏向于姿势-呼吸耦合的评估：与光电容积脉搏图的比较

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-02-01 Epub Date: 2025-12-11 DOI: 10.1016/j.resp.2025.104528

Rémi Valentin , Benoit Fabre , Delphine Chadefaux , Nathan Ouvrai , Thomas Similowski , Baptiste Sandoz , Valérie Attali

Posturo-respiratory coupling (PRC) reflects the interaction between breathing and postural control, and its accurate assessment is essential for understanding breathing-related balance disorders. This study investigates whether the use of a fixed-point spirometer to assess breathing profile biases PRC evaluation compared to a contactless method—optoelectronic plethysmography (OEP). Thirty healthy participants underwent two conditions in a random order: natural breathing and breathing through a spirometer. Segmental oscillations and center of pressure (CoP) displacements were recorded using contactless motion capture and force platform. Respiratory emergence (REm) and Time Lock Averaging (TLA) were used to assess the effect of breathing on the multi-segmental balance. Breathing through a spirometer significantly reduced the amplitude and velocity of segmental oscillations and CoP displacement compared to natural breathing, while breathing frequency remained unchanged. The spirometer condition induced higher incidence of neck flexion during inspiration (TLA), and altered the REm, particularly by increasing REm at the shoulder level. These findings suggest that using a fixed-point, in-contact spirometer introduces a significant bias in PRC measurements. Two mechanisms of PRC alteration are suggested: (1) due to the physical constraints associated with subject’s connection with the device; (2) of cortical origin in response to mouth breathing. In conclusion, although spirometry remains a gold standard for breathing assessment, it is unsuitable for PRC evaluation due to its disruptive influence on natural postural-respiratory dynamics. OEP, by preserving natural breathing and posture, offers a more reliable alternative for studying PRC, especially in ecological or clinical contexts such as respiratory rehabilitation or musical performance.

姿势-呼吸耦合（PRC）反映了呼吸和姿势控制之间的相互作用，其准确评估对于理解呼吸相关平衡障碍至关重要。本研究调查了使用定点肺活量计评估呼吸廓形与非接触式方法-光电容积脉搏图（OEP）相比是否存在PRC评估偏差。30名健康的参与者按随机顺序接受了两种条件：自然呼吸和通过肺活量计呼吸。采用非接触式运动捕捉和受力平台记录了关节的节段振荡和压力中心位移。采用呼吸发生（REm）和时间锁平均（TLA）评价呼吸对多节段平衡的影响。与自然呼吸相比，通过肺活计呼吸显著降低了节段振荡的幅度和速度以及CoP位移，而呼吸频率保持不变。呼吸计条件下吸气时颈部屈曲（TLA）的发生率较高，并改变REm，特别是增加肩部水平的REm。这些发现表明，使用定点接触式肺活量计在PRC测量中引入了显著的偏差。PRC改变的两种机制是：(1)由于受试者与设备连接的物理限制；(2)对口部呼吸反应的皮层起源。总之，尽管肺活量测定法仍然是呼吸评估的金标准，但由于其对自然姿势呼吸动力学的破坏性影响，它不适合用于PRC评估。OEP通过保持自然呼吸和姿势，为研究PRC提供了更可靠的选择，特别是在生态或临床背景下，如呼吸康复或音乐表演。

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引用次数: 0

Autonomic cardiac regulation to slow-paced respiration in seated and supine positions 自主心脏调节慢节奏呼吸在坐位和仰卧位。

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-02-01 Epub Date: 2025-11-07 DOI: 10.1016/j.resp.2025.104511

Florian Chouchou , Claire Fournié , Georges Dalleau , Chantal Verkindt

Purpose

Respiratory modulation and positional control are the main two regulators of cardiac autonomic activity. Although both slow-paced breathing and supine position promote parasympathetic regulation, their interaction remains poorly documented. Here, the objective of this work is to study the interaction between these two autonomic controls.

Methods

Twenty healthy volunteers (12 males, 8 females), age of 25.9 ± 3.9 years were included in this study. They were randomly subjected to 6 different slow and controlled breathing at 4.5, 5, 5.5, 6, 6.5, and 7 min/cycles for 3 min in supine or seated position after a 3 min baseline recording in spontaneous breathing. ECG was continuously monitored and RR intervals (RRI), total power (Ptot), the standard deviation of normal R–R intervals (SDNN), high frequency power (HF), the root mean square of successive R–R interval differences (RMSSD), and low frequency power (LF) were calculated to study autonomic regulation.

Results

We observed (1) a similar increase in parasympathetic (RMSSD and LF) and overall autonomic (RRI, Ptot, and SDNN) activities in slow-paced breathing conditions, whatever the respiratory rate in comparison with control spontaneous breathing; (2) these autonomic parameters increased in sitting position, but in parasympathetic (RMSSD and LF) and overall autonomic (Ptot, and SDNN) activities interacted with respiratory control and were higher in seated slow-paced breathing.

Conclusion

These results showed that (1) whatever the slow-paced breathing frequency, slow breathing favours parasympathetic control and slow heart rhythm; and (2) seated position favors autonomic cardiovascular interaction between respiratory modulation and positional control.

目的：呼吸调节和体位控制是心脏自主活动的两种主要调节机制。虽然慢节奏呼吸和仰卧位都能促进副交感神经调节，但它们之间的相互作用文献很少。在这里，这项工作的目的是研究这两个自主控制之间的相互作用。方法：选取健康志愿者20例，男12例，女8例，年龄25.9±3.9岁。在自主呼吸基线记录3分钟后，他们随机接受6种不同的缓慢和控制呼吸，分别为4.5、5、5.5、6、6.5和7min/次，仰卧或坐位，持续3分钟。连续监测心电图，计算RR间期（RRI）、总功率（ppt）、正常R-R间期标准差（SDNN）、高频功率（HF）、连续R-R间期差的均方根（RMSSD）、低频功率（LF），研究自主调节。结果：我们观察到(1)在慢节奏呼吸条件下，无论呼吸频率如何，与对照自主呼吸相比，副交感神经（RMSSD和LF）和整体自主神经（RRI， pto和SDNN）活动也有类似的增加；(2)这些自主神经参数在坐姿时增加，但副交感神经（RMSSD和LF）和整体自主神经（ppt和SDNN）活动与呼吸控制相互作用，并且在坐姿慢节奏呼吸时更高。结论：结果表明：(1)无论呼吸频率多慢，呼吸慢有利于副交感神经控制和心律减慢；(2)坐姿有利于自主心血管呼吸调节和位置控制之间的相互作用。

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引用次数: 0

AAV9 gene therapy to target respiratory insufficiency in the D2.mdx mouse model of duchenne muscular dystrophy AAV9基因治疗D2患者呼吸功能不全。mdx小鼠杜氏肌营养不良模型。

IF 1.6 4区医学 Q3 PHYSIOLOGY

Respiratory Physiology & Neurobiology

Pub Date : 2026-02-01 Epub Date: 2025-11-14 DOI: 10.1016/j.resp.2025.104513

Debolina D. Biswas , Nicolas H. Han , Marán Y. Hernández Rodríguez, Jane Lee, Sarra M. Abdelbarr, Evelyn R. Scarrow, Mai K. ElMallah

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by a deficiency of dystrophin. Dystrophin deficiency leads to progressive muscle weakness, including involvement of the respiratory muscles, ultimately resulting in respiratory failure. Adeno-associated virus (AAV)-mediated gene therapy carrying a microdystrophin (µDys) transgene was recently approved by the Food and Drug Administration (FDA); however, its effects on the respiratory system remain unclear. Further, effective transduction of all muscle groups requires high systemic AAV doses, which are associated with dose-dependent toxicities. In this study, we investigated whether respiratory-directed gene therapy can 1) specifically target respiratory muscles and (2) reduce the total AAV-µDys dose required for therapeutic benefit. We compared the efficiency of AAV9-µDys delivery using different administration routes and dosages in D2.mdx mice, a mouse model of DMD. AAV9-µDys was administered either systemically at a high dose, locally at intermediate doses via intralingual and intrathoracic injections, or through a combination of systemic and respiratory-directed intermediate dosing. All treatments resulted in improved respiratory muscle dystrophin expression and decreased pathology; however, the intermediate and combination dosing led to lower liver vector genome expression. In conclusion, respiratory-targeted gene therapy can improve respiratory muscle pathology while reducing the need for high systemic AAV doses associated with liver toxicity.

杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白缺乏引起的x连锁隐性疾病。肌营养不良蛋白缺乏会导致进行性肌肉无力，包括累及呼吸肌，最终导致呼吸衰竭。携带微营养不良蛋白（µDys）转基因的腺相关病毒（AAV）介导的基因治疗最近获得了美国食品和药物管理局（FDA）的批准；然而，它对呼吸系统的影响尚不清楚。此外，所有肌群的有效转导需要高的全身AAV剂量，这与剂量依赖性毒性有关。在这项研究中，我们研究了呼吸导向基因治疗是否可以1)特异性靶向呼吸肌，(2)减少治疗获益所需的总AAV-µDys剂量。我们比较了不同给药途径和给药剂量下AAV9-µDys在D2中的递送效率。mdx小鼠，DMD小鼠模型。AAV9-µDys采用高剂量全身性给药、舌内和胸内局部中剂量给药或全身和呼吸定向中剂量联合给药。所有治疗均改善了呼吸肌肌营养不良蛋白的表达，降低了病理水平；然而，中间剂量和联合剂量导致肝脏载体基因组表达降低。总之，呼吸靶向基因治疗可以改善呼吸肌病理，同时减少与肝毒性相关的高系统性AAV剂量的需要。

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