Respiratory Physiology & Neurobiology最新文献

{"title":"The potential role of the anterior insular cortex and interoception on dyspnea in chronic obstructive pulmonary disease","authors":"Anna L. Hudson ,&nbsp;Molly-Eve Day ,&nbsp;Marie T. Williams ,&nbsp;Olivia K. Harrison","doi":"10.1016/j.resp.2025.104441","DOIUrl":"10.1016/j.resp.2025.104441","url":null,"abstract":"<div><div>Dyspnea (the perception of breathing discomfort) can be an immensely debilitating symptom for people with chronic obstructive pulmonary disease (COPD) and is not fully reflective of physiological measures of disease severity. We propose that the anterior insular cortex (AIC) and its key role in interoception (the perception of signals from within the body) are important mediators of dyspnea symptomology. Interoception encompasses respiratory motor drive, corollary discharge, sensory afferents, central neural integration, error signal generation, gating, decision processing and behavioral adaptation. Neuroimaging evidence supports this notion as decreased AIC activity in people with COPD is associated with heightened dyspnea, and respiratory interoceptive attention tasks have been shown to increase activation in this area of the brain. Therefore, activity in the AIC within the interoceptive processing pathway may explain some of the variability in symptom burden in people living with COPD. We explore these theories in the context of the current knowledge on the physiology and neuroscience of dyspnea, drawing on the implementation of interoceptive measures in other respiratory and mental health conditions. Given the evidence that the AIC has a key role in interoception and is a likely mediator within dyspnea symptomology, advances in our understanding of the role of interoceptive processing on symptom burden in people living with COPD, as well as appropriate methods to measure and treat it, should be research priorities.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"336 ","pages":"Article 104441"},"PeriodicalIF":1.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935734","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}

{"title":"Diagnostic pathways for earlier diagnosis and treatment towards better outcomes for adults living with chronic breathlessness","authors":"Gillian E. Doe ,&nbsp;Max Olsson ,&nbsp;Rachael A. Evans","doi":"10.1016/j.resp.2025.104439","DOIUrl":"10.1016/j.resp.2025.104439","url":null,"abstract":"<div><div>Chronic breathlessness is a common and distressing symptom, negatively impacting physical function and quality of life. Many individuals presenting with chronic breathlessness wait years for an explanatory diagnosis, leading to delays in accessing effective treatments and worse individual outcomes including premature mortality. In addition, delays to diagnosis are associated with increased healthcare utilisation and therefore potentially avoidable burden on healthcare systems. Diagnosing the underlying causes of chronic breathlessness is complex and can be challenging for clinicians. The current clinical diagnostic approach, related guidelines, and healthcare service structure are typically aligned with a disease-based focus. For this article, we are using a working definition of ‘Chronic Breathlessness’ to infer breathlessness that has persisted for at least eight weeks. In this narrative review, using the latest available evidence, we aimed to describe a symptom-based approach to diagnosis for adults presenting with chronic breathlessness alongside describing the potential for this approach to improve both clinical outcomes and efficiency for healthcare systems. Therefore, our objectives were to: 1) summarise what is currently known about the time to diagnosis for adults presenting with breathlessness, 2) describe the impact and possible explanations for the current delays to diagnosis, 3) describe potential solutions towards an effective symptom-based diagnosis, 4) review the potential for Artificial Intelligence (AI) to support several areas along the diagnostic pathway for breathlessness, 5) describe how a symptom-based approach to diagnosis can be directly utilised to enable a ‘matched’ personalised holistic approach to treatment.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"336 ","pages":"Article 104439"},"PeriodicalIF":1.9,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143935739","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}

{"title":"Role of non-NMDA glutamate receptors in respiratory control and hyperoxia-induced plasticity in neonatal rats","authors":"Matthew D. Danielson,&nbsp;Brielle J. Antonelli,&nbsp;Megan R. Gonzalez,&nbsp;Ryan W. Bavis","doi":"10.1016/j.resp.2025.104440","DOIUrl":"10.1016/j.resp.2025.104440","url":null,"abstract":"<div><div>Newborn rats have a biphasic hypoxic ventilatory response (HVR) that typically matures during the second postnatal week, but rats reared in moderate hyperoxia (30–60 % O₂) already exhibit a sustained increase in ventilation during the late-phase of the HVR by 3 days of age (P3). Enhanced glutamatergic neurotransmission through NMDA receptors contributes to both normal maturation of the HVR and hyperoxia-induced developmental plasticity, but the role of non-NMDA glutamate receptors is unclear. To investigate the involvement of non-NMDA glutamate receptors in respiratory control and hyperoxia-induced plasticity, newborn Sprague Dawley rats were exposed to 21 % O₂ (Control) or 60 % O₂ (Hyperoxia) until their HVR was measured by head-body plethysmography at P3–4. Systemic administration of the AMPA/kainate receptor antagonist NBQX (12.5 mg kg⁻¹, i.p.) caused rats from both treatment groups to adopt a slower, deeper breathing pattern with a modest reduction in baseline minute ventilation and convection requirement. NBQX also attenuated the HVR measured during the first minute of hypoxia in both treatment groups, but it did not alter the overall shape of the HVR; Hyperoxia rats exhibited a sustained increase in ventilation throughout the entire 15-min exposure to 11 % O₂ regardless of whether they received saline or NBQX injections, while Control rats had a strongly biphasic HVR. Therefore, glutamatergic neurotransmission via non-NMDA glutamate receptors plays an important role in the respiratory control of neonatal rats but not in the respiratory plasticity expressed after chronic postnatal hyperoxia.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"336 ","pages":"Article 104440"},"PeriodicalIF":1.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911672","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}

{"title":"GAA replacement improves respiratory muscle, neural, and alveolar pathology in the pompe mouse","authors":"Angela L. Roger ,&nbsp;Lea El Haddad ,&nbsp;Meredith L. Huston ,&nbsp;Sean Kehoe ,&nbsp;Davina Le ,&nbsp;Mainur Khan ,&nbsp;Evelyn Scarrow ,&nbsp;Trevor Gonzalez ,&nbsp;Abigail Benkert ,&nbsp;Aravind Asokan ,&nbsp;Mai K. ElMallah","doi":"10.1016/j.resp.2025.104433","DOIUrl":"10.1016/j.resp.2025.104433","url":null,"abstract":"<div><div>Pompe disease is a devastating neuromuscular disorder caused by mutations in the gene <em>GAA</em>. These mutations result in a deficiency of the enzyme acid α-glucosidase (GAA), leading to lysosomal glycogen accumulation in cardiac, skeletal, and smooth muscle, motor neurons, and alveolar epithelial cells. Respiratory failure due to neuromuscular weakness, recurrent aspiration pneumonia, and tracheo-bronchomalacia are the leading causes of morbidity and mortality in PD patients. Enzyme replacement therapy (ERT) is currently the only FDA approved treatment for Pompe disease, however, gene therapy with naturally occurring and engineered adeno-associated viral vectors are also widely studied as an alternative treatment. In the present study we directly compared the benefits of existing and novel treatment modalities - ERT, AAV9-<em>GAA</em>, and AAVcc47-<em>GAA</em>, with an emphasis on correction of pathologies related to respiratory function. We find that GAA replacement in early adult mice improves respiration through 9 months of age. This improvement is attributed to glycogen clearance in the tongue, diaphragm, and lungs, which subsequently improved diaphragm neuromuscular junctions and reduced lysosomes within the alveolar epithelia.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"335 ","pages":"Article 104433"},"PeriodicalIF":1.9,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886235","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}

{"title":"Cockroach allergen exposure alters redox homeostasis and mediates airway inflammation","authors":"Swati Sharma ,&nbsp;Ekta Nagar ,&nbsp;Naveen Arora","doi":"10.1016/j.resp.2025.104438","DOIUrl":"10.1016/j.resp.2025.104438","url":null,"abstract":"<div><div>Allergic diseases are orchestrated by complex interplay of allergens with components of immune system as well as structural cells. As airway epithelium lies at the interface of environment and host immune responses, therefore we sought to study role of cockroach allergen exposure in context of oxidative stress in epithelia and its functional role in allergic pathophysiology. In vitro studies on Beas2B cells indicated elevation of intracellular ROS levels upon cockroach allergen (CE) exposure and transcriptional regulation of epithelial activation markers (CXCL-8 and IL-1 α) and endogenous antioxidant SOD-2. To corroborate ROS induction in vivo, mice model of cockroach hypersensitivity was generated and cytosolic and mitochondrial superoxide levels in lung of mice were estimated along with markers of allergic inflammation (cellular infiltration and epithelial activation cytokines (IL-33, TSLP and IL-25), proinflammatory (Th2 cytokines) and antioxidant pathways. Antioxidant supplementation with NAC, GSH and mitochondria specific ROS scavenger Mito-Tempo significantly reduced allergic inflammation. To discern the role of antioxidant pathways, we examined Nrf2 and SOD2 levels in mice lungs. Our results indicate that cockroach allergen exposure offsets the redox balance in lung with reduced glutathione peroxidase and catalase levels, however antioxidant treatment was able to restore redox equilibrium in lung by upregulating the expression of major regulator of antioxidant signalling, Nrf2 and enzymatic antioxidant SOD2. Our studies indicate crucial role of cockroach allergen induced ROS in allergic pathophysiology and targeting allergen induced oxidative stress may be utilised as an adjunct therapy for allergic diseases.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"335 ","pages":"Article 104438"},"PeriodicalIF":1.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878136","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}

{"title":"Ventilatory response and dyspnea on exertion in children with obesity and respiratory symptoms","authors":"Daniel P. Wilhite ,&nbsp;Dharini M. Bhammar ,&nbsp;Bryce N. Balmain ,&nbsp;Tanya Martinez-Fernandez ,&nbsp;Yulun Liu ,&nbsp;Tony G. Babb","doi":"10.1016/j.resp.2025.104437","DOIUrl":"10.1016/j.resp.2025.104437","url":null,"abstract":"<div><div>We investigated whether the exercise ventilatory response is associated with dyspnea on exertion (DOE) in children with (CWO;n = 25) and without (CWOO;n = 49) obesity, and with obesity and respiratory symptoms (CWORS;n = 14). The ventilatory response to exercise (V̇_E/V̇CO₂ slope) and ratings of perceived breathlessness (RPB, Borg 0–10 scale) were measured during 6-min cycling at 45 % maximal work rate. The V̇_E<strong>/</strong>V̇CO₂ slope (CWOO=34 ± 7; CWO=34 ± 5; CWORS=37 ± 6) and RPB (CWORS=4.0 ± 3.4; CWOO=2.5 ± 1.7; CWO=3.2 ± 2.1) were similar among groups (p &gt; 0.05). A significant association between the V̇_E/V̇CO₂ slope and RPB in CWORS (r²=0.49;p &lt; 0.05) was observed. To investigate this relationship more closely, children with an RPB≤ 2 were classified as having no or mild DOE (-DOE;n = 39;RPB=1.2 ± 0.7), and those with RPB≥ 3 were classified as having moderate to severe DOE (+DOE;n = 49;RPB=4.7 ± 1.9). +DOE had a higher V̇_E/V̇CO₂ slope (+DOE=36 ± 6;-DOE=33 ± 5;p = 0.02), higher breathing frequency, and higher V̇_E (%max;p &lt; 0.05). These findings suggest a heightened sensitivity to ventilatory demand among children, and that +DOE may be driven by factors other than obesity alone, possibly increased ventilatory response to exercise.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"335 ","pages":"Article 104437"},"PeriodicalIF":1.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143867714","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}

{"title":"Biological sex differences in the perception of CO2-induced air hunger","authors":"Louis M. Hall,&nbsp;Graham R. Sharpe,&nbsp;Neil C. Williams,&nbsp;Michael A. Johnson","doi":"10.1016/j.resp.2025.104436","DOIUrl":"10.1016/j.resp.2025.104436","url":null,"abstract":"<div><h3>Introduction</h3><div>Biological sex may mediate ‘dyspnoea’ during submaximal exercise, but whether it mediates air hunger (AH), a highly unpleasant form of dyspnoea, remains unclear.</div></div><div><h3>Method</h3><div>Forty healthy adults (twenty females) completed 6-min of quiet breathing (rest) followed by a hyperoxic CO₂ rebreathing task to evoke AH. AH intensity (AH-I) and unpleasantness (AH-U) were measured every 30-s. The Multidimensional Dyspnoea Profile (MDP) was administered after CO₂ rebreathing.</div></div><div><h3>Results</h3><div>Compared to males, AH-I and AH-U thresholds occurred at lower PETCO₂ in females (AH-I: 44.15 ± 2.81 vs 48.90 ± 4.47 mmHg, <em>P</em> &lt; 0.001; AH-U: 43.86 ± 2.57 vs 47.59 ± 2.75 mmHg, <em>P</em> &lt; 0.001) and after a smaller increase in PETCO₂ above resting PETCO₂ (AH-I: 7.04 ± 2.63 vs 10.08 ± 5.28 mmHg, <em>P</em> = 0.027; AH-U: 6.75 ± 2.22 vs 8.77 ± 2.99 mmHg, <em>P</em> = 0.020). AH-I and AH-U were higher in females than males at standardised absolute V̇_E of 25, 30 and 35 L/min (<em>P</em> &lt; 0.05). AH-U, but not AH-I, remained higher (main effect of sex, <em>P</em> = 0.026) in females than males at standardised relative V̇_E of 20, 25, and 30 % MVV. More females (<em>n</em> <em>=</em> 9) than males (<em>n=</em> 4) terminated CO₂ rebreathing due to maximal AH perception (<em>P</em> = 0.001). Compared to males, females reported greater intensities of ‘mental effort/concentration’ (7 ± 3 vs 4 ± 3), ‘tight/constricted lungs’ (6 ± 3 vs 2 ± 2), and ‘breathing work/effort’ (6 ± 2 vs 4 ± 3) (all <em>P</em> &lt; 0.05) on the MDP.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that sex differences exist in the perception of AH, which are not entirely accounted for by sex differences in ventilatory capacity.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"335 ","pages":"Article 104436"},"PeriodicalIF":1.9,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877112","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}

{"title":"Neurophysiological mechanisms of exertional dyspnea in advanced pregnancy: A case study","authors":"Devin B. Phillips ,&nbsp;Christine A. Darko ,&nbsp;Matthew D. James ,&nbsp;Sandra G. Vincent ,&nbsp;Alexandra M. McCartney ,&nbsp;Lara K. Sreibers ,&nbsp;Nicolle J. Domnik ,&nbsp;J. Alberto Neder ,&nbsp;Denis E. O’Donnell","doi":"10.1016/j.resp.2025.104434","DOIUrl":"10.1016/j.resp.2025.104434","url":null,"abstract":"<div><div>The neurophysiological mechanisms of exertional dyspnea in advanced pregnancy remain incompletely understood. This short case report describes the neurophysiological and sensory responses during standardized cardiopulmonary exercise testing (CPET) in one healthy adult female at three timepoints: a) 3 months pre-pregnancy, b) 35 weeks pregnant (third trimester [T3]), and, c) 1 year post-partum. At rest and during exercise, detailed measurements of neurophysiological, gas-exchange and sensory parameters were completed. Compared to both pre-pregnancy and post-partum, ventilatory requirements, electrical activation of the diaphragm (EMGdi, index of inspiratory neural drive) and esophageal pressure swings were higher in T3 throughout exercise. Moreover, at a given work rate, perceived dyspnea was greater in T3 compared with pre-pregnancy and post-partum and increased in close association with heightened EMGdi throughout exercise. At peak exercise in T3, dyspnea/ventilation and EMGdi/ventilation ratios were greater, compared with pre-pregnancy and post-partum. Compared with pre-pregnancy, EMGdi and perceived dyspnea were greater post-partum near the limits of exercise tolerance, secondary to earlier onset of respiratory compensation-mediated increases in ventilation. In the current case, advanced pregnancy was associated with markedly elevated ratings of dyspnea and lower exercise capacity during a standardized clinical CPET. At submaximal intensities, the heightened dyspnea reflected the awareness of pregnancy-induced increases in ventilatory requirements, inspiratory neural drive, and respiratory muscle effort. At the limits of tolerance, heightened dyspnea and inspiratory neural drive reflected a complex combination of increase ventilatory requirements and mechanical constraints on tidal volume expansion. Compared with pre-pregnancy, residual activity-related dyspnea 1-year post-partum appears to reflect physical deconditioning.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"335 ","pages":"Article 104434"},"PeriodicalIF":1.9,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143867713","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}

{"title":"Roflumilast, a phosphodiesterase-4 (PDE4) inhibitor, induces respiratory frequency plasticity that is resistant to inflammation in neonatal rat in vitro preparations","authors":"Stephen M. Johnson,&nbsp;Jacob P. Rastas,&nbsp;Pujal S. Desai,&nbsp;Tracy L. Baker,&nbsp;Jyoti J. Watters","doi":"10.1016/j.resp.2025.104435","DOIUrl":"10.1016/j.resp.2025.104435","url":null,"abstract":"<div><div>Premature and newborn infants often have prolonged apneas and are susceptible to bacterial infections that further disrupt breathing. Phoshodiesterase-4 (PDE4) inhibitor drugs increase inspiratory motor activity and appear to induce a long-lasting increase in inspiratory frequency (“frequency plasticity”). To test whether a PDE4 inhibitor drug induces frequency plasticity, neonatal rat brainstem-spinal cords were isolated and exposed to bath-applied roflumilast (10 min, 0.02–1.0 µM). Roflumilast acutely increased burst frequency and induced frequency plasticity in a concentration-dependent manner. Blockade of protein kinase A (PKA) or exchange protein activated by cAMP (EPAC) signaling pathways abolished the induction, but not the maintenance, of roflumilast-induced frequency plasticity. Brainstem-spinal cords isolated from neonatal rats injected with lipopolysaccharide (LPS, 0.1 mg/kg, 3 h prior) expressed frequency plasticity following bath-applied roflumilast at 0.05–0.5 µM, but not at lower concentrations. This shows that roflumilast-induced frequency plasticity is largely resistant to LPS-induced inflammation. Thus, roflumilast increases inspiratory burst frequency acutely and induces frequency plasticity even during ongoing inflammation, which could have important clinical implications.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"335 ","pages":"Article 104435"},"PeriodicalIF":1.9,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829381","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}

{"title":"Pathophysiological mechanisms of exertional dyspnea in people with cardiopulmonary disease: Recent advances","authors":"Matthew D. James ,&nbsp;Devin B. Phillips ,&nbsp;Nicolle J. Domnik ,&nbsp;J.Alberto Neder","doi":"10.1016/j.resp.2025.104423","DOIUrl":"10.1016/j.resp.2025.104423","url":null,"abstract":"<div><div>Physical activity is a leading trigger of dyspnea in chronic cardiopulmonary diseases. Recently, there has been a renewed interest in uncovering the mechanisms underlying this distressing symptom. We start by articulating a conceptual framework linking cardiorespiratory abnormalities with the central perception of undesirable respiratory sensations during exercise. We specifically emphasize that exertional dyspnea ultimately reflects an imbalance between (high) demand and (low) capacity. As such, the symptom arises in the presence of a heightened inspiratory neural drive – the will to breathe – secondary to a) increased ventilatory output relative to the instantaneous ventilatory capacity (<em>excessive</em> breathing) and/or b) its impeded translation into the act of breathing due to constraints on tidal volume expansion (<em>constrained</em> breathing). In patients with chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and interstitial lung disease (ILD), <em>constrained</em> breathing assumes a more dominant role as the disease progresses. <em>Excessive</em> breathing due to heightened wasted ventilation in the physiological dead space is particularly important in the initial stages of COPD, while alveolar hyperventilation has a major contributory role in hypoxemic patients with ILD. Hyperventilation is also a leading driver of dyspnea in heart failure (HF) with reduced ejection fraction (EF), while high physiological dead space is the main underlying mechanism in HF with preserved EF. Similarly, wasted ventilation in poorly perfused lung tissue dominates the scene in pulmonary vascular disease. New artificial intelligence-based approaches to expose the contribution of <em>excessive</em> and <em>constrained</em> breathing may enhance the yield of cardiopulmonary exercise testing in investigating exertional dyspnea in these patients.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"336 ","pages":"Article 104423"},"PeriodicalIF":1.9,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739229","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}