Pub Date : 2025-04-25DOI: 10.1016/j.resp.2025.104433
Angela L. Roger , Lea El Haddad , Meredith L. Huston , Sean Kehoe , Davina Le , Mainur Khan , Evelyn Scarrow , Trevor Gonzalez , Abigail Benkert , Aravind Asokan , Mai K. ElMallah
Pompe disease is a devastating neuromuscular disorder caused by mutations in the gene GAA. 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-GAA, and AAVcc47-GAA, 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.
{"title":"GAA replacement improves respiratory muscle, neural, and alveolar pathology in the pompe mouse","authors":"Angela L. Roger , Lea El Haddad , Meredith L. Huston , Sean Kehoe , Davina Le , Mainur Khan , Evelyn Scarrow , Trevor Gonzalez , Abigail Benkert , Aravind Asokan , 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}
Pub Date : 2025-04-23DOI: 10.1016/j.resp.2025.104438
Swati Sharma , Ekta Nagar , Naveen Arora
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.
{"title":"Cockroach allergen exposure alters redox homeostasis and mediates airway inflammation","authors":"Swati Sharma , Ekta Nagar , 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}
Pub Date : 2025-04-22DOI: 10.1016/j.resp.2025.104437
Daniel P. Wilhite , Dharini M. Bhammar , Bryce N. Balmain , Tanya Martinez-Fernandez , Yulun Liu , Tony G. Babb
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 (V̇E/V̇CO2 slope) and ratings of perceived breathlessness (RPB, Borg 0–10 scale) were measured during 6-min cycling at 45 % maximal work rate. The V̇E/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 > 0.05). A significant association between the V̇E/V̇CO2 slope and RPB in CWORS (r2=0.49;p < 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 V̇E/V̇CO2 slope (+DOE=36 ± 6;-DOE=33 ± 5;p = 0.02), higher breathing frequency, and higher V̇E (%max;p < 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.
{"title":"Ventilatory response and dyspnea on exertion in children with obesity and respiratory symptoms","authors":"Daniel P. Wilhite , Dharini M. Bhammar , Bryce N. Balmain , Tanya Martinez-Fernandez , Yulun Liu , 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<sub>E</sub>/V̇CO<sub>2</sub> slope) and ratings of perceived breathlessness (RPB, Borg 0–10 scale) were measured during 6-min cycling at 45 % maximal work rate. The V̇<sub>E</sub><strong>/</strong>V̇CO<sub>2</sub> 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 > 0.05). A significant association between the V̇<sub>E</sub>/V̇CO<sub>2</sub> slope and RPB in CWORS (r<sup>2</sup>=0.49;p < 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<sub>E</sub>/V̇CO<sub>2</sub> slope (+DOE=36 ± 6;-DOE=33 ± 5;p = 0.02), higher breathing frequency, and higher V̇<sub>E</sub> (%max;p < 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}
Pub Date : 2025-04-22DOI: 10.1016/j.resp.2025.104436
Louis M. Hall, Graham R. Sharpe, Neil C. Williams, Michael A. Johnson
Introduction
Biological sex may mediate ‘dyspnoea’ during submaximal exercise, but whether it mediates air hunger (AH), a highly unpleasant form of dyspnoea, remains unclear.
Method
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.
Results
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, P < 0.001; AH-U: 43.86 ± 2.57 vs 47.59 ± 2.75 mmHg, P < 0.001) and after a smaller increase in PETCO2 above resting PETCO2 (AH-I: 7.04 ± 2.63 vs 10.08 ± 5.28 mmHg, P = 0.027; AH-U: 6.75 ± 2.22 vs 8.77 ± 2.99 mmHg, P = 0.020). AH-I and AH-U were higher in females than males at standardised absolute V̇E of 25, 30 and 35 L/min (P < 0.05). AH-U, but not AH-I, remained higher (main effect of sex, P = 0.026) in females than males at standardised relative V̇E of 20, 25, and 30 % MVV. More females (n= 9) than males (n= 4) terminated CO2 rebreathing due to maximal AH perception (P = 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 P < 0.05) on the MDP.
Conclusion
Our findings suggest that sex differences exist in the perception of AH, which are not entirely accounted for by sex differences in ventilatory capacity.
{"title":"Biological sex differences in the perception of CO2-induced air hunger","authors":"Louis M. Hall, Graham R. Sharpe, Neil C. Williams, 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 CO<sub>2</sub> 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 CO<sub>2</sub> rebreathing.</div></div><div><h3>Results</h3><div>Compared to males, AH-I and AH-U thresholds occurred at lower PETCO<sub>2</sub> in females (AH-I: 44.15 ± 2.81 vs 48.90 ± 4.47 mmHg, <em>P</em> < 0.001; AH-U: 43.86 ± 2.57 vs 47.59 ± 2.75 mmHg, <em>P</em> < 0.001) and after a smaller increase in PETCO<sub>2</sub> above resting PETCO<sub>2</sub> (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<sub>E</sub> of 25, 30 and 35 L/min (<em>P</em> < 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<sub>E</sub> of 20, 25, and 30 % MVV. More females (<em>n</em> <em>=</em> 9) than males (<em>n=</em> 4) terminated CO<sub>2</sub> 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> < 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}
Pub Date : 2025-04-18DOI: 10.1016/j.resp.2025.104434
Devin B. Phillips , Christine A. Darko , Matthew D. James , Sandra G. Vincent , Alexandra M. McCartney , Lara K. Sreibers , Nicolle J. Domnik , J. Alberto Neder , Denis E. O’Donnell
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.
{"title":"Neurophysiological mechanisms of exertional dyspnea in advanced pregnancy: A case study","authors":"Devin B. Phillips , Christine A. Darko , Matthew D. James , Sandra G. Vincent , Alexandra M. McCartney , Lara K. Sreibers , Nicolle J. Domnik , J. Alberto Neder , 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}
Pub Date : 2025-04-13DOI: 10.1016/j.resp.2025.104435
Stephen M. Johnson, Jacob P. Rastas, Pujal S. Desai, Tracy L. Baker, Jyoti J. Watters
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.
{"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, Jacob P. Rastas, Pujal S. Desai, Tracy L. Baker, 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}
Pub Date : 2025-03-29DOI: 10.1016/j.resp.2025.104423
Matthew D. James , Devin B. Phillips , Nicolle J. Domnik , J.Alberto Neder
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 (excessive breathing) and/or b) its impeded translation into the act of breathing due to constraints on tidal volume expansion (constrained breathing). In patients with chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis, and interstitial lung disease (ILD), constrained breathing assumes a more dominant role as the disease progresses. Excessive 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 excessive and constrained breathing may enhance the yield of cardiopulmonary exercise testing in investigating exertional dyspnea in these patients.
{"title":"Pathophysiological mechanisms of exertional dyspnea in people with cardiopulmonary disease: Recent advances","authors":"Matthew D. James , Devin B. Phillips , Nicolle J. Domnik , 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}
Our study aimed to investigate swallowing coordination by analyzing ventilatory patterns during of solids and liquids food intakes. Twenty-one patients with severe to very severe stable COPD (GOLD III and IV) underwent ventilation and swallowing recordings while performing standardized swallowing tasks. The results revealed that the expiratory-expiratory (EE) swallowing pattern was predominant, accounting for 80 % of swallows, with no significant differences between solid and liquid swallows. Non-EE patterns occurred in an average of 20.68 % of swallows per patient. Our results demonstrated an increased inspiratory time (IT) during liquid swallows compared to rest (1.05 ± 0.28 s vs 1.29 ± 0.22 s; p < 0.0125), as well as prolonged expiratory time (ET: 2.09 ± 0.78 s vs 3.42 ± 1.16 s; p < 0.001) and total respiratory cycle time (TT: 3.14 ± 1.03 s vs 4.70 ± 1.21 s; p < 0.01) during both solid and liquid swallows compared to rest. These changes resulted in a decreased IT/TT ratio during swallowing. Our findings confirm that the EE swallowing pattern remains predominant in stable COPD patients, consistent with observations in healthy individuals. Additionally, the study highlights significant alterations in ventilatory patterns during swallowing. These results contribute to a better understanding of the interplay between swallowing and ventilation in COPD and its potential implications for airways protection.
我们的研究旨在通过分析固体和液体食物摄入时的通气模式来研究吞咽协调。21例重度至极重度稳定期COPD （GOLD III和IV）患者在执行标准化吞咽任务时进行通气和吞咽记录。结果显示，以呼气-呼气（EE）吞咽方式为主，占吞咽方式的80%，固体吞咽与液体吞咽无显著差异。每位患者平均有20.68%的燕子出现非ee模式。我们的研究结果表明，与休息时相比，液体吞咽时吸气时间（IT）增加(1.05±0.28s vs. 1.29±0.22s；p < 0.0125)，以及呼气时间延长(ET: 2.09±0.78s vs. 3.42±1.16s；p < 0.001)和总呼吸周期时间(TT: 3.14±1.03s∶4.70±1.21s；P < 0.01)。这些变化导致吞咽时IT/TT比值降低。我们的研究结果证实，在稳定型COPD患者中，EE吞咽模式仍然占主导地位，这与健康个体的观察结果一致。此外，该研究还强调了吞咽过程中通气模式的显著改变。这些结果有助于更好地理解COPD患者吞咽和通气之间的相互作用及其对气道保护的潜在影响。
{"title":"Swallowing and ventilation patterns in stable COPD patients: An observational study","authors":"Virgil Rolland , Armand Bonne , Rimeh Ayari , Grégoire Prum , Eric Verin","doi":"10.1016/j.resp.2025.104419","DOIUrl":"10.1016/j.resp.2025.104419","url":null,"abstract":"<div><div>Our study aimed to investigate swallowing coordination by analyzing ventilatory patterns during of solids and liquids food intakes. Twenty-one patients with severe to very severe stable COPD (GOLD III and IV) underwent ventilation and swallowing recordings while performing standardized swallowing tasks. The results revealed that the expiratory-expiratory (EE) swallowing pattern was predominant, accounting for 80 % of swallows, with no significant differences between solid and liquid swallows. Non-EE patterns occurred in an average of 20.68 % of swallows per patient. Our results demonstrated an increased inspiratory time (IT) during liquid swallows compared to rest (1.05 ± 0.28 s vs 1.29 ± 0.22 s; <em>p</em> < 0.0125), as well as prolonged expiratory time (ET: 2.09 ± 0.78 s vs 3.42 ± 1.16 s; <em>p</em> < 0.001) and total respiratory cycle time (TT: 3.14 ± 1.03 s vs 4.70 ± 1.21 s; <em>p</em> < 0.01) during both solid and liquid swallows compared to rest. These changes resulted in a decreased IT/TT ratio during swallowing. Our findings confirm that the EE swallowing pattern remains predominant in stable COPD patients, consistent with observations in healthy individuals. Additionally, the study highlights significant alterations in ventilatory patterns during swallowing. These results contribute to a better understanding of the interplay between swallowing and ventilation in COPD and its potential implications for airways protection.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"336 ","pages":"Article 104419"},"PeriodicalIF":1.9,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753922","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 : 2025-03-26DOI: 10.1016/j.resp.2025.104422
Kohei Sato , Tatsuki Kamoda , Rintaro Sakamoto , Keisho Katayama , Toru Neki , Masaki Katayose , Erika Iwamoto
Purpose
This study aimed to clarify the effects of inspiratory muscle metaboreflex on cerebral circulation at rest and during exercise.
Methods
Twelve young males randomly completed two trials (rest and exercise [leg cycling at 40 % peak oxygen uptake] trials) on separate days. In each trial, the internal carotid artery (ICA), an index of cerebral circulation, was measured using Doppler ultrasound 2 min after inspiratory loading breathing (IL condition) or non-loading breathing (control condition). During ICA assessments, participants engaged in 3 min of spontaneous breathing (SB), followed by 3 min of isocapnic hyperventilation (IHV).
Results
ICA conductance was lower in the IL condition than in the control condition in both rest and exercise trials. Inspiratory muscle metaboreflex did not reduce ICA blood flow during SB but decreased it during IHV in both trials.
Conclusion
Our findings suggest that inspiratory muscle metaboreflex could decrease cerebrovascular conductance from rest to light-intensity exercise and attenuates cerebral blood flow with increased respiratory muscle work.
{"title":"Effects of inspiratory muscle metaboreflex on cerebral circulation at rest and during light-intensity exercise in healthy males","authors":"Kohei Sato , Tatsuki Kamoda , Rintaro Sakamoto , Keisho Katayama , Toru Neki , Masaki Katayose , Erika Iwamoto","doi":"10.1016/j.resp.2025.104422","DOIUrl":"10.1016/j.resp.2025.104422","url":null,"abstract":"<div><h3>Purpose</h3><div>This study aimed to clarify the effects of inspiratory muscle metaboreflex on cerebral circulation at rest and during exercise.</div></div><div><h3>Methods</h3><div>Twelve young males randomly completed two trials (rest and exercise [leg cycling at 40 % peak oxygen uptake] trials) on separate days. In each trial, the internal carotid artery (ICA), an index of cerebral circulation, was measured using Doppler ultrasound 2 min after inspiratory loading breathing (IL condition) or non-loading breathing (control condition). During ICA assessments, participants engaged in 3 min of spontaneous breathing (SB), followed by 3 min of isocapnic hyperventilation (IHV).</div></div><div><h3>Results</h3><div>ICA conductance was lower in the IL condition than in the control condition in both rest and exercise trials. Inspiratory muscle metaboreflex did not reduce ICA blood flow during SB but decreased it during IHV in both trials.</div></div><div><h3>Conclusion</h3><div>Our findings suggest that inspiratory muscle metaboreflex could decrease cerebrovascular conductance from rest to light-intensity exercise and attenuates cerebral blood flow with increased respiratory muscle work.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"336 ","pages":"Article 104422"},"PeriodicalIF":1.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143739228","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 : 2025-03-26DOI: 10.1016/j.resp.2025.104421
Ethan S. Benevides , Sabhya Rana , David D. Fuller
We tested the hypothesis that activation of DREADDs in the mid-cervical spinal cord could restore diaphragm activation during spontaneous breathing after cervical spinal cord injury (SCI). Adult Sprague Dawley rats (n = 7) received bilateral mid-cervical ventral horn injections of an AAV construct encoding an excitatory DREADD (AAV9-hSyn-HA-hM3D(Gq)-mCherry; titer: 2.44 × 1013 vg/mL). Subsequently, diaphragm electromyogram (EMG) activity was recorded during spontaneous breathing under isoflurane anesthesia. The selective DREADD ligand JHU37160 (J60) was administered intravenously at acute (3 days), sub-acute (2 weeks), and chronic (2 months) timepoints following cervical hemilesion at spinal level C2. J60 administration resulted in robust increases in diaphragm EMG output at all timepoints, and near-complete restoration of diaphragm EMG activity from the paralyzed hemi-diaphragm in 50 % of trials. Administration of J60 to DREADD naïve, spinal intact rats (n = 8) did not produce an increase in diaphragm activity. These proof-of-concept results indicate that refinement of this technique may provide a strategy for improving diaphragm activation after cervical SCI.
{"title":"Chemogenetic activation of the diaphragm after spinal cord injury in rats","authors":"Ethan S. Benevides , Sabhya Rana , David D. Fuller","doi":"10.1016/j.resp.2025.104421","DOIUrl":"10.1016/j.resp.2025.104421","url":null,"abstract":"<div><div>We tested the hypothesis that activation of DREADDs in the mid-cervical spinal cord could restore diaphragm activation during spontaneous breathing after cervical spinal cord injury (SCI). Adult Sprague Dawley rats (n = 7) received bilateral mid-cervical ventral horn injections of an AAV construct encoding an excitatory DREADD (AAV9-hSyn-HA-hM3D(Gq)-mCherry; titer: 2.44 × 10<sup>13</sup> vg/mL). Subsequently, diaphragm electromyogram (EMG) activity was recorded during spontaneous breathing under isoflurane anesthesia. The selective DREADD ligand JHU37160 (J60) was administered intravenously at acute (3 days), sub-acute (2 weeks), and chronic (2 months) timepoints following cervical hemilesion at spinal level C2. J60 administration resulted in robust increases in diaphragm EMG output at all timepoints, and near-complete restoration of diaphragm EMG activity from the paralyzed hemi-diaphragm in 50 % of trials. Administration of J60 to DREADD naïve, spinal intact rats (n = 8) did not produce an increase in diaphragm activity. These proof-of-concept results indicate that refinement of this technique may provide a strategy for improving diaphragm activation after cervical SCI.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"336 ","pages":"Article 104421"},"PeriodicalIF":1.9,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143743516","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}
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