Pub Date : 2025-10-10DOI: 10.1164/rccm.202503-0596rl
Avery M Bogart,Sarah N Obeidalla,Rombout B E van Amstel,Olaf Cremer,Lieuwe D J Bos,Brian Bartek,Pratik Sinha,Carolyn S Calfee,V Eric Kerchberger,Lorraine B Ware,
{"title":"Premorbid Metabolic Syndrome Is Associated with the Hypoinflammatory Phenotype in Acute Respiratory Distress Syndrome and Sepsis.","authors":"Avery M Bogart,Sarah N Obeidalla,Rombout B E van Amstel,Olaf Cremer,Lieuwe D J Bos,Brian Bartek,Pratik Sinha,Carolyn S Calfee,V Eric Kerchberger,Lorraine B Ware, ","doi":"10.1164/rccm.202503-0596rl","DOIUrl":"https://doi.org/10.1164/rccm.202503-0596rl","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"19 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1164/rccm.202501-0262oc
Whitney N Souery,Ehab Billatos,Rim Elalami,Raúl San José Estépar,Michael H Cho,Alejandro A Diaz,Marc E Lenburg
RATIONALEMucus plug formation and chronic bronchitis are manifestations of mucus pathology in chronic obstructive pulmonary disease. Identifying gene expression changes related to mucus pathology could provide insight into its pathogenesis.OBJECTIVESTo investigate gene expression changes in individuals with mucus plugs, identify related biological pathways, and assess whether mucus plug-related gene expression associates with clinical features of other mucus pathologies.METHODSWe studied 290 participants from the Detection of Early Lung Cancer Among Military Personnel 2 study with mainstem bronchial brush bulk RNA-sequencing data (n = 204 discovery, n = 86 validation). We scored mucus plugging based on the number of lung segments with mucus plugs identified on chest computed tomography scans and used correlative analysis to identify differentially expressed genes and examine their association with chronic bronchitis symptoms.RESULTS76 participants (37%) in the discovery set had mucus plugs. Differentially expressed genes were broadly epithelial- or immune-related. Epithelial-related genes show decreased expression of genes involved in cilia maintenance and microtubule function and increased expression of genes related to epithelial maintenance and protection. Expression patterns of epithelial-related genes are associated with chronic bronchitis symptoms. Immune-related genes are enriched for innate and adaptive pathways. Expression of immune genes varies by lung function and was more weakly associated with mucus plugs than that of epithelial-related genes. Findings were replicated in an independent validation set.CONCLUSIONSeveral distinct gene expression patterns are linked to the presence of mucus plugs, highlighting biological pathways involved in mucus pathophysiology. Variability in gene expression suggests a spectrum of mucus pathophysiology contributes to mucus plugs and chronic bronchitis symptoms.
{"title":"Mucus Plugs-associated Gene Expression Identifies Pathophysiology Shared with Chronic Bronchitis.","authors":"Whitney N Souery,Ehab Billatos,Rim Elalami,Raúl San José Estépar,Michael H Cho,Alejandro A Diaz,Marc E Lenburg","doi":"10.1164/rccm.202501-0262oc","DOIUrl":"https://doi.org/10.1164/rccm.202501-0262oc","url":null,"abstract":"RATIONALEMucus plug formation and chronic bronchitis are manifestations of mucus pathology in chronic obstructive pulmonary disease. Identifying gene expression changes related to mucus pathology could provide insight into its pathogenesis.OBJECTIVESTo investigate gene expression changes in individuals with mucus plugs, identify related biological pathways, and assess whether mucus plug-related gene expression associates with clinical features of other mucus pathologies.METHODSWe studied 290 participants from the Detection of Early Lung Cancer Among Military Personnel 2 study with mainstem bronchial brush bulk RNA-sequencing data (n = 204 discovery, n = 86 validation). We scored mucus plugging based on the number of lung segments with mucus plugs identified on chest computed tomography scans and used correlative analysis to identify differentially expressed genes and examine their association with chronic bronchitis symptoms.RESULTS76 participants (37%) in the discovery set had mucus plugs. Differentially expressed genes were broadly epithelial- or immune-related. Epithelial-related genes show decreased expression of genes involved in cilia maintenance and microtubule function and increased expression of genes related to epithelial maintenance and protection. Expression patterns of epithelial-related genes are associated with chronic bronchitis symptoms. Immune-related genes are enriched for innate and adaptive pathways. Expression of immune genes varies by lung function and was more weakly associated with mucus plugs than that of epithelial-related genes. Findings were replicated in an independent validation set.CONCLUSIONSeveral distinct gene expression patterns are linked to the presence of mucus plugs, highlighting biological pathways involved in mucus pathophysiology. Variability in gene expression suggests a spectrum of mucus pathophysiology contributes to mucus plugs and chronic bronchitis symptoms.","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"86 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1164/rccm.202507-1790ed
Mark E Mikkelsen,Chiara Robba
{"title":"Oxygenation and Organ Function: The Timeless Quest to Preserve Function and Avoid Toxicity.","authors":"Mark E Mikkelsen,Chiara Robba","doi":"10.1164/rccm.202507-1790ed","DOIUrl":"https://doi.org/10.1164/rccm.202507-1790ed","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"40 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1164/rccm.202503-0544oc
Francesco Murgolo,Savino Spadaro,Domenico L Grieco,Michele Bertoni,Luigi Pisani,Giorgia Spinazzola,Rosa Di Mussi,Teresa Michi,Nicola Bartolomeo,Vito Fanelli,Pierpaolo Terragni,Massimo Antonelli,V Marco Ranieri,Salvatore Grasso
RATIONALEConventional parameters to determine spontaneous breathing trials (SBTs) success may fail to detect impending respiratory distress.OBJECTIVESTo assess whether SBT-induced changes in respiratory system compliance, inspiratory effort and respiratory drive (P0.1), all assessed noninvasively through airway occlusions, are associated with extubation outcomes.METHODSMulticenter study on patients at high-risk of extubation failure who successfully passed a 30-minute SBT based on conventional parameters. The SBT was reproduced using a specific ventilator immediately before extubation to continuously monitor respiratory system compliance, inspiratory effort and P0.1. Extubation failure was defined as reintubation within 72 hours.MAIN RESULTSForty-six of 238 extubated patients (19%) required reintubation. No differences in tidal volume or respiratory rate were observed between successfully extubated and reintubated patients, at any time. In success group, inspiratory effort and normalized compliance (i.e. scaled to predicted body weight) remained unchanged throughout the SBT. In failure group, normalized compliance declined (1.0 [0.8-1.2] to 0.7 [0.6-0.9] mL/cmH2O/kg, p<0.001) while inspiratory effort increased (12 [10-15] to 18 [15-20] cmH2O, p<0.001) during the SBT. P0.1 increased in both groups, but more markedly in reintubated patients (2 [1.5-2.4] to 3.2 [2.9-3.5] cmH2O, p<0.001). SBT-induced normalized compliance reduction ≤ -0.2 ml/cmH2O/Kg [≤-0.1; ≤ -0.2] and inspiratory effort increase >2 cmH2O [>1; >3] were the most accurate predictors of extubation failure (AUC 0.90 [0.84-0.93], sensitivity 80%, specificity 83%; AUC 0.94 [0.90-0.97], sensitivity 89%, specificity 93%, respectively).CONCLUSIONIn high-risk patients, SBT-induced declines in respiratory system compliance and increases in inspiratory effort are associated with extubation failure.
{"title":"Assessment of Respiratory Mechanics and Inspiratory Effort During Spontaneous Breathing Trials to Predict Extubation Failure in High-Risk Patients.","authors":"Francesco Murgolo,Savino Spadaro,Domenico L Grieco,Michele Bertoni,Luigi Pisani,Giorgia Spinazzola,Rosa Di Mussi,Teresa Michi,Nicola Bartolomeo,Vito Fanelli,Pierpaolo Terragni,Massimo Antonelli,V Marco Ranieri,Salvatore Grasso","doi":"10.1164/rccm.202503-0544oc","DOIUrl":"https://doi.org/10.1164/rccm.202503-0544oc","url":null,"abstract":"RATIONALEConventional parameters to determine spontaneous breathing trials (SBTs) success may fail to detect impending respiratory distress.OBJECTIVESTo assess whether SBT-induced changes in respiratory system compliance, inspiratory effort and respiratory drive (P0.1), all assessed noninvasively through airway occlusions, are associated with extubation outcomes.METHODSMulticenter study on patients at high-risk of extubation failure who successfully passed a 30-minute SBT based on conventional parameters. The SBT was reproduced using a specific ventilator immediately before extubation to continuously monitor respiratory system compliance, inspiratory effort and P0.1. Extubation failure was defined as reintubation within 72 hours.MAIN RESULTSForty-six of 238 extubated patients (19%) required reintubation. No differences in tidal volume or respiratory rate were observed between successfully extubated and reintubated patients, at any time. In success group, inspiratory effort and normalized compliance (i.e. scaled to predicted body weight) remained unchanged throughout the SBT. In failure group, normalized compliance declined (1.0 [0.8-1.2] to 0.7 [0.6-0.9] mL/cmH2O/kg, p<0.001) while inspiratory effort increased (12 [10-15] to 18 [15-20] cmH2O, p<0.001) during the SBT. P0.1 increased in both groups, but more markedly in reintubated patients (2 [1.5-2.4] to 3.2 [2.9-3.5] cmH2O, p<0.001). SBT-induced normalized compliance reduction ≤ -0.2 ml/cmH2O/Kg [≤-0.1; ≤ -0.2] and inspiratory effort increase >2 cmH2O [>1; >3] were the most accurate predictors of extubation failure (AUC 0.90 [0.84-0.93], sensitivity 80%, specificity 83%; AUC 0.94 [0.90-0.97], sensitivity 89%, specificity 93%, respectively).CONCLUSIONIn high-risk patients, SBT-induced declines in respiratory system compliance and increases in inspiratory effort are associated with extubation failure.","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"115 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1164/rccm.202506-1386oc
David G Tingay,Monique Fatmous,Kelly Kenna,Ellen Douglas,Arun Sett,Tuyen Kim Quach,Joel T Hooder,Qi Hui Poh,Magdy Sourial,Prue M Pereira-Fantini
Rationale: The lung protective and injurious potential of spontaneous breathing effort during positive pressure ventilation (PPV) in adults is well-understood but has never been defined in the preterm lung. Objectives: To determine the role of synchronous and asynchronous breathing during PPV on lung injury. Methods: Steroid-exposed intubated preterm lambs (n=59; 126-130d gestation) were randomly allocated to receive 1) fully synchronised PPV, 2) asynchronous PPV or apnoeic PPV for 90-min from birth using an otherwise standardised lung protective PPV strategy. Breathing was supported with caffeine, doxapram and stimulation. Measurements and Main Results: Lung mechanics, gas exchange and regional ventilation and aeration characteristics were measured during PPV. Lung tissue and bronchoalveolar fluid was taken for histology and proteomic analysis. Clinical characteristics and gas exchange were similar. Each PPV strategy generated unique flow and pressure characteristics that were associated with different lung proteome expression. Overall, asynchronous breathing created the most injury, least developed alveolar morphology and 5-fold more dependent lung differentially expressed proteins (compared to synchronous and apnoeic PPV). Synchronous and apnoeic PPV resulted in similar morphology and minimal acute injury. At study completion, dynamic compliance and gravity-dependent centre of ventilation were better in the synchronous PPV group compared to apnoeic PPV; mean (95% CI) difference 0.26 (0.08, 0.43) ml/kg/min and 3.6 (1.0, 6.1)% respectively (ANOVA). Conclusions: Different breathing efforts during PPV support of the preterm lung creates complex lung states, each with unique and measurable injury events. This offers the potential to develop lung protective strategies that target minimising breathing-related injury.
{"title":"Role of Spontaneous Effort During Mechanical Ventilation on Lung Injury in Preterm Lambs.","authors":"David G Tingay,Monique Fatmous,Kelly Kenna,Ellen Douglas,Arun Sett,Tuyen Kim Quach,Joel T Hooder,Qi Hui Poh,Magdy Sourial,Prue M Pereira-Fantini","doi":"10.1164/rccm.202506-1386oc","DOIUrl":"https://doi.org/10.1164/rccm.202506-1386oc","url":null,"abstract":"Rationale: The lung protective and injurious potential of spontaneous breathing effort during positive pressure ventilation (PPV) in adults is well-understood but has never been defined in the preterm lung. Objectives: To determine the role of synchronous and asynchronous breathing during PPV on lung injury. Methods: Steroid-exposed intubated preterm lambs (n=59; 126-130d gestation) were randomly allocated to receive 1) fully synchronised PPV, 2) asynchronous PPV or apnoeic PPV for 90-min from birth using an otherwise standardised lung protective PPV strategy. Breathing was supported with caffeine, doxapram and stimulation. Measurements and Main Results: Lung mechanics, gas exchange and regional ventilation and aeration characteristics were measured during PPV. Lung tissue and bronchoalveolar fluid was taken for histology and proteomic analysis. Clinical characteristics and gas exchange were similar. Each PPV strategy generated unique flow and pressure characteristics that were associated with different lung proteome expression. Overall, asynchronous breathing created the most injury, least developed alveolar morphology and 5-fold more dependent lung differentially expressed proteins (compared to synchronous and apnoeic PPV). Synchronous and apnoeic PPV resulted in similar morphology and minimal acute injury. At study completion, dynamic compliance and gravity-dependent centre of ventilation were better in the synchronous PPV group compared to apnoeic PPV; mean (95% CI) difference 0.26 (0.08, 0.43) ml/kg/min and 3.6 (1.0, 6.1)% respectively (ANOVA). Conclusions: Different breathing efforts during PPV support of the preterm lung creates complex lung states, each with unique and measurable injury events. This offers the potential to develop lung protective strategies that target minimising breathing-related injury.","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"28 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1164/rccm.202509-2289ed
Mark T Gladwin,Gregory J Kato,Roberto F Machado
{"title":"10-Year Longitudinal Study Clarifies Impact of Hemolysis and Pulmonary Hypertension on Patients with Sickle Cell Anemia.","authors":"Mark T Gladwin,Gregory J Kato,Roberto F Machado","doi":"10.1164/rccm.202509-2289ed","DOIUrl":"https://doi.org/10.1164/rccm.202509-2289ed","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"1 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-10DOI: 10.1164/rccm.202504-0890le
Xiangxia Zeng
{"title":"VEGF-based Therapy for CDH: A Breakthrough or a Hidden Risk?","authors":"Xiangxia Zeng","doi":"10.1164/rccm.202504-0890le","DOIUrl":"https://doi.org/10.1164/rccm.202504-0890le","url":null,"abstract":"","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"85 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145261456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-07DOI: 10.1164/rccm.202505-1260oc
Arianne Tardif,G A Whitmore,Katherine L Vandemheen,Celine Bergeron,Louis-Philippe Boulet,Andréanne Côté,R Andrew McIvor,Erika Penz,Stephen K Field,Catherine Lemière,Irvin Mayers,Mohit Bhutani,Tanweer Azher,M Diane Lougheed,Samir Gupta,Nicole Ezer,Christopher J Licskai,Paul Hernandez,Martha Ainslie,Gonzalo G Alvarez,Sunita Mulpuru,Shawn D Aaron
RATIONALEThe Undiagnosed COPD and Asthma Population trial showed that early diagnosis and treatment of asthma and COPD by pulmonologists improved healthcare utilization, respiratory symptoms, and quality of life.OBJECTIVESTo determine if the benefits of early diagnosis and treatment were greater in individuals with more advanced disease, or in individuals with asthma as opposed to COPD. We also assessed whether pulmonologist-directed care benefited asthma and COPD subgroups equally.METHODSCase finding was used to identify undiagnosed adults with chronic respiratory symptoms in the community. Five hundred and eight newly diagnosed participants with COPD or asthma were randomized to a pulmonologist-care intervention or usual care. Low and high disease-burden categories for St. Georges Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) were defined using a median-split of baseline scores, and MCID thresholds were used to define significant responses. Benefits of pulmonologist care were assessed by evaluating treatment effects within subgroups and by assessing treatment-by-subgroup interactions.MEASUREMENTS AND MAIN RESULTSPatients with higher disease burden at diagnosis were more likely to benefit from early diagnosis and treatment compared to those with lower disease-burden. 71% of those with high disease-burden improved their CAT by ≥ 2 points over 12 months compared to 47% with low disease burden; OR 2.78, 95% CI: 1.90 to 4.07, p<0.001. Similar results were seen for SGRQ and FEV1 improvements. In contrast, responses to early diagnosis and treatment were similar for those with asthma vs COPD. Individuals with asthma randomized to pulmonologist-directed care showed greater one-year improvements in CAT, SGRQ, SF36 and FEV1 compared to individuals randomized to primary care. However, individuals with COPD experienced similar improvements regardless of whether their treatment was managed by a pulmonologist or primary care provider. Treatment-by-disease interaction terms were not statistically significant.CONCLUSIONSPatients with greater disease burden who exhibited more advanced and symptomatic asthma and COPD at the time of diagnosis, benefited more from earlier diagnosis and treatment. Patients with asthma tended to derive greater benefit from pulmonologist-directed care than patients with COPD.
{"title":"Patient Factors and Clinical Efficacy of Early Identification and Treatment of COPD and Asthma.","authors":"Arianne Tardif,G A Whitmore,Katherine L Vandemheen,Celine Bergeron,Louis-Philippe Boulet,Andréanne Côté,R Andrew McIvor,Erika Penz,Stephen K Field,Catherine Lemière,Irvin Mayers,Mohit Bhutani,Tanweer Azher,M Diane Lougheed,Samir Gupta,Nicole Ezer,Christopher J Licskai,Paul Hernandez,Martha Ainslie,Gonzalo G Alvarez,Sunita Mulpuru,Shawn D Aaron","doi":"10.1164/rccm.202505-1260oc","DOIUrl":"https://doi.org/10.1164/rccm.202505-1260oc","url":null,"abstract":"RATIONALEThe Undiagnosed COPD and Asthma Population trial showed that early diagnosis and treatment of asthma and COPD by pulmonologists improved healthcare utilization, respiratory symptoms, and quality of life.OBJECTIVESTo determine if the benefits of early diagnosis and treatment were greater in individuals with more advanced disease, or in individuals with asthma as opposed to COPD. We also assessed whether pulmonologist-directed care benefited asthma and COPD subgroups equally.METHODSCase finding was used to identify undiagnosed adults with chronic respiratory symptoms in the community. Five hundred and eight newly diagnosed participants with COPD or asthma were randomized to a pulmonologist-care intervention or usual care. Low and high disease-burden categories for St. Georges Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) were defined using a median-split of baseline scores, and MCID thresholds were used to define significant responses. Benefits of pulmonologist care were assessed by evaluating treatment effects within subgroups and by assessing treatment-by-subgroup interactions.MEASUREMENTS AND MAIN RESULTSPatients with higher disease burden at diagnosis were more likely to benefit from early diagnosis and treatment compared to those with lower disease-burden. 71% of those with high disease-burden improved their CAT by ≥ 2 points over 12 months compared to 47% with low disease burden; OR 2.78, 95% CI: 1.90 to 4.07, p<0.001. Similar results were seen for SGRQ and FEV1 improvements. In contrast, responses to early diagnosis and treatment were similar for those with asthma vs COPD. Individuals with asthma randomized to pulmonologist-directed care showed greater one-year improvements in CAT, SGRQ, SF36 and FEV1 compared to individuals randomized to primary care. However, individuals with COPD experienced similar improvements regardless of whether their treatment was managed by a pulmonologist or primary care provider. Treatment-by-disease interaction terms were not statistically significant.CONCLUSIONSPatients with greater disease burden who exhibited more advanced and symptomatic asthma and COPD at the time of diagnosis, benefited more from earlier diagnosis and treatment. Patients with asthma tended to derive greater benefit from pulmonologist-directed care than patients with COPD.","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"4 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-07DOI: 10.1164/rccm.202504-0854oc
Joselyn Rojas-Quintero,Rosa Faner,Chia-Ying Chiu,Jeff T Kue,Yun Zhang,David Sanz Rubio,Adrianne S Colborg,Constanze A Jakwerth,Carsten B Schmidt-Weber,Anke-Hilse Maitland-van der Zee,Mahmoud I Abdel-Aziz,Aprile L Pilon,Caroline A Owen,Erin J Plosa,Gregory L Kinney,Sharon Mc-Grath Morrow,Mariacarolina G Gazzaneo,Nahir Cortes Santiago,Krithika Lingappan,Julie Ledford,Jason Spence,Jennifer M Sucre,Maor Sauler,Tianshi David Wu,Alvar Agusti,Asa Wheelock,Sabina Illi,Erika von Mutius,Russell P Bowler,Bartolome Celli,Steven H Abman,J Michael Wells,Francesca Polverino,
RATIONALEEarly-life lung function trajectories predict long-term respiratory health, including COPD risk. Club Cell protein 16 (CC16) is a key determinant of lung health, with low levels associated with impaired lung development, reduced lung function, and COPD. Cigarette smoking lowers CC16, but it is unknown whether maternal smoking leads to persistent CC16 deficiency from early life, thereby disrupting lung development and predisposing to COPD risk and progression Methods: CC16 expression was analyzed across 4 human cohorts, in plasma samples (COPDGene [n=1,062] and ECLIPSE [n=2,164]), nasal brushings (ALLIANCE [n=63]), and peripheral lung sections (LTRC [n=44]) from participants with and without a history of maternal smoking exposure. Lung histology and respiratory mechanics were assessed in WT and Cc16-/- mice with and without maternal smoking exposure. Recombinant human (rh)CC16 effects on lung maturation were assessed in embryonic murine lung explants.RESULTSMaternal smoking was linked to reduced circulating and airway CC16 in COPD patients, controls, and a preclinical murine COPD model. In human adults, lower CC16 correlated with accelerated lung function decline and emphysema progression, while in children it was associated with obstructive physiology and early small airway impairment. In both mice and humans, maternal smoking-induced CC16 reduction was accompanied by greater epithelial injury (fibrosis, inflammation, apoptosis, oxidative stress). In murine explants, smoking impaired lung branching, whereas rhCC16 restored branching via α2-integrin binding Conclusions: Maternal smoking reduces CC16 levels, disrupting lung development in ways that predispose to lifelong impairment of lung function and worse COPD outcomes. Defining the mechanisms by which CC16 regulates lung maturation is essential for establishing reliable outcome measures and designing trials aimed at preventing early COPD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).
{"title":"Maternal Smoking and CC-16: Implications for Lung Development and COPD Across the Lifespan.","authors":"Joselyn Rojas-Quintero,Rosa Faner,Chia-Ying Chiu,Jeff T Kue,Yun Zhang,David Sanz Rubio,Adrianne S Colborg,Constanze A Jakwerth,Carsten B Schmidt-Weber,Anke-Hilse Maitland-van der Zee,Mahmoud I Abdel-Aziz,Aprile L Pilon,Caroline A Owen,Erin J Plosa,Gregory L Kinney,Sharon Mc-Grath Morrow,Mariacarolina G Gazzaneo,Nahir Cortes Santiago,Krithika Lingappan,Julie Ledford,Jason Spence,Jennifer M Sucre,Maor Sauler,Tianshi David Wu,Alvar Agusti,Asa Wheelock,Sabina Illi,Erika von Mutius,Russell P Bowler,Bartolome Celli,Steven H Abman,J Michael Wells,Francesca Polverino, ","doi":"10.1164/rccm.202504-0854oc","DOIUrl":"https://doi.org/10.1164/rccm.202504-0854oc","url":null,"abstract":"RATIONALEEarly-life lung function trajectories predict long-term respiratory health, including COPD risk. Club Cell protein 16 (CC16) is a key determinant of lung health, with low levels associated with impaired lung development, reduced lung function, and COPD. Cigarette smoking lowers CC16, but it is unknown whether maternal smoking leads to persistent CC16 deficiency from early life, thereby disrupting lung development and predisposing to COPD risk and progression Methods: CC16 expression was analyzed across 4 human cohorts, in plasma samples (COPDGene [n=1,062] and ECLIPSE [n=2,164]), nasal brushings (ALLIANCE [n=63]), and peripheral lung sections (LTRC [n=44]) from participants with and without a history of maternal smoking exposure. Lung histology and respiratory mechanics were assessed in WT and Cc16-/- mice with and without maternal smoking exposure. Recombinant human (rh)CC16 effects on lung maturation were assessed in embryonic murine lung explants.RESULTSMaternal smoking was linked to reduced circulating and airway CC16 in COPD patients, controls, and a preclinical murine COPD model. In human adults, lower CC16 correlated with accelerated lung function decline and emphysema progression, while in children it was associated with obstructive physiology and early small airway impairment. In both mice and humans, maternal smoking-induced CC16 reduction was accompanied by greater epithelial injury (fibrosis, inflammation, apoptosis, oxidative stress). In murine explants, smoking impaired lung branching, whereas rhCC16 restored branching via α2-integrin binding Conclusions: Maternal smoking reduces CC16 levels, disrupting lung development in ways that predispose to lifelong impairment of lung function and worse COPD outcomes. Defining the mechanisms by which CC16 regulates lung maturation is essential for establishing reliable outcome measures and designing trials aimed at preventing early COPD. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":"86 1","pages":""},"PeriodicalIF":24.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145241101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-06DOI: 10.1164/rccm.202508-1841le
Anna J Podolanczuk,Gary M Hunninghake,David A Schwartz,Christopher J Ryerson
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