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BACKGROUND: Pectus excavatum (PE) is a common congenital chest wall deformity with various associated health concerns, including psychosocial impacts, academic challenges, and potential cardiopulmonary effects. OBJECTIVE: This study aimed to investigate the cardiac consequences of right atrioventricular groove compression in PE using cardiac magnetic resonance imaging. MATERIALS AND METHODS: A retrospective analysis was conducted on 661 patients with PE referred for evaluation. Patients were categorized into three groups based on the degree of right atrioventricular groove compression (no compression (NC), partial compression (PC), and complete compression(CC)). Chest wall indices were measured: pectus index (PI), depression index (DI), correction index (CI), and sternal torsion. RESULTS: The study revealed significant differences in chest wall indices between the groups: PE, NC=4.15 ± 0.94, PC=4.93 ± 1.24, and CC=7.2 ± 4.01 (P<0.0001). Left ventricle ejection fraction (LVEF) showed no significant differences: LVEF, NC=58.72% ± 3.94, PC=58.49% ± 4.02, and CC=57.95% ± 3.92 (P=0.0984). Right ventricular ejection fraction (RVEF) demonstrated significant differences: RVEF, NC=55.2% ± 5.3, PC=53.8% ± 4.4, and CC=53.1% ± 4.8 (P≥0.0001). Notably, the tricuspid valve (TV) measurement on the four-chamber view decreased in patients with greater compression: NC=29.52 ± 4.6; PC=28.26 ± 4.8; and CC=24.74 ± 5.73 (P<0.0001). CONCLUSION: This study provides valuable insights into the cardiac consequences of right atrioventricular groove compression in PE and lends further evidence of mild cardiac changes due to PE.
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Tórax en Embudo , Humanos , Tórax en Embudo/diagnóstico por imagen , Tórax en Embudo/complicaciones , Tórax en Embudo/fisiopatología , Masculino , Femenino , Estudios Retrospectivos , Adolescente , Niño , Imagen por Resonancia Magnética/métodos , Válvula Tricúspide/diagnóstico por imagen , Válvula Tricúspide/fisiopatología , Adulto , Adulto JovenRESUMEN
Introduction: Patients with congenital heart disease (CHD) often have pulmonary abnormalities and exercise intolerance following cardiac surgery. Cardiac rehabilitation (CR) improves exercise capacity in patients with CHD, but minimal study has been performed to see if resting and dynamic pulmonary performance improves following CR in those with prior cardiac surgery. Methods: This was a retrospective cohort study of all patients who completed ≥12 weeks of CR from 2018 through 2022. Demographic, cardiopulmonary exercise test (CPET), spirometry, 6-minute walk, functional strength measures, and outcomes data were collected. Data are presented as median[IQR]. A Student's t-test was used for comparisons between groups and serial measurements were measured with a paired t-test. A p < 0.05 was considered significant. Results: There were a total of 37 patients [age 16.7 (14.2-20.1) years; 46% male] included. Patients with prior surgery (n = 26) were more likely to have abnormal spirometry data than those without heart disease (n = 11) (forced vital capacity [FVC] 76.7 [69.1-84.3]% vs. 96.4 [88.1-104.7]%, p = 0.002), but neither group experienced a significant change in spirometry. On CPET, peak oxygen consumption increased but there was no change in other pulmonary measures during exercise. Percent predicted FVC correlated with hand grip strength (r = 0.57, p = 0.0003) and percent predicted oxygen consumption (r = 0.43, p = 0.009). The number of prior sternotomies showed negative associations with both percent predicted FVC (r = -0.43, p = 0.04) and FEV1 (r = -0.47, p = 0.02). Discussion: Youth and young adults with a prior history of cardiac surgery have resting and dynamic pulmonary abnormalities that do not improve following CR. Multiple sternotomies are associated with worse pulmonary function.
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PURPOSE: The utility of pulmonary function testing (PFT) in pectus excavatum (PE) has been subject to debate. Although some evidence shows improvement from preoperative to postoperative values, the clinical significance is uncertain. A high failure-to-completion rate for operative PFT (48%) was identified in our large institutional cohort. With such a high non-completion rate, we questioned the overall utility of PFT in the preoperative assessment of PE and sought to evaluate if other measures of PE severity or cardiopulmonary function could explain this finding. METHODS: Demographics, clinical findings, and results from cardiac MRI, PFT (spirometry and plethysmography), and cardiopulmonary exercise tests (CPET) were reviewed in 270 patients with PE evaluated preoperatively between 2015 and 2018. Regression modeling was used to measure associations between PFT completion and cardiopulmonary function. RESULTS: There were no differences in demographics, symptoms, connective tissue disorders, or multiple indices of pectus severity and cardiac deformation in PFT completers versus non-completers. While regression analysis revealed higher RVEF, LVEF, and LVEF-Z scores, lower RV-ESV/BSA, LV-ESV/BSA, and LV-ESV/BSA-Z scores, and abnormal breathing reserve in PFT completers vs. non-completers, these findings were not consistent across continuous and binary analyses. CONCLUSIONS: We found that PFT completers were not significantly different from non-completers in most structural and functional measures of pectus deformity and cardiopulmonary function. Inability to complete PFT is not an indicator of pectus severity.
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Tórax en Embudo , Humanos , Tórax en Embudo/cirugía , EspirometríaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is marked by the activation of fibroblasts, leading to excessive production and deposition of extracellular matrix (ECM) within the lung parenchyma. Despite the pivotal role of ECM overexpression in IPF, potential negative regulators of ECM production in fibroblasts have yet to be identified. Semaphorin class 3B (SEMA3B), a secreted protein highly expressed in lung tissues, has established roles in axonal guidance and tumor suppression. However, the role of SEMA3B in ECM production by fibroblasts in the pathogenesis of IPF remains unexplored. Here, we show the downregulation of SEMA3B and its cognate binding receptor, neuropilin 1 (NRP1), in IPF lungs compared with healthy controls. Notably, the reduced expression of SEMA3B and NRP1 is associated with a decline in lung function in IPF. The downregulation of SEMA3B and NRP1 transcripts was validated in the lung tissues of patients with IPF, and two alternative mouse models of pulmonary fibrosis. In addition, we show that transforming growth factor-ß (TGFß) functions as a negative regulator of SEMA3B and NRP1 expression in lung fibroblasts. Furthermore, we demonstrate the antifibrotic effects of SEMA3B against TGFß-induced ECM production in IPF lung fibroblasts. Overall, our findings uncovered a novel role of SEMA3B in the pathogenesis of pulmonary fibrosis and provided novel insights into modulating the SEMA3B-NRP1 axis to attenuate pulmonary fibrosis.NEW & NOTEWORTHY The excessive production and secretion of collagens and other extracellular matrix proteins by fibroblasts lead to the scarring of the lung in severe fibrotic lung diseases. This study unveils an antifibrotic role for semaphorin class 3B (SEMA3B) in the pathogenesis of idiopathic pulmonary fibrosis. SEMA3B functions as an inhibitor of transforming growth factor-ß-driven fibroblast activation and reduced levels of SEMA3B and its receptor, neuropilin 1, are associated with decreased lung function in idiopathic pulmonary fibrosis.
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Proteínas de la Matriz Extracelular , Fibroblastos , Fibrosis Pulmonar Idiopática , Pulmón , Neuropilina-1 , Semaforinas , Factor de Crecimiento Transformador beta , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Células Cultivadas , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Fibroblastos/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Fibrosis Pulmonar Idiopática/genética , Pulmón/metabolismo , Pulmón/patología , Glicoproteínas de Membrana , Ratones Endogámicos C57BL , Neuropilina-1/metabolismo , Neuropilina-1/genética , Semaforinas/metabolismo , Semaforinas/genética , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Elastin is a long-lived fibrous protein that is abundant in the extracellular matrix of the lung. Elastic fibers provide the lung the characteristic elasticity during inhalation with recoil during exhalation thereby ensuring efficient gas exchange. Excessive deposition of elastin and other extracellular matrix proteins reduces lung compliance by impairing ventilation and compromising gas exchange. Notably, the degree of elastosis is associated with the progressive decline in lung function and survival in patients with interstitial lung diseases. Currently there are no proven therapies which effectively reduce the elastin burden in the lung nor prevent dysregulated elastosis. This review describes elastin's role in the healthy lung, summarizes elastosis in pulmonary diseases, and evaluates the current understanding of elastin regulation and dysregulation with the goal of guiding future research efforts to develop novel and effective therapies.
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Enfermedades Pulmonares Intersticiales , Pulmón , Humanos , Pulmón/metabolismo , Enfermedades Pulmonares Intersticiales/metabolismo , Fibrosis , Elastina , Tejido Elástico/metabolismoRESUMEN
Introduction: Research is an important aspect of many students' training. However, formal research training is rarely included in curricula. Thus, we developed an online, asynchronous series of modules to introduce trainees to multiple topics that are relevant to the conduct of research. Methods: Research 101 was utilized by first-year medical students and undergraduate students conducting mentored research projects. Students' knowledge, confidence, and satisfaction were assessed using pre- and post-module surveys with five-point Likert scaled questions, open-ended text responses, and a final quiz. Results: Pre-module survey results showed that learners felt most confident with the Conducting a literature search and Race and racism in medicine modules and least confident with the Submitting an Institutional Review Board protocol at UC module. Post-module survey responses were significantly increased compared to pre-module results for all modules and questions (p < 0.0001). The response to "The content of this module met my needs" was endorsed across all modules (84.9% "yes" responses). A final quiz of 25 multiple-choice questions was completed by 92 participants who received a median score of 21. Content analysis of open-ended post-module survey responses identified several strengths and opportunities for improvement in course content and instructional methods. Conclusions: These data demonstrate that significant learning resulted from completion of Research 101, as post-module survey scores were significantly higher than pre-module survey scores for all modules and questions. Final quiz scores were positive but also highlighted opportunity for additional trainee learning and will guide evolution of future modules.
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PURPOSE: We sought to analyze differences in presentation and cardiopulmonary function between those referred for surgical consultation as adolescents (11-17 years) versus adults (18 + years). METHODS: Presenting symptoms, past medical history, and results from cardiac MRI (CMR), pulmonary function testing (PFT), and cardiopulmonary exercise testing (CPET) were reviewed in 329 patients evaluated preoperatively between 2015 and 2018. Adjusted regression modeling was used to measure associations between pectus indices and clinical endpoints of cardiopulmonary function. RESULTS: Our sample included 276 adolescents and 53 adults. Adults presented more frequently with chest pain (57% vs. 38%, p = 0.01), shortness of breath (76% vs. 59%, p = 0.02), palpitations (21% vs. 11%, p = 0.04), and exercise intolerance (76% vs. 59%, p = 0.02). Their Haller indices (5.2 [4.2, 7.0] vs. 4.7 [4.0, 5.7], p = 0.05) and cardiac asymmetry (1.8 [0.5] vs. 1.6 [0.5], p = 0.02) were also higher. In continuous outcome analysis, adolescents had higher FEV1/FVC on PFT and higher work on CPET (p < 0.01). CONCLUSIONS: Adults with pectus excavatum were more symptomatic than adolescents with deeper, more asymmetric deformities, decreased FEV1/FVC and exercise capacity. These findings may support earlier versus later repair to prevent age-related decline. Further studies are warranted.
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Tórax en Embudo , Humanos , Adolescente , Adulto , Tórax en Embudo/cirugía , Pruebas de Función Respiratoria/métodos , Imagen por Resonancia MagnéticaRESUMEN
Introduction: Research is an important aspect of many medical students' training. However, many medical students are not required to complete a scholarly project, and formal research training is often fragmented across the medical school curriculum. Thus, we developed an online, structured, asynchronous set of modules to introduce trainees to multiple topics relevant to the conduct of research. Methods: Research 101 was piloted by 27 first-year medical students at the University of Cincinnati College of Medicine. Students' knowledge, confidence, and satisfaction were assessed using a final quiz and pre- and post-module surveys with five-point Likert-scaled questions and open-ended text responses. Results: Pre-module survey results showed that learners felt most confident in Conducting a literature search and least confident in Submitting an Institutional Review Board (IRB) protocol at UC. Post-module mean scores were significantly increased compared to pre-module results for all modules and questions (P < 0.05). The response to "The content of this module met my needs" was high across all modules with 236 (84.0%) "yes" responses. Thematic analysis of open-ended text responses from post-module surveys identified several improvements to individual modules and to the overall structure of Research 101. A final quiz of 25 multiple choice questions covering content from all required modules was required. The median score was 21. Conclusions: Comparison of post-module to pre-module survey scores provided clear evidence of improved learning across all topics. The modules developed were responsive to the students' needs, and students provided additional improvements for subsequent iterations of Research 101.
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PURPOSE: Pectus excavatum (PE) is a chest wall deformity of variable severity and symptomatology. Existing female-specific literature highlights breast asymmetry and cosmetic reconstruction. We sought to evaluate gender differences in cardiopulmonary function. METHODS: Cardiac MRIs, pulmonary function tests (PFTs), and cardiopulmonary exercise tests (CPETs) were reviewed in 345 patients undergoing preoperative evaluation for PE. Regression modeling was used to evaluate associations between gender and clinical endpoints of cardiopulmonary function. RESULTS: Mean age was 15.2 years, 19% were female, 98% were white. Pectus indices included median Haller Index (HI) of 4.8, mean depression index (DI) of 0.63, correction index (CI) of 33.6%, and Cardiac Compression Index (CCI) of 2.79. Cardiac assessment revealed decreased right and left ventricular ejection fraction (RVEF, LVEF) in 16% and 22% of patients, respectively. PFTs and CPETs were abnormal in ~ 30% of patients. While females had deeper PE deformities-represented by higher pectus indices-they had superior function with higher RVEF, LVEF Z-scores, FEV1, VO2 max, O2 pulse, work, and breathing reserve (p < 0.05). CONCLUSION: Despite worse PE deformity and symptomatology, females had a better cardiopulmonary function and exercise tolerance than males. Further research is needed to assess the precise mechanisms of this phenomenon and postoperative outcomes in this population.
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Tolerancia al Ejercicio/fisiología , Tórax en Embudo/fisiopatología , Frecuencia Cardíaca/fisiología , Volumen Sistólico/fisiología , Pared Torácica/fisiopatología , Función Ventricular Izquierda/fisiología , Adolescente , Adulto , Niño , Preescolar , Femenino , Tórax en Embudo/epidemiología , Humanos , Incidencia , Imagen por Resonancia Magnética , Masculino , Factores Sexuales , Estados Unidos/epidemiología , Adulto JovenRESUMEN
To longitudinally monitor progressive fibrosis in the transforming growth factor-α (TGF-α) transgenic mouse model of lung fibrosis, we used retrospective self-gating ultrashort echo time (UTE) magnetic resonance imaging (MRI) to image mouse lung at baseline and after 4 and 8 wk of fibrosis initiation via doxycycline administration. Only bitransgenic mice were used in this study and divided into two cohorts: six mice were fed doxycycline food to induce lung fibrosis (referred to as Dox cohort), and five other mice were fed normal food (referred to as control cohort). Lung mechanics, histology, and hydroxyproline were assessed after the final MRI. A linear mixed-effects model was used to analyze MRI-derived longitudinal lung-function parameters. Tidal volume decreased at a rate of -0.016 ± 0.002 ml/week [χ2(1) = 16.48, P < 0.001] for Dox cohort and increased at a rate of 0.010 ± 0.003 ml/week [χ2(1) = 6.37, P = 0.01] for control cohort. Minute ventilation decreased at a rate of -1.71 ± 0.26 ml·min-1·wk-1 [χ2(1) = 14.04, P < 0.001] for Dox cohort but did not change significantly over time for control cohort. High-density lung volume percentage increased at a rate of 3.9 ± 0.7%/wk for Dox cohort [χ2(1) = 11.47, P < 0.001] but did not change significantly over time for control cohort. MRI-derived lung structure and function parameters were strongly correlated with pleural thickness, hydroxyproline content, lung compliance, airway resistance, and airway elastance. We conclude that self-gating UTE MRI could be used to longitudinally monitor lung fibrosis in the TGF-α transgenic mouse model. NEW & NOTEWORTHY Self-gating UTE MRI was used to monitor morphology and physiology in lung fibrosis in a transforming growth factor-α transgenic mouse model. Tidal volume was shown for the first time to correlate strongly with conventional metrics of fibrosis such as hydroxyproline and pleural thickness.
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Pulmón/fisiopatología , Fibrosis Pulmonar/fisiopatología , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Hidroxiprolina/metabolismo , Interpretación de Imagen Asistida por Computador/métodos , Imagenología Tridimensional/métodos , Estudios Longitudinales , Pulmón/metabolismo , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Ratones Transgénicos , Fibrosis Pulmonar/metabolismo , Respiración , Pruebas de Función Respiratoria/métodos , Estudios Retrospectivos , Factor de Crecimiento Transformador alfa/metabolismoRESUMEN
Cystic fibrosis (CF) produces variable lung disease phenotypes that are, in part, independent of the CF transmembrane conductance regulator ( CFTR) genotype. Transforming growth factor-ß (TGFß) is the best described genetic modifier of the CF phenotype, but its mechanism of action is unknown. We hypothesized that TGFß is sufficient to drive pathognomonic features of CF lung disease in vivo and that CFTR deficiency enhances susceptibility to pathological TGFß effects. A CF mouse model and littermate controls were exposed intratracheally to an adenoviral vector containing the TGFß1 cDNA (Ad-TGFß), empty vector, or PBS only. Studies were performed 1 wk after treatment, including lung mechanics, collection of bronchoalveolar lavage fluid, and analysis of lung histology, RNA, and protein. CF and non-CF mice showed similar weight loss, inflammation, goblet cell hyperplasia, and Smad pathway activation after Ad-TGFß treatment. Ad-TGFß produced greater abnormalities in lung mechanics in CF versus control mice, which was uniquely associated with induction of phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. CFTR transcripts were reduced, and epithelial sodium channel transcripts were increased in CF and non-CF mice, whereas the goblet cell transcription factors, forkhead ortholog A3 and SAM-pointed domain-containing ETS-like factor, were increased in non-CF but not CF mice following Ad-TGFß treatment. Pulmonary TGFß1 expression was sufficient to produce pulmonary remodeling and abnormalities in lung mechanics that were associated with both shared and unique cell signaling pathway activation in CF and non-CF mice. These results highlight the multifunctional impact of TGFß on pulmonary pathology in vivo and identify cellular-response differences that may impact CF lung pathology.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Fibrosis Quística/metabolismo , Regulación de la Expresión Génica , Células Caliciformes/metabolismo , Pulmón/metabolismo , Factor de Crecimiento Transformador beta1/biosíntesis , Adenoviridae , Animales , Fibrosis Quística/genética , Fibrosis Quística/patología , Fibrosis Quística/fisiopatología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Células Caliciformes/patología , Hiperplasia , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Pulmón/patología , Pulmón/fisiopatología , Ratones , Ratones Transgénicos , Transducción Genética , Factor de Crecimiento Transformador beta1/genéticaRESUMEN
Pulmonary fibrosis contributes to morbidity and mortality in a range of diseases, and there are no approved therapies for reversing its progression. To understand the mechanisms underlying pulmonary fibrosis and assess potential therapies, mouse models are central to basic and translational research. Unfortunately, metrics commonly used to assess murine pulmonary fibrosis require animals to be grouped and euthanized, increasing experimental difficulty and cost. We examined the ability of magnetic resonance imaging (MRI) to noninvasively assess lung fibrosis progression and resolution in a doxycycline (Dox) regulatable, transgenic mouse model that overexpresses transforming growth factor-α (TGF-α) under control of a lung-epithelial-specific promoter. During 7 wk of Dox treatment, fibrotic lesions were readily observed as high-signal tissue. Mean weighted signal and percent signal volume were found to be the most robust MRI-derived measures of fibrosis, and these metrics correlated significantly with pleural thickness, histology scores, and hydroxyproline content (R = 0.75-0.89). When applied longitudinally, percent high signal volume increased by 1.5% wk-1 (P < 0.001) and mean weighted signal increased at a rate of 0.0065 wk-1 (P = 0.0062). Following Dox treatment, lesions partially resolved, with percent high signal volume decreasing by -3.2% wk-1 (P = 0.0034) and weighted mean signal decreasing at -0.015 wk-1 (P = 0.0028). Additionally, longitudinal MRI revealed dynamic remodeling in a subset of lesions, a previously unobserved behavior in this model. These results demonstrate MRI can noninvasively assess experimental lung fibrosis progression and resolution and provide unique insights into its pathobiology.
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Progresión de la Enfermedad , Imagen por Resonancia Magnética/métodos , Fibrosis Pulmonar/patología , Animales , Modelos Animales de Enfermedad , Hidroxiprolina/metabolismo , Imagenología Tridimensional , Ratones , Ratones Transgénicos , Factor de Crecimiento Transformador alfa/farmacologíaRESUMEN
RATIONALE: Measurement of the diffusing capacity of the lung for carbon monoxide (DlCO) is significantly influenced by the pulmonary capillary blood volume. Consequently, measurements require adjustment for blood hemoglobin concentration (DlCOadj) to allow meaningful clinical interpretation. Noninvasive point-of-care devices that measure hemoglobin transcutaneously provide immediate values for hemoglobin that may be useful in pulmonary function laboratories for determining DlCOadj. OBJECTIVES: To test the hypothesis that DlCOadj determinations obtained with a commercially available device for noninvasive, point-of-care measurement of blood hemoglobin concentrations are not significantly different from determinations obtained using hemoglobin concentrations measured conventionally in venous blood samples. METHODS: In a prospective open trial, hemoglobin measurements were obtained with the Pronto-7 spot check pulse CO-oximeter (Massimo, Irvine, CA) and by venipuncture for 205 patients referred for DlCO testing at Cincinnati Children's Hospital. Hemoglobin and DlCOadj measurements were compared between the two methods, using Student paired t tests and Bland-Altman plots. To assess variability, the differences in DlCOadj between the two methods were also compared by a modification of the current standard for acceptable within-session variability for DlCO. Clinical interpretation for individual DlCO tests based on DlCOadj values obtained from the two methods were compared statistically using Kendall's coefficient of concordance to determine whether the Pronto-7 altered the classification of the severity of DlCO defects. MEASUREMENTS AND MAIN RESULTS: Measurements of hemoglobin concentration by the Pronto-7 analyzer were significantly lower than those obtained from venipuncture blood samples (13.1 ± 1.8 vs. 13.4 ± 2.0; P = 0.01). However, there were no differences for DlCOadj between both methods (23.6 ± 7.7 vs. 23.7 ± 7.5 ml/min/mm Hg; P = 0.42). There was strong correlation between the Pronto-7 and venipuncture DlCOadj values (r = 0.99, P < 0.0001). Variability between the two methods was low for DlCOadj, with a bias of -0.07. More than 96% of tests met acceptable within-session variability. There was no significant difference in the clinical interpretation of the DlCO test based on DlCOadj values recovered from both methods (Kendall's coefficient, 0.96). CONCLUSIONS: Noninvasive measurement of hemoglobin for determination of DlCOadj was accurate and provided acceptable within-session variability. The results obtained noninvasively did not alter clinical interpretation of test results compared with venipuncture. These findings support noninvasive point-of-care devices as an alternative to venipuncture for determining hemoglobin to measure DlCOadj in most patients.
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Hemoglobinas/metabolismo , Pulmón/fisiopatología , Capacidad de Difusión Pulmonar , Adolescente , Adulto , Monóxido de Carbono , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oximetría , Pruebas en el Punto de Atención , Estudios Prospectivos , Pruebas de Función Respiratoria , Adulto JovenRESUMEN
The p70 ribosomal S6 kinase (p70S6K) is a downstream substrate that is phosphorylated and activated by the mammalian target of rapamycin complex and regulates multiple cellular processes associated with pulmonary fibrogenesis. Two isoforms of the p70S6K have been identified (S6K1 and S6K2), but their relative contributions in mediating pulmonary fibrosis are unknown. To interrogate the roles of the p70S6K isoforms, we overexpressed transforming growth factor (TGF)-α in mice deficient for the S6K1 or S6K2 genes and measured changes in lung histology, morphometry, total lung collagen, lung function, and proliferation between wild-type and isoform-deficient mice. Deficiency of S6K1, but not S6K2, had a significant effect on reducing proliferation in subpleural fibrotic lesions during TGF-α-induced fibrosis. Migration was significantly decreased in mesenchymal cells isolated from the lungs of S6K1 knockout mice compared with wild-type or S6K2 knockout mice. Conversely, increases in subpleural thickening were significantly decreased in S6K2-deficient mice compared with wild type. Deficiency of S6K2 significantly reduced phosphorylation of the downstream S6 ribosomal protein in lung homogenates and isolated mesenchymal cells after TGF-α expression. However, deficiency of neither isoform alone significantly altered TGF-α-induced collagen accumulation or lung function decline in vivo. Furthermore, deficiency in neither isoform prevented changes in collagen accumulation or lung compliance decline after administration of intradermal bleomycin. Together, these findings demonstrate that the p70S6K isoforms have unique and redundant functions in mediating fibrogenic processes, including proliferation, migration, and S6 phosphorylation, signifying that both isoforms must be targeted to modulate p70S6K-mediated pulmonary fibrosis.
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Movimiento Celular , Mesodermo/patología , Fibrosis Pulmonar/enzimología , Fibrosis Pulmonar/patología , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Animales , Bleomicina , Proliferación Celular , Colágeno/metabolismo , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Isoenzimas/metabolismo , Antígeno Ki-67/metabolismo , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Ratones Transgénicos , Fosforilación , Fibrosis Pulmonar/fisiopatología , Proteínas Quinasas S6 Ribosómicas 70-kDa/deficiencia , Transducción de Señal , Factor de Crecimiento Transformador alfa/metabolismoRESUMEN
Fibrogenesis involves a dynamic interplay between factors that promote the biosynthesis and deposition of extracellular matrix along with pathways that degrade the extracellular matrix and eliminate the primary effector cells. Opposing the often held perception that fibrotic tissue is permanent, animal studies and clinical data now demonstrate the highly plastic nature of organ fibrosis that can, under certain circumstances, regress. This review describes the current understanding of the mechanisms whereby the lung is known to resolve fibrosis focusing on degradation of the extracellular matrix, removal of myofibroblasts, and the role of inflammatory cells. Although there are significant gaps in understanding lung fibrosis resolution, accelerated improvements in biotechnology and bioinformatics are expected to improve the understanding of these mechanisms and have high potential to lead to novel and effective restorative therapies in the treatment not only of pulmonary fibrosis, but also of a wide-ranging spectrum of chronic disorders.
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Matriz Extracelular/metabolismo , Fibrosis Pulmonar/fisiopatología , Animales , Colágeno/fisiología , Enzimas/fisiología , Matriz Extracelular/fisiología , Humanos , Lisosomas/metabolismo , Ratones , Modelos Animales , Proteolisis , Fibrosis Pulmonar/metabolismoRESUMEN
RATIONALE: Chorioamnionitis is an important cause of preterm birth, but its impact on postnatal outcomes is understudied. OBJECTIVES: To evaluate whether fetal exposure to inflammation is associated with adverse pulmonary outcomes at 6 to 12 months' chronological age in infants born moderate to late preterm. METHODS: Infants born between 32 and 36 weeks' gestational age were prospectively recruited (N = 184). Chorioamnionitis was diagnosed by placenta and umbilical cord histology. Select cytokines were measured in samples of cord blood. Validated pulmonary questionnaires were administered (n = 184), and infant pulmonary function testing was performed (n = 69) between 6 and 12 months' chronological age by the raised volume rapid thoracoabdominal compression technique. MEASUREMENTS AND MAIN RESULTS: A total of 25% of participants had chorioamnionitis. Although infant pulmonary function testing variables were lower in infants born preterm compared with historical normative data for term infants, there were no differences between infants with chorioamnionitis (n = 20) and those without (n = 49). Boys and black infants had lower infant pulmonary function testing measurements than girls and white infants, respectively. Chorioamnionitis exposure was associated independently with wheeze (odds ratio [OR], 2.08) and respiratory-related physician visits (OR, 3.18) in the first year of life. Infants exposed to severe chorioamnionitis had increased levels of cord blood IL-6 and greater pulmonary morbidity at age 6 to 12 months than those exposed to mild chorioamnionitis. Elevated IL-6 was associated with significantly more respiratory problems (OR, 3.23). CONCLUSIONS: In infants born moderate or late preterm, elevated cord blood IL-6 and exposure to histologically identified chorioamnionitis was associated with respiratory morbidity during infancy without significant changes in infant pulmonary function testing measurements. Black compared with white and boy compared with girl infants had lower infant pulmonary function testing measurements and worse pulmonary outcomes.
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Corioamnionitis/fisiopatología , Recien Nacido Prematuro , Interleucina-6/sangre , Pulmón/fisiopatología , Adulto , Población Negra/estadística & datos numéricos , Femenino , Sangre Fetal/metabolismo , Edad Gestacional , Humanos , Lactante , Recién Nacido , Modelos Logísticos , Masculino , Análisis Multivariante , Ohio , Embarazo , Estudios Prospectivos , Pruebas de Función Respiratoria , Ruidos Respiratorios/etiología , Factores Sexuales , Población Blanca/estadística & datos numéricos , Adulto JovenRESUMEN
The p70 ribosomal S6 kinase (S6K) is a downstream substrate that is phosphorylated and activated by the mammalian target of rapamycin complex and regulates multiple cellular processes associated with fibrogenesis. Recent studies demonstrate that aberrant mTORC1-S6K signaling contributes to various pathological conditions, but a direct role in pulmonary fibroproliferation has not been established. Increased phosphorylation of the S6K pathway is detected immediately following transforming growth factor-α (TGF-α) expression in a transgenic model of progressive lung fibrosis. To test the hypothesis that the S6K directly regulates pulmonary fibroproliferative disease we determined the cellular sites of S6K phosphorylation during the induction of fibrosis in the TGF-α model and tested the efficacy of specific pharmacological inhibition of the S6K pathway to prevent and reverse fibrotic disease. Following TGF-α expression increased phosphorylation of the S6K was detected in the airway and alveolar epithelium and the mesenchyme of advanced subpleural fibrotic regions. Specific inhibition of the S6K with the small molecule inhibitor LY-2584702 decreased TGF-α and platelet-derived growth factor-ß-induced proliferation of lung fibroblasts in vitro. Administration of S6K inhibitors to TGF-α mice prevented the development of extensive subpleural fibrosis and alterations in lung mechanics, and attenuated the increase in total lung hydroxyproline. S6K inhibition after fibrosis was established attenuated the progression of subpleural fibrosis. Together these studies demonstrate targeting the S6K pathway selectively modifies the progression of pulmonary fibrosis in the subpleural compartment of the lung.