Pub Date : 2022-03-10DOI: 10.1183/23120541.lsc-2022.193
R. Fuentes-Mateos, C. Ciminieri, Xinhui Wu, A. Fernández-Medarde, R. Gosens, E. Santos
{"title":"Using lung organoids to recapitulate HRas/NRas-double knockout alveolar maturation defects in mice","authors":"R. Fuentes-Mateos, C. Ciminieri, Xinhui Wu, A. Fernández-Medarde, R. Gosens, E. Santos","doi":"10.1183/23120541.lsc-2022.193","DOIUrl":"https://doi.org/10.1183/23120541.lsc-2022.193","url":null,"abstract":"","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"18 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2022-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128097151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-28DOI: 10.1183/13993003.congress-2019.oa3609
S. Hermelijn, B. Elders, P. Ciet, R. Wijnen, H. Tiddens, M. Schnater
Introduction: While a distinct pathological description exists, standardized guidelines on the description of CT-features of congenital lung abnormalities(CLA) is lacking even though it is the golden standard in pre-operative imaging and diagnosis. Aims and Objectives: To develop a clinical guide for the structured assessment and uniform reporting of anomalies on CT-scan in patients with CLA. Methods: A systematic literature search was conducted for relevant articles on CLA including congenital pulmonary airway malformation(CPAM), bronchopulmonary sequestration(BPS), congenital lobar emphysema(CLE) and bronchogenic cyst(BC). Paediatric patient cohorts and reports describing CLA features exceeding 5 cases were included. Results: Of 1581 articles identified, 28 retrospective cohort-studies remained after assessing full-texts by two independent reviewers. Features exclusively seen in one diagnosis are anomalous arteries in BPS and contralateral herniation and vessel attenuation in CLE. Air-containing cysts are found in CPAM as well as BC. Soft tissue masses are seen in both CPAM and BPS; anomalous arterial blood supply in BPS can help distinguish between both. Perilesional low-attenuation, atelectasis and mediastinal shift can be found in both aforementioned abnormalities as well as CLE. Conclusions: Nomenclature used to describe CT-imaging findings in CLA are highly variable, and due to overlap between and within abnormalities, diagnostic features are difficult to standardize. Based on the literature and on consensus between experts we created a clinical guide to systematically assess CLA using objective radiologic features and uniform nomenclature.
{"title":"A clinical guide in the structured assessment of CT-imaging in congenital lung abnormalities","authors":"S. Hermelijn, B. Elders, P. Ciet, R. Wijnen, H. Tiddens, M. Schnater","doi":"10.1183/13993003.congress-2019.oa3609","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.oa3609","url":null,"abstract":"Introduction: While a distinct pathological description exists, standardized guidelines on the description of CT-features of congenital lung abnormalities(CLA) is lacking even though it is the golden standard in pre-operative imaging and diagnosis. Aims and Objectives: To develop a clinical guide for the structured assessment and uniform reporting of anomalies on CT-scan in patients with CLA. Methods: A systematic literature search was conducted for relevant articles on CLA including congenital pulmonary airway malformation(CPAM), bronchopulmonary sequestration(BPS), congenital lobar emphysema(CLE) and bronchogenic cyst(BC). Paediatric patient cohorts and reports describing CLA features exceeding 5 cases were included. Results: Of 1581 articles identified, 28 retrospective cohort-studies remained after assessing full-texts by two independent reviewers. Features exclusively seen in one diagnosis are anomalous arteries in BPS and contralateral herniation and vessel attenuation in CLE. Air-containing cysts are found in CPAM as well as BC. Soft tissue masses are seen in both CPAM and BPS; anomalous arterial blood supply in BPS can help distinguish between both. Perilesional low-attenuation, atelectasis and mediastinal shift can be found in both aforementioned abnormalities as well as CLE. Conclusions: Nomenclature used to describe CT-imaging findings in CLA are highly variable, and due to overlap between and within abnormalities, diagnostic features are difficult to standardize. Based on the literature and on consensus between experts we created a clinical guide to systematically assess CLA using objective radiologic features and uniform nomenclature.","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115767749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-28DOI: 10.1183/13993003.congress-2019.oa3608
V. Jentgen, K. Dinger, C. Vohlen, S. Dabral, Johannes Will, S. V. Koningsbruggen-Rietschel, M. Odenthal, S. Pullamsetti, J. Dötsch, M. A. Alcázar
Introduction: Obesity triggers lung diseases. We showed that maternal obesity promotes proliferation of lung smooth muscle cells (SMC) through an IL-6-FoxO1 axis in offspring. These processes are also central in the pathogenesis of pulmonary arterial hypertension (PAH). However, it remains elusive if maternal obesity causes PAH. Aims: (1) To investigate the impact of maternal obesity on lung micro-vessels in the offspring, and if it is IL-6 dependent; (2) To analyze if Paclitaxel, an anti-proliferative FoxO1 activator, protects against vascular remodeling. Methods: (1) Female wildtype (WT) and IL-6-/- mice were fed high-fat diet (HFD) or standard diet (SD) prior mating, and during gestation and lactation. After weaning, offspring of both groups received SD. (2) At postnatal day (P) 50, offspring were treated with intravenous Paclitaxel. Lungs were harvested at P21 and P70. Results: (1) Increased microvascular muscularisation, medial wall thickness and micro-vessel formation at P70 were linked to more proliferating (ki67-positive) vascular SMC at P21 in WTHFD when compared to WTSD. Gene expression of endothelial and pro-angiogenetic markers was elevated at P21; moreover, laser-microdissected vessels and bronchi showed reduced FoxO1 mRNA and altered FoxO1 target genes in WTHFD at P21. IL-6-/-HFD offspring were protected from these changes. (2) Paclitaxel treatment protected WTHFD offspring from remodeling and proliferation of vSMC. Conclusion: Maternal obesity is a potential risk factor for PAH via an IL-6-FoxO1 mediated hyperplasia of vSMC HFD offspring. FoxO1 activation could be a novel preventive strategy in the therapy of early metabolic origins of cardiovascular diseases.
{"title":"FoxO1 activation protects against IL-6-mediated perinatal metabolic programming of lung micro-vessels","authors":"V. Jentgen, K. Dinger, C. Vohlen, S. Dabral, Johannes Will, S. V. Koningsbruggen-Rietschel, M. Odenthal, S. Pullamsetti, J. Dötsch, M. A. Alcázar","doi":"10.1183/13993003.congress-2019.oa3608","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.oa3608","url":null,"abstract":"Introduction: Obesity triggers lung diseases. We showed that maternal obesity promotes proliferation of lung smooth muscle cells (SMC) through an IL-6-FoxO1 axis in offspring. These processes are also central in the pathogenesis of pulmonary arterial hypertension (PAH). However, it remains elusive if maternal obesity causes PAH. Aims: (1) To investigate the impact of maternal obesity on lung micro-vessels in the offspring, and if it is IL-6 dependent; (2) To analyze if Paclitaxel, an anti-proliferative FoxO1 activator, protects against vascular remodeling. Methods: (1) Female wildtype (WT) and IL-6-/- mice were fed high-fat diet (HFD) or standard diet (SD) prior mating, and during gestation and lactation. After weaning, offspring of both groups received SD. (2) At postnatal day (P) 50, offspring were treated with intravenous Paclitaxel. Lungs were harvested at P21 and P70. Results: (1) Increased microvascular muscularisation, medial wall thickness and micro-vessel formation at P70 were linked to more proliferating (ki67-positive) vascular SMC at P21 in WTHFD when compared to WTSD. Gene expression of endothelial and pro-angiogenetic markers was elevated at P21; moreover, laser-microdissected vessels and bronchi showed reduced FoxO1 mRNA and altered FoxO1 target genes in WTHFD at P21. IL-6-/-HFD offspring were protected from these changes. (2) Paclitaxel treatment protected WTHFD offspring from remodeling and proliferation of vSMC. Conclusion: Maternal obesity is a potential risk factor for PAH via an IL-6-FoxO1 mediated hyperplasia of vSMC HFD offspring. FoxO1 activation could be a novel preventive strategy in the therapy of early metabolic origins of cardiovascular diseases.","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"1 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126034360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-28DOI: 10.1183/13993003.congress-2019.oa3607
J. Mohr, M. Koch, S. Danopoulos, Lena K. Ebert, N. Oikonomou, C. Vohlen, D. Hirani, D. A. Alam, B. Schermer, J. Dötsch, M. A. Alcázar
Background: Bronchopulmonary dysplasia (BPD) is characterized by impaired alveolarization and regeneration. Kruppel-like factor 4 (Klf4), a transcription factor regulating cell homeostasis and pluripotency, is highly expressed in human and mice during lung development and linked to lung growth arrest. Aim: To study (1) if hyperoxia-induced lung injury reduces Klf4 in ATII cells in mice; (2) if ATII-specific loss of Klf4 depletes number of ATII cells; (3) the function of Klf4 in ATII cells in vitro. Methods: (1) Newborn mice were exposed to 85% O2 (HYX) or room air (NOX). (2) Cell-specific deletion of Klf4 was induced in mice during late lung development. (3) Overexpression (Klf4OE) and ablation of Klf4 (Klf4del; CRISPR/Cas9) in murine lung epithelial cells (MLE-12). Results: (1) Dual immunofluorescent staining determined Klf4 in ATII cells during late murine lung development and in epithelial cells in the human fetal lung. Reduced ATII markers after HYX were linked to reduced Klf4 expression and lung growth. (2) ATII-specific Klf4 ablation during late lung development reduced ATII cells in mice. (3) In MLE-12, HYX decreased Klf4 expression and cell survival. Klf4OE and Klf4del in MLE-12 induced apoptosis and decreased epithelial cell markers. Klf4OE aggravated HYX-related decreased proliferation, activated Smad2 and blocked Stat3 signaling. Inhibition of Smad2, using an inhibitor, activated Stat3. Klf4del activated Stat3 and inhibited Smad2. Conclusion: We identified a novel Klf4-Smad2-Stat3 axis cell homeostasis that HYX disrupts in ATII cells and in lungs of newborn mice, suggesting Klf4 as potential target regulating lung regeneration.
{"title":"Krüppel-like Factor 4 is a Stat3-Smad2 regulator in ATII cells determining ATII cell fate during lung development and hyperoxia-induced lung injury","authors":"J. Mohr, M. Koch, S. Danopoulos, Lena K. Ebert, N. Oikonomou, C. Vohlen, D. Hirani, D. A. Alam, B. Schermer, J. Dötsch, M. A. Alcázar","doi":"10.1183/13993003.congress-2019.oa3607","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.oa3607","url":null,"abstract":"Background: Bronchopulmonary dysplasia (BPD) is characterized by impaired alveolarization and regeneration. Kruppel-like factor 4 (Klf4), a transcription factor regulating cell homeostasis and pluripotency, is highly expressed in human and mice during lung development and linked to lung growth arrest. Aim: To study (1) if hyperoxia-induced lung injury reduces Klf4 in ATII cells in mice; (2) if ATII-specific loss of Klf4 depletes number of ATII cells; (3) the function of Klf4 in ATII cells in vitro. Methods: (1) Newborn mice were exposed to 85% O2 (HYX) or room air (NOX). (2) Cell-specific deletion of Klf4 was induced in mice during late lung development. (3) Overexpression (Klf4OE) and ablation of Klf4 (Klf4del; CRISPR/Cas9) in murine lung epithelial cells (MLE-12). Results: (1) Dual immunofluorescent staining determined Klf4 in ATII cells during late murine lung development and in epithelial cells in the human fetal lung. Reduced ATII markers after HYX were linked to reduced Klf4 expression and lung growth. (2) ATII-specific Klf4 ablation during late lung development reduced ATII cells in mice. (3) In MLE-12, HYX decreased Klf4 expression and cell survival. Klf4OE and Klf4del in MLE-12 induced apoptosis and decreased epithelial cell markers. Klf4OE aggravated HYX-related decreased proliferation, activated Smad2 and blocked Stat3 signaling. Inhibition of Smad2, using an inhibitor, activated Stat3. Klf4del activated Stat3 and inhibited Smad2. Conclusion: We identified a novel Klf4-Smad2-Stat3 axis cell homeostasis that HYX disrupts in ATII cells and in lungs of newborn mice, suggesting Klf4 as potential target regulating lung regeneration.","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"32 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"115180679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-28DOI: 10.1183/13993003.congress-2019.oa3604
Hideaki Isago, A. Mitani, S. Kohno, Hiroyuki Nagoshi, Taro Ishimori, Minako Saito, H. Tamiya, Yu Mikami, Masafumi Horie, H. Urushiyama, T. Jo, G. Tanaka, Ryuji Hamamoto, Y. Terasaki, T. Nagase
Background: Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) are key downstream effectors of the Hippo pathway. TAZ is considered as a homolog of YAP. Recent studies revealed that TAZ knockout mice exhibit lung emphysema, while YAP knockout mice show abnormalities in bronchial morphogenesis, and the cause of these differences remains unknown. Objective: To compare the role of TAZ and YAP in lung development, by generating lung epithelial-specific conditional knockout mice (cKO mice) of Taz and Yap. Methods: Taz and Yap cKO mice were generated by using a surfactant protein C-driven Cre recombinase allele. To identify genes affected by Yap ablation from lung epithelial cells, RNA-seq analysis was performed in Yap cKO embryo lung. We confirmed our in vivo findings by using human lung epithelial cell lines, which YAP and TAZ were suppressed by siRNA. Results: In lung development, Yap was highly expressed in embryonic stage of lung development, conversely Taz was highly expressed in the early alveolar stage. Taz cKO adult mice exhibited lung emphysema in adults, whereas Yap cKO mice were lethal at birth and showed bronchial branching abnormalities. RNA-seq analysis revealed that YAP ablation decreased Sonic hedgehog (Shh) expression, which is essential in proper branching morphogenesis. We also found that TGF-beta stimulation induces Shh expression in cell lines, which was suppressed by knockdown of TAZ or YAP. Conclusion: Our results indicate that TAZ and YAP function at different stages of lung development in lung epithelial cells and essential for proper lung development. Our results suggested the existence of a novel pathway between TGF-beta and Shh.
{"title":"The Hippo pathway effectors TAZ and YAP are sequentially required in lung development","authors":"Hideaki Isago, A. Mitani, S. Kohno, Hiroyuki Nagoshi, Taro Ishimori, Minako Saito, H. Tamiya, Yu Mikami, Masafumi Horie, H. Urushiyama, T. Jo, G. Tanaka, Ryuji Hamamoto, Y. Terasaki, T. Nagase","doi":"10.1183/13993003.congress-2019.oa3604","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.oa3604","url":null,"abstract":"Background: Transcriptional co-activator with PDZ-binding motif (TAZ) and Yes-associated protein (YAP) are key downstream effectors of the Hippo pathway. TAZ is considered as a homolog of YAP. Recent studies revealed that TAZ knockout mice exhibit lung emphysema, while YAP knockout mice show abnormalities in bronchial morphogenesis, and the cause of these differences remains unknown. Objective: To compare the role of TAZ and YAP in lung development, by generating lung epithelial-specific conditional knockout mice (cKO mice) of Taz and Yap. Methods: Taz and Yap cKO mice were generated by using a surfactant protein C-driven Cre recombinase allele. To identify genes affected by Yap ablation from lung epithelial cells, RNA-seq analysis was performed in Yap cKO embryo lung. We confirmed our in vivo findings by using human lung epithelial cell lines, which YAP and TAZ were suppressed by siRNA. Results: In lung development, Yap was highly expressed in embryonic stage of lung development, conversely Taz was highly expressed in the early alveolar stage. Taz cKO adult mice exhibited lung emphysema in adults, whereas Yap cKO mice were lethal at birth and showed bronchial branching abnormalities. RNA-seq analysis revealed that YAP ablation decreased Sonic hedgehog (Shh) expression, which is essential in proper branching morphogenesis. We also found that TGF-beta stimulation induces Shh expression in cell lines, which was suppressed by knockdown of TAZ or YAP. Conclusion: Our results indicate that TAZ and YAP function at different stages of lung development in lung epithelial cells and essential for proper lung development. Our results suggested the existence of a novel pathway between TGF-beta and Shh.","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"51 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"114907339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-28DOI: 10.1183/13993003.congress-2019.oa3603
A. Gie, T. Salaets, J. Deprest, J. Toelen
Introduction: Continuous positive airway pressure (CPAP) and supplemental oxygen are used to treat respiratory failure in preterm infants, however little is known of the functional and structural effects of CPAP on preterm lungs exposed to hyperoxia. Aims and Objectives: This study aims to characterize the effects of intermittent CPAP on lung function and structure in preterm rabbits reared in hyperoxia. We hypothesized the distending pressure of CPAP is biomechanically transduced to have downstream effects on lung function, development and structure in hyperoxia. Methods: Prematurely delivered pups were randomized to normoxia, hyperoxia (FiO2 0.9), hyperoxia plus CPAP (4 hours/day, 5cm H2O). On day 7 of life, pulmonary function tests (pressure-volume, forced oscillation) were performed. Alveolar, vascular and airway morphology was done on pressure fixed lung sections. Results: Hyperoxia significantly altered lung functional and structure. CPAP attenuated the changes of hyperoxia to tissue damping, elastance and the pulmonary artery media and respiratory epithelium. Conclusion: Intermittent CPAP mitigated the functional and structural effects of hyperoxia in preterm rabbits.
{"title":"The influence of intermittent CPAP on hyperoxic lung injury in a preterm rabbit model of bronchopulmonary dysplasia","authors":"A. Gie, T. Salaets, J. Deprest, J. Toelen","doi":"10.1183/13993003.congress-2019.oa3603","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.oa3603","url":null,"abstract":"Introduction: Continuous positive airway pressure (CPAP) and supplemental oxygen are used to treat respiratory failure in preterm infants, however little is known of the functional and structural effects of CPAP on preterm lungs exposed to hyperoxia. Aims and Objectives: This study aims to characterize the effects of intermittent CPAP on lung function and structure in preterm rabbits reared in hyperoxia. We hypothesized the distending pressure of CPAP is biomechanically transduced to have downstream effects on lung function, development and structure in hyperoxia. Methods: Prematurely delivered pups were randomized to normoxia, hyperoxia (FiO2 0.9), hyperoxia plus CPAP (4 hours/day, 5cm H2O). On day 7 of life, pulmonary function tests (pressure-volume, forced oscillation) were performed. Alveolar, vascular and airway morphology was done on pressure fixed lung sections. Results: Hyperoxia significantly altered lung functional and structure. CPAP attenuated the changes of hyperoxia to tissue damping, elastance and the pulmonary artery media and respiratory epithelium. Conclusion: Intermittent CPAP mitigated the functional and structural effects of hyperoxia in preterm rabbits.","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"25 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"121142139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-28DOI: 10.1183/13993003.congress-2019.oa3605
Cecilia Hagman, L. Björklund, L. Bjermer, I. Hansen-Pupp, E. Tufvesson
Introduction: Pulmonary disease after very preterm birth may cause permanent lung damage and as a consequence, lung function impairment in long-term survivors, bronchopulmonary dysplasia being one of the earliest manifestation. Aims: The aim of this study was to assess lung function in children 12 years of age, born very preterm and compare with children born at term. In addition we determined the impact of BPD and prematurity during childhood. Methods: Spirometry, impulse oscillometry, body plethysmograhy and diffusing capacity was performed at 12 years of age in 98 children, born at gestational age of 22-31 weeks (median 27 weeks and birth weight 950g). Age-matched children born at term were included as controls (n=17). BPD was defined as need for supplemental oxygen at 36 weeks postmenstrual age. Results: Prematurity was associated with lower forced expiratory flow (FEF25-75), p=0.05, higher total (R5) and peripheral (R5-20) resistance, p=0.01 resp p Prematurity was also associated with lower diffusion capacity, p=0.01 and higher residual volume, p=0.02. Preterm children with BPD showed no significant lung function impairment at the age of 12 compared to preterm children without BPD. Conclusion: Preterm birth is associated with an increased risk of significant obstructive airway disease and lung function impairment at the age of 12, regardless of BPD diagnosis. Children born preterm would benefit from regular assessment of lung function to give an insight regarding long-term sequele and respiratory health throughout adolescence and adulthood.
{"title":"Development of lung function in children born preterm with and without bronchopulmonary dysplasia - a follow-up study at 12 years of age","authors":"Cecilia Hagman, L. Björklund, L. Bjermer, I. Hansen-Pupp, E. Tufvesson","doi":"10.1183/13993003.congress-2019.oa3605","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.oa3605","url":null,"abstract":"Introduction: Pulmonary disease after very preterm birth may cause permanent lung damage and as a consequence, lung function impairment in long-term survivors, bronchopulmonary dysplasia being one of the earliest manifestation. Aims: The aim of this study was to assess lung function in children 12 years of age, born very preterm and compare with children born at term. In addition we determined the impact of BPD and prematurity during childhood. Methods: Spirometry, impulse oscillometry, body plethysmograhy and diffusing capacity was performed at 12 years of age in 98 children, born at gestational age of 22-31 weeks (median 27 weeks and birth weight 950g). Age-matched children born at term were included as controls (n=17). BPD was defined as need for supplemental oxygen at 36 weeks postmenstrual age. Results: Prematurity was associated with lower forced expiratory flow (FEF25-75), p=0.05, higher total (R5) and peripheral (R5-20) resistance, p=0.01 resp p Prematurity was also associated with lower diffusion capacity, p=0.01 and higher residual volume, p=0.02. Preterm children with BPD showed no significant lung function impairment at the age of 12 compared to preterm children without BPD. Conclusion: Preterm birth is associated with an increased risk of significant obstructive airway disease and lung function impairment at the age of 12, regardless of BPD diagnosis. Children born preterm would benefit from regular assessment of lung function to give an insight regarding long-term sequele and respiratory health throughout adolescence and adulthood.","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"62 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"122299275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-09-28DOI: 10.1183/13993003.congress-2019.oa3602
V. Kuchibhotla, Jane Read, I. Heijink, M. Nawijn, A. Reid, D. Knight
Increased activation of β-catenin and Notch signalling pathways in vivo leads to increased airway mucous cell differentiation, a common feature of asthma. Both these pathways play key roles in the normal development and maintenance of airway epithelium but appear to be dysregulated in asthma. While increased β-catenin activates Notch signalling in intestinal epithelium, it is not clear whether this occurs in asthmatic airway epithelium. We hypothesise that in the asthmatic airway, elevated β-catenin signalling activates Notch resulting in increased mucous cell differentiation. To test this, we modelled asthmatic (n=10) and healthy airway (n=10) epithelium using air-liquid interface (ALI) cultures and compared the activities of β-catenin, Notch, and the expression of their respective targets. Immunohistochemistry (IHC) and qPCR analyses were performed at different stages of epithelial development; 0, 11, 20, and 28 days. IHC staining revealed varying levels of active β-catenin and Notch1 in primary bronchial epithelial cells (PBECs) from healthy and asthma groups during development. There was no significant difference in mRNA expression of β-catenin and Notch targets; Cyclin D1 and Hes1 between healthy and asthma groups during development. Additionally, differentiation markers FOXJ1, FOXA2 and MUC5AC were not found to be significantly different in healthy and asthma groups. Therefore, our data shows that there was no significant difference in β-catenin and Notch signalling between PBECs from asthma and healthy donors. We are currently activating/inhibiting β-catenin and/or Notch pathways in healthy PBECs to get a better understanding of the mechanism of mucous cell differentiation.
{"title":"Late Breaking Abstract - Role of ß-catenin and Notch signalling in increased airway mucous cell differentiation in asthma","authors":"V. Kuchibhotla, Jane Read, I. Heijink, M. Nawijn, A. Reid, D. Knight","doi":"10.1183/13993003.congress-2019.oa3602","DOIUrl":"https://doi.org/10.1183/13993003.congress-2019.oa3602","url":null,"abstract":"Increased activation of β-catenin and Notch signalling pathways in vivo leads to increased airway mucous cell differentiation, a common feature of asthma. Both these pathways play key roles in the normal development and maintenance of airway epithelium but appear to be dysregulated in asthma. While increased β-catenin activates Notch signalling in intestinal epithelium, it is not clear whether this occurs in asthmatic airway epithelium. We hypothesise that in the asthmatic airway, elevated β-catenin signalling activates Notch resulting in increased mucous cell differentiation. To test this, we modelled asthmatic (n=10) and healthy airway (n=10) epithelium using air-liquid interface (ALI) cultures and compared the activities of β-catenin, Notch, and the expression of their respective targets. Immunohistochemistry (IHC) and qPCR analyses were performed at different stages of epithelial development; 0, 11, 20, and 28 days. IHC staining revealed varying levels of active β-catenin and Notch1 in primary bronchial epithelial cells (PBECs) from healthy and asthma groups during development. There was no significant difference in mRNA expression of β-catenin and Notch targets; Cyclin D1 and Hes1 between healthy and asthma groups during development. Additionally, differentiation markers FOXJ1, FOXA2 and MUC5AC were not found to be significantly different in healthy and asthma groups. Therefore, our data shows that there was no significant difference in β-catenin and Notch signalling between PBECs from asthma and healthy donors. We are currently activating/inhibiting β-catenin and/or Notch pathways in healthy PBECs to get a better understanding of the mechanism of mucous cell differentiation.","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"54 35 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2019-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"126781607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-15DOI: 10.1183/13993003.CONGRESS-2018.PA1382
M. Syed, D. Shah, V. Bhandari
{"title":"Role of TREM1-Ripk3 axis in hyperoxia induced lung injury in neonates.","authors":"M. Syed, D. Shah, V. Bhandari","doi":"10.1183/13993003.CONGRESS-2018.PA1382","DOIUrl":"https://doi.org/10.1183/13993003.CONGRESS-2018.PA1382","url":null,"abstract":"","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"49 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"128335740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-15DOI: 10.1183/13993003.CONGRESS-2018.PA1381
D. Hirani, K. Dinger, J. Mohr, C. Vohlen, Behrus Darvishan, F. Klein, E. L. Garcia, M. Odenthal, J. Dötsch, M. A. Alcázar
Background: Prolonged exposure to increased oxygen induces inflammation, matrix remodeling, and alveolar arrested in lungs of preterm infants, leading to Bronchopulmonary dysplasia (BPD). Interleukin 6 (IL-6) has been shown to be increased in tracheal aspirates of infants evolving BPD. Aim: We hypothesized that activation of IL-6 signaling is linked to impaired alveolarization; loss of IL-6 protects from neonatal hyperoxia-induced lung injury. Methods: (1) Wildtype and IL-6 deficient newborn mice (IL-6-/-) or (2) cultured macrophages and lung epithelial cells were exposed to 85% O2 (HYX) or 21% O2 (NOX). Results: (1) HYX increased IL-6 mRNA and activates Stat3/SOCS3 signaling in lungs of WT mice. Quantitative lung morphometry showed increased mean linear intercept, alveolar surface area, and septal thickness, and reduced radial alveolar count, indicating impaired alveolar formation. Furthermore, microvessels (20-100µm) were reduced in lungs after HYX. In contrast, IL-6-/- were partially protected from these structural changes. Elastic fibers, elastin protein, and collagen Iα1 mRNA were significantly increased after HYX in IL-6-/- when compared to WT. Moreover, IL-6 deficiency protected from decreased lung expression of surfactant protein A (SP-A) and SP-C, and increased SP-D mRNA. (2) HYX induced the release of IL-6 from cultured macrophages; conditioned media of hyperoxia-exposed macrophages reduced survival of lung epithelial cells. Conclusion: Here, we do not only show that loss of IL-6 partially protects from neonatal hyperoxia-induced lung injury, but also the antiproliferative effect of macrophage secretome. This could offer novel therapeutic approaches for BPD.
{"title":"Loss of IL-6 enables lung growth in newborn mice exposed to prolonged hyperoxia","authors":"D. Hirani, K. Dinger, J. Mohr, C. Vohlen, Behrus Darvishan, F. Klein, E. L. Garcia, M. Odenthal, J. Dötsch, M. A. Alcázar","doi":"10.1183/13993003.CONGRESS-2018.PA1381","DOIUrl":"https://doi.org/10.1183/13993003.CONGRESS-2018.PA1381","url":null,"abstract":"Background: Prolonged exposure to increased oxygen induces inflammation, matrix remodeling, and alveolar arrested in lungs of preterm infants, leading to Bronchopulmonary dysplasia (BPD). Interleukin 6 (IL-6) has been shown to be increased in tracheal aspirates of infants evolving BPD. Aim: We hypothesized that activation of IL-6 signaling is linked to impaired alveolarization; loss of IL-6 protects from neonatal hyperoxia-induced lung injury. Methods: (1) Wildtype and IL-6 deficient newborn mice (IL-6-/-) or (2) cultured macrophages and lung epithelial cells were exposed to 85% O2 (HYX) or 21% O2 (NOX). Results: (1) HYX increased IL-6 mRNA and activates Stat3/SOCS3 signaling in lungs of WT mice. Quantitative lung morphometry showed increased mean linear intercept, alveolar surface area, and septal thickness, and reduced radial alveolar count, indicating impaired alveolar formation. Furthermore, microvessels (20-100µm) were reduced in lungs after HYX. In contrast, IL-6-/- were partially protected from these structural changes. Elastic fibers, elastin protein, and collagen Iα1 mRNA were significantly increased after HYX in IL-6-/- when compared to WT. Moreover, IL-6 deficiency protected from decreased lung expression of surfactant protein A (SP-A) and SP-C, and increased SP-D mRNA. (2) HYX induced the release of IL-6 from cultured macrophages; conditioned media of hyperoxia-exposed macrophages reduced survival of lung epithelial cells. Conclusion: Here, we do not only show that loss of IL-6 partially protects from neonatal hyperoxia-induced lung injury, but also the antiproliferative effect of macrophage secretome. This could offer novel therapeutic approaches for BPD.","PeriodicalId":290970,"journal":{"name":"Lung and airway developmental biology","volume":"113 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2018-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"133146796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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