Fibroblast growth factors (FGFs) control organ morphogenesis during development as well as tissue homeostasis and repair in the adult organism. Despite their importance, many mechanisms that regulate FGF function are still poorly understood. Interestingly, the thermodynamic stability of 22 mammalian FGFs varies widely, with some FGFs remaining stable at body temperature for more than 24 h, while others lose their activity within minutes. How thermodynamic stability contributes to the function of FGFs during development remains unknown. Here we show that FGF10, an important limb and lung morphogen, exists as an intrinsically unstable protein that is prone to unfolding and is rapidly inactivated at 37 °C. Using rationally driven directed mutagenesis, we have developed several highly stable (STAB) FGF10 variants with a melting temperature of over 19 °C more than that of wildtype FGF10. In cellular assays in vitro, the FGF10-STABs did not differ from wildtype FGF10 in terms of binding to FGF receptors, activation of downstream FGF receptor signaling in cells, and induction of gene expression. In mouse embryonal lung explants, FGF10-STABs, but not wildtype FGF10, suppressed branching, resulting in increased alveolarization and expansion of epithelial tissue. Similarly, FGF10-STAB1, but not FGF10 wildtype, inhibited the growth of mouse embryonic tibias and markedly altered limb morphogenesis when implanted into chicken limb buds, collectively demonstrating that thermal instability should be considered an important regulator of FGF function that prevents ectopic signaling. Furthermore, we show enhanced differentiation of human iPSC-derived lung organoids and improved regeneration in ex vivo lung injury models mediated by FGF10-STABs, suggesting an application in cell therapy.

• Klíčová slova
• Development, FGF10, Fibroblast growth factor, Lung, Morphogen, Stability,
• MeSH
• fibroblastový růstový faktor 10 * metabolismus   genetika   chemie   MeSH
• lidé MeSH
• myši MeSH
• plíce metabolismus   embryologie   MeSH
• receptory fibroblastových růstových faktorů metabolismus   MeSH
• signální transdukce * MeSH
• stabilita proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Fgf10 protein, mouse MeSH Prohlížeč
• fibroblastový růstový faktor 10 * MeSH
• receptory fibroblastových růstových faktorů MeSH

BACKGROUND: Lung ultrasonography (LUS) is a point-of-care imaging modality with growing potential in primary care. OBJECTIVES: While its use is well established in hospital settings, data on its accuracy when performed by general practitioners (GPs) remain limited. This study aimed to assess the diagnostic accuracy of LUS conducted by GPs following structured training. METHODS: We recruited 17 GPs from various regions of the Czech Republic. They completed a two-day educational course focused on LUS. Patients with current dyspnoea (NYHA II-IV) or a history of dyspnoea within the last four weeks were included and underwent LUS to assess the presence of pleural effusion and interstitial syndrome. An independent expert sonographer, blinded to clinical data, evaluated recorded LUS video loops as the reference standard. LUS findings were categorized into A profile (presence of A lines and intact lung sliding, indicating normal aeration), B profile (three or more B lines per intercostal space in at least two intercostal spaces per hemithorax, suggesting interstitial syndrome), pulmonary consolidation and pleural effusion. RESULTS: A total of 128 patients were enrolled in the study. A total of 768 thoracic segments were examined. A profile was identified in 642 (83.6%) segments, B profile in 108 (14.1%), pulmonary consolidation in 8 (1.0%), and pleural effusion in 12 (1.6%). For the identification of A profile, the sensitivity was 97.51% (95% CI 95.98-98.57), and the specificity was 88.10% (95% CI 81,13-93,18); for B profile, the sensitivity was 87.04% (95% CI 79,21-92,73), and the specificity was 97.73% (95% CI96,28-98,72); for pulmonary consolidation, the sensitivity was 100.0% (95% CI 63,06-100,00), and the specificity was 100.0% (95% CI 99,52-100,0); for pleural effusion, the sensitivity was 83.33% (95% CI 51,59-97,91), and the specificity was 99.87% (95% CI 99,27-100,00). CONCLUSION: Our findings provide important preliminary data, demonstrating that GPs can perform LUS accurately after a structured training program. THE TRIAL REGISTRATION IDENTIFIER: is NCT04905719.

• Klíčová slova
• Accuracy, COVID-19, Lung examination, Point-of-care ultrasound, Primary care,
• MeSH
• dospělí MeSH
• dyspnoe diagnostické zobrazování   MeSH
• intersticiální plicní nemoci diagnostické zobrazování   MeSH
• klinické kompetence MeSH
• lidé středního věku MeSH
• lidé MeSH
• pleurální výpotek diagnostické zobrazování   MeSH
• plíce * diagnostické zobrazování   MeSH
• plicní nemoci * diagnostické zobrazování   MeSH
• praktičtí lékaři * výchova   MeSH
• primární zdravotní péče MeSH
• průřezové studie MeSH
• senioři MeSH
• senzitivita a specificita MeSH
• ultrasonografie MeSH
• vyšetření u lůžka * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Geografické názvy
• Česká republika MeSH

The effects of a large arteriovenous fistula (AVF) on pulmonary perfusion remains to be elucidated. We aimed to study, for the first time, the real-time acute effects of a large AVF on regional distribution of pulmonary perfusion in a novel porcine model. Ten healthy swine under general anesthesia were studied. AVF was created by the connection of femoral artery and femoral vein using high-diameter perfusion cannulas. The AVF was closed and after 30 min of stabilization the first values were recorded. The fistula was then opened, and new data were collected after reaching stable state. Continuous hemodynamic monitoring was performed throughout the protocol. The following functional images were analyzed by electrical impedance tomography (EIT): perfusion and ventilation distributions. We found an increased cardiac output and right ventricular work, which was strongly correlated to an increased pulmonary artery mean pressure (r=0.878, P=0.001). The ventral/dorsal ratio of pulmonary perfusion decreased from 1.9+/-1.0 to 1.5+/-0.7 (P=0.025). The percentage of total pulmonary blood flow through the dorsal lung region increased from 38.6+/-11.7 to 42.2+/-10.4 (P=0.016). In conclusion, we have used EIT for the first time for studying the acute effects of a large AVF on regional distribution of pulmonary perfusion in a novel porcine model. In this new experimental model of hyperkinetic circulation caused by AVF, we documented an increased percentage of total pulmonary blood flow through the dorsal lung region and a more homogeneous perfusion distribution. Key words Arteriovenous fistula, Hyperkinetic circulation, Tissue perfusion, Animal model, Pulmonary blood flow.

• MeSH
• arteria pulmonalis diagnostické zobrazování   patofyziologie   MeSH
• arteriovenózní píštěl patofyziologie   diagnostické zobrazování   MeSH
• arteriovenózní zkrat MeSH
• plíce krevní zásobení   diagnostické zobrazování   MeSH
• plicní oběh * fyziologie   MeSH
• prasata MeSH
• vena femoralis diagnostické zobrazování   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Concerns regarding chronic injuries (e.g., fibrosis and carcinogenesis) induced by nanoparticles raised public health concerns and need to be rapidly assessed in hazard identification. Although in silico analysis is commonly used for risk assessment of chemicals, predicting chronic in vivo nanotoxicity remains challenging due to the intricate interactions at multiple interfaces like nano-biofluids and nano-subcellular organelles. Herein, we develop a multimodal feature fusion analysis framework to predict the fibrogenic potential of metal oxide nanoparticles (MeONPs) in female mice. Treating each nano-bio interface as an independent entity, eighty-seven features derived from MeONP-lung interactions are used to develop a machine learning-based predictive framework for lung fibrosis. We identify cell damage and cytokine (IL-1β and TGF-β1) production in macrophages and epithelial cells as key events closely associated with particle size, surface charge, and lysosome interactions. Experimental validations show that the developed in silico model has 85% accuracy. Our findings demonstrate the potential usefulness of this predictive model for risk assessment of nanomaterials and in assisting regulatory decision-making. While the model is developed based on 52 MeONPs, further validation using a larger nanoparticle library is necessary to confirm its broader applicability.

• MeSH
• epitelové buňky účinky léků   metabolismus   patologie   MeSH
• hodnocení rizik metody   MeSH
• interleukin-1beta metabolismus   MeSH
• kovové nanočástice * toxicita   chemie   MeSH
• lidé MeSH
• lyzozomy metabolismus   účinky léků   MeSH
• makrofágy účinky léků   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• plíce patologie   účinky léků   metabolismus   MeSH
• plicní fibróza chemicky indukované   patologie   metabolismus   MeSH
• počítačová simulace MeSH
• strojové učení * MeSH
• transformující růstový faktor beta1 metabolismus   MeSH
• velikost částic MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• interleukin-1beta MeSH
• transformující růstový faktor beta1 MeSH

BACKGROUND: Pulmonary hernia is a rare condition characterized by the protrusion of lung tissue through a chest wall defect. Trauma and thoracic surgery are the most common causes of acquired lung hernias. We present an unusual case of (sequential) bilateral lung herniation with parenchymal infarction after bilateral lobar lung transplantation. CASE PRESENTATION: A 50-year-old female, wait-listed as high-urgency candidate, with a body mass index (BMI) of 29 kg/m2 underwent a bilateral lobar lung transplantation for pulmonary fibrosis through a clamshell thoracotomy approach. Due to a size mismatch, stapler resection of the segment 3 and the middle lobe of the right lung, as well as an upper left lobectomy was required. The chest was closed with 3 braided non-absorbable pericostal sutures on each side. Sternal osteosynthesis was performed with a titanium sternal splint along with 7 self-tapping screws with a length of 18 mm. On the posttransplant day (PTD) 18, patient's clinical condition deteriorated. Physical examination didn't reveal any palpable subcutaneous chest resistance. However, a computed tomography (CT) scan showed a herniation of the segment 6 of the right lung. During acute surgical revision, perioperative finding revealed posterior pericostal suture failure. Therefore, a stapler resection was performed due to the infarction of the herniated segment. On the PTD 36, herniation of the left lung parenchyma was detected by acute CT scan. The protruding vital parenchyma was surgically repositioned without necessity of resection. Two posterior pericostal sutures were broken, and distal part of sternal splint detached. Thoracotomy was closed using 5 braided non-absorbable sutures. Sternum was re-osteosynthesized with the STRATOS™ system. After 3 months of intensive postoperative care, the patient was transferred to the rehabilitation department. She was discharged on the PTD 99. After 20 months of follow-up, lung function remains stable without the need for oxygen support. CONCLUSION: Clamshell incision remains ultimate approach in thoracic surgery. However, pulmonary herniation after clamshell thoracotomy is a rare complication and may manifest as acute respiratory distress syndrome with an inflammatory response. In these cases, CT scan should be always considered, even if no palpable pathology of chest is present.

• Klíčová slova
• Clamshell thoracotomy, Lung hernia, Lung transplantation,
• MeSH
• hernie * etiologie   MeSH
• infarkt etiologie   chirurgie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• operace kýly metody   škodlivé účinky   MeSH
• plíce diagnostické zobrazování   MeSH
• plicní nemoci chirurgie   etiologie   MeSH
• počítačová rentgenová tomografie MeSH
• pooperační komplikace chirurgie   MeSH
• torakotomie * metody   MeSH
• transplantace plic * škodlivé účinky   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

BACKGROUND: The advancement of nanotechnology underscores the imperative need for establishing in silico predictive models to assess safety, particularly in the context of chronic respiratory afflictions such as lung fibrosis, a pathogenic transformation that is irreversible. While the compilation of predictive descriptors is pivotal for in silico model development, key features specifically tailored for predicting lung fibrosis remain elusive. This study aimed to uncover the essential predictive descriptors governing nanoparticle-induced pulmonary fibrosis. METHODS: We conducted a comprehensive analysis of the trajectory of metal oxide nanoparticles (MeONPs) within pulmonary systems. Two biological media (simulated lung fluid and phagolysosomal simulated fluid) and two cell lines (macrophages and epithelial cells) were meticulously chosen to scrutinize MeONP behaviors. Their interactions with MeONPs, also referred to as nano-bio interactions, can lead to alterations in the properties of the MeONPs as well as specific cellular responses. Physicochemical properties of MeONPs were assessed in biological media. The impact of MeONPs on cell membranes, lysosomes, mitochondria, and cytoplasmic components was evaluated using fluorescent probes, colorimetric enzyme substrates, and ELISA. The fibrogenic potential of MeONPs in mouse lungs was assessed by examining collagen deposition and growth factor release. Random forest classification was employed for analyzing in chemico, in vitro and in vivo data to identify predictive descriptors. RESULTS: The nano-bio interactions induced diverse changes in the 4 characteristics of MeONPs and had variable effects on the 14 cellular functions, which were quantitatively evaluated in chemico and in vitro. Among these 18 quantitative features, seven features were found to play key roles in predicting the pro-fibrogenic potential of MeONPs. Notably, IL-1β was identified as the most important feature, contributing 27.8% to the model's prediction. Mitochondrial activity (specifically NADH levels) in macrophages followed closely with a contribution of 17.6%. The remaining five key features include TGF-β1 release and NADH levels in epithelial cells, dissolution in lysosomal simulated fluids, zeta potential, and the hydrodynamic size of MeONPs. CONCLUSIONS: The pro-fibrogenic potential of MeONPs can be predicted by combination of key features at nano-bio interfaces, simulating their behavior and interactions within the lung environment. Among the 18 quantitative features, a combination of seven in chemico and in vitro descriptors could be leveraged to predict lung fibrosis in animals. Our findings offer crucial insights for developing in silico predictive models for nano-induced pulmonary fibrosis.

• Klíčová slova
• biotransformation, lung fibrosis, nanosafety, nanotoxicity, predictive toxicology,
• MeSH
• buňky A549 MeSH
• kovové nanočástice * toxicita   chemie   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• plíce účinky léků   patologie   metabolismus   MeSH
• plicní fibróza * chemicky indukované   metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The alveolar-capillary interface is the key functional element of gas exchange in the human lung, and disruptions to this interface can lead to significant medical complications. However, it is currently challenging to adequately model this interface in vitro, as it requires not only the co-culture of human alveolar epithelial and endothelial cells but mainly the preparation of a biocompatible scaffold that mimics the basement membrane. This scaffold should support cell seeding from both sides, and maintain optimal cell adhesion, growth, and differentiation conditions. Our study investigates the use of polycaprolactone (PCL) nanofibers as a versatile substrate for such cell cultures, aiming to model the alveolar-capillary interface more accurately. We optimized nanofiber production parameters, utilized polyamide mesh UHELON as a mechanical support for scaffold handling, and created 3D-printed inserts for specialized co-cultures. Our findings confirm that PCL nanofibrous scaffolds are manageable and support the co-culture of diverse cell types, effectively enabling cell attachment, proliferation, and differentiation. Our research establishes a proof-of-concept model for the alveolar-capillary interface, offering significant potential for enhancing cell-based testing and advancing tissue-engineering applications that require specific nanofibrous matrices.

• Klíčová slova
• alveolar‐capillary interface, electrospinning, nanofibers, polycaprolactone (PCL), scaffold, tissue engineering,
• MeSH
• bazální membrána MeSH
• lidé MeSH
• nanovlákna * chemie   MeSH
• ověření koncepční studie MeSH
• plicní alveoly * chemie   cytologie   MeSH
• polyestery * chemie   MeSH
• tkáňové inženýrství * metody   MeSH
• tkáňové podpůrné struktury * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• polycaprolactone MeSH Prohlížeč
• polyestery * MeSH

AIM: Transbronchial cryobiopsies are increasingly used for the diagnosis of interstitial lung disease (ILD), but there is a lack of published information on the features of specific ILD in cryobiopsies. Here we attempt to provide pathological guidelines for separating usual interstitial pneumonia (UIP) of idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (FHP) and connective tissue disease-associated ILD (CTD-ILD) in cryobiopsies. METHODS: We examined 120 cryobiopsies from patients with multidisciplinary discussion (MDD)-established CTD-ILD and compared them to a prior series of 121 biopsies from patients with MDD-established IPF or FHP. RESULTS: A non-specific interstitial pneumonia (NSIP) pattern alone was seen in 36 of 120 (30%) CTD-ILD, three of 83 (3.6%) FHP and two of 38 (5.2%) IPF cases, statistically favouring a diagnosis of CTD-ILD. The combination of NSIP + OP was present in 29 of 120 (24%) CTD-ILD, two of 83 (2.4%) FHP and none of 38 (0%) IPF cases, favouring a diagnosis of CTD-ILD. A UIP pattern, defined as fibroblast foci plus any of patchy old fibrosis/fibrosis with architectural distortion/honeycombing, was identified in 28 of 120 (23%) CTD-ILD, 45 of 83 (54%) FHP and 27 of 38 (71%) IPF cases and supported a diagnosis of FHP or IPF. The number of lymphoid aggregates/mm2 and fibroblast foci/mm2 was not different in IPF, CTD-ILD or FHP cases with a UIP pattern. Interstitial giant cells supported a diagnosis of FHP or CTD-ILD over IPF, but were infrequent. CONCLUSIONS: In the correct clinical/radiological context the pathological findings of NSIP, and particularly NSIP plus OP, favour a diagnosis of CTD-ILD in a cryobiopsy, but CTD-ILD with a UIP pattern, FHP with a UIP pattern and IPF generally cannot be distinguished.

• Klíčová slova
• connective tissue disease‐associated interstitial lung disease, cryobiopsy, hypersensitivity pneumonitis, usual interstitial pneumonia,
• MeSH
• biopsie metody   MeSH
• dospělí MeSH
• idiopatická plicní fibróza patologie   komplikace   diagnóza   MeSH
• intersticiální plicní nemoci * patologie   diagnóza   komplikace   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci pojiva * komplikace   patologie   diagnóza   MeSH
• plíce patologie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Five cases of patients with systemic connective tissue diseases (CTD) who developed connective tissue disease-associated interstitial lung disease (CTD-ILD) with progressive pulmonary fibrosis (PPF) are reported here. Unspecified ILD was diagnosed using high-resolution computed tomography (HRCT). Histologically, all cases were usual interstitial pneumonia (UIP) with findings of advanced (3/5) to diffuse (2/5) fibrosis, with a partially (4/5) to completely (1/5) formed image of a honeycomb lung. The fibrosis itself spread subpleurally and periseptally to more central parts (2/5) of the lung, around the alveolar ducts (2/5), or even without predisposition (1/5). Simultaneously, there was architectural reconstruction based on the mutual fusion of fibrosis without compression of the surrounding lung parenchyma (1/5), or with its compression (4/5). The whole process was accompanied by multifocal (1/5), dispersed (2/5), or organized inflammation in aggregates and lymphoid follicles (2/5). As a result of continuous fibroproduction and maturation of the connective tissue, the alveolar septa thickened, delimiting groups of alveoli that merged into air bullae. Few indistinctly visible (2/5), few clearly visible (1/5), multiple indistinctly visible (1/5), and multiple clearly visible (1/5) fibroblastic foci were present. Among the concomitant changes, areas of emphysema, bronchioloectasia, and bronchiectasis, as well as bronchial and vessel wall hypertrophy, and mucostasis in the alveoli and edema were observed. The differences in the histological appearance of usual interstitial pneumonia associated with systemic connective tissue diseases (CTD-UIP) versus the pattern associated with idiopathic pulmonary fibrosis (IPF-UIP) are discussed here. The main differences lie in spreading lung fibrosis, architectural lung remodeling, fibroblastic foci, and inflammatory infiltrates.

• MeSH
• dospělí MeSH
• idiopatická plicní fibróza patologie   komplikace   MeSH
• intersticiální plicní nemoci * patologie   komplikace   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nemoci pojiva * patologie   komplikace   MeSH
• plíce patologie   diagnostické zobrazování   MeSH
• počítačová rentgenová tomografie MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

INTRODUCTION: The aging process is intricately linked to alterations in cellular and tissue structures, with the respiratory system being particularly susceptible to age-related changes. Therefore, this study aimed to profile the activity of proteases using activity-based probes in lung tissues of old and young rats, focusing on the expression levels of different, in particular cathepsins G and X and matrix Metalloproteinases (MMPs). Additionally, the impact on extracellular matrix (ECM) components, particularly fibronectin, in relation to age-related histological and ultrastructural changes in lung tissues was investigated. MATERIALS AND METHODS: Lung tissues from old and young rats were subjected to activity-based probe profiling to assess the activity of different proteases. Expression levels of cathepsins G and X were quantified, and zymography was performed to evaluate matrix metalloproteinases activity. Furthermore, ECM components, specifically fibronectin, were examined for signs of degradation in the old lung tissues compared to the young ones. Moreover, histological, immunohistochemical and ultrastructural assessments of old and young lung tissue were also conducted. RESULTS: Our results showed that the expression levels of cathepsins G and X were notably higher in old rat lung tissues in contrast to those in young rat lung tissues. Zymography analysis revealed elevated MMP activity in the old lung tissues compared to the young ones. Particularly, significant degradation of fibronectin, an essential ECM component, was observed in the old lung tissues. Numerous histological and ultrastructural alterations were observed in old lung tissues compared to young lung tissues. DISCUSSION AND CONCLUSION: The findings indicate an age-related upregulation of cathepsins G and X along with heightened MMP activity in old rat lung tissues, potentially contributing to the degradation of fibronectin within the ECM. These alterations highlight potential mechanisms underlying age-associated changes in lung tissue integrity and provide insights into protease-mediated ECM remodeling in the context of aging lungs.

• MeSH
• extracelulární matrix metabolismus   ultrastruktura   MeSH
• fibronektiny * metabolismus   MeSH
• kathepsin G metabolismus   MeSH
• krysa rodu Rattus MeSH
• lyzozomy ultrastruktura   metabolismus   MeSH
• matrixové metaloproteinasy metabolismus   MeSH
• plíce * ultrastruktura   metabolismus   MeSH
• proteasy metabolismus   MeSH
• stárnutí * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fibronektiny * MeSH
• kathepsin G MeSH
• matrixové metaloproteinasy MeSH
• proteasy MeSH