Die Inzidenz des Atemnotsyndroms ist bei männlichen Neugeborenen etwa 1,7-mal so hoch wie bei weiblichen. Zur Erforschung der Ursachen dieser Tatsache wurden in der vorliegenden Arbeit geschlechtsabhängige Unterschiede im transepithelialen Natriumtransport an fetalen distalen Lungenepithelzellen von Ratten untersucht. Die zugrunde liegende Versuchsanordnung stellt ein Modell der Typ II Pneumozyten des späten Frühgeborenen dar. In Ussing Kammer Messungen wurde ein höherer Natriumtransport in weiblichen Zellen im Vergleich zu männlichen Zellen nachgewiesen. Des Weiteren zeigten Genexpressionsanalysen eine höhere Expression der am Natriumtransport beteiligten Kanäle und Transporter in weiblichen Zellen. Um mögliche Ursachen der festgestellten Geschlechtsunterschiede zu eruieren, wurde die Genexpression von Hormonrezeptoren untersucht. Die Ergebnisse lassen vermuten, dass die Rezeptoren weiblicher Geschlechtshormone dabei eine wichtige Rolle spielen. Abschließend betrachtet diese Arbeit die absolute Zahl fetaler distaler Lungenepithelzellen in Rattenfeten beider Geschlechter. Hierbei fanden sich ebenfalls Geschlechtsdifferenzen. Zusammenfassend kann die vorliegende Arbeit zu einem besseren Verständnis der Pathogenese und der Inzidenz des Atemnotsyndroms des Frühgeborenen beitragen.

MUDr. Michal Otáhal Biomechanický model interakce oběhu a ventilace za podmínek UPV Abstract: Conventional mechanical ventilation provides gas exchange in conditions of respiratory failure by application positive airway pressure in the respiratory system. Due to the significant change in pressure conditions inside the thorax during conventional artificial ventilation the circulation can be significantly affected. Recruitment maneuver (RM) techniques can be a part of ventilation strategy in patients with the Acute Respiratory Distress Syndrome (ARDS), that are used to re-aerate collapsed parts of the lung parenchyma. During these RMs a significantly higher airway pressure is used than in protective ventilation strategy, which can limit the flow through the lung capillary network and can significantly affect the systemic hemodynamics of the patient. The aim of this work was to develop an optimized animation model of ARDS, then to compare the influence that has the application of different types of recruitment maneuvers on hemodynamics and to create a biomechanical simulation model of interaction and blood circulation and its verification with data obtained during the implementation of different types of RM in the experimental animal ARDS model. Results from the experimental animal model and simulations...

Le syndrome de détresse respiratoire aiguë (SDRA) est une forme sévère de défaillance respiratoire qui se caractérise par la présence de dommages alvéolaires, d’un oedème pulmonaire et d’une réponse inflammatoire exacerbée. C’est une condition pour laquelle il n’existe à ce jour aucun traitement pharmacologique efficace. Lors des dernières années, des antagonistes des récepteurs de l’IL-1 (Kineret) et de l’IL-6 (tocilizumab) ont fait preuve d’une efficacité modérée pour le traitement du SDRA causé par la COVID-19. Cependant, leur potentiel thérapeutique en SDRA clinique non causé par la COVID reste à démontrer et les résultats obtenus dans les modèles animaux sont mitigés. Nous avons émis l’hypothèse que le tocilizumab et le Kineret pourraient améliorer la résolution des différents paramètres du SDRA non causé par la COVID-19. Nous avons aussi posé l’hypothèse que des peptides, antagonistes des récepteurs de l’IL-1 (rytvela) ou de l’IL- 6 (HSJ633) et permettant de préserver certaines voies aux propriétés cytoprotectrices en aval de ces récepteurs, pourraient potentiellement être plus efficaces que le Kineret et le tocilizumab pour le traitement des paramètres du SDRA. L’objectif de ma maîtrise était donc de tester ces deux hypothèses dans un modèle murin d’atteinte pulmonaire aiguë (ALI) induite par la bléomycine, qui mime pendant sa phase aiguë les principaux paramètres du SDRA. Mes travaux montrent qu’aucun des quatre antagonistes n’a permis d’améliorer significativement les paramètres observés à jour 7 post-bléomycine (état général, dommages alvéolaires, oedème et inflammation pulmonaire). Ainsi, mes données suggèrent que dans notre modèle d’ALI induit par la bléomycine, la réponse inflammatoire induite via le IL-1R ou le IL-6R ne semble pas constituer un des mécanismes principaux engendrant les différentes atteintes, puisqu’elles ne sont pas prévenues par les antagonistes de ces récepteurs. En plus de contribuer à mieux comprendre ce modèle animal, mes résultats permettent de mettre en lumière que la réparation des dommages ainsi que la résorption secondaire de l’oedème sont cruciales pour la résolution du SDRA et que de viser seulement la voie inflammatoire est insuffisant. / Acute respiratory distress syndrome (ARDS) is a form of severe lung failure characterized by the presence of a pulmonary edema, an inflammatory response, and alveolar damage. There is currently no effective pharmacological treatment for ARDS. In recent years, IL-1 and IL-6 receptor antagonists Kinerert and tocilizumab, respectively, have shown some efficacy as a treatment of ARDS caused by COVID-19. However, their therapeutic potential in non-COVID ARDS remains to be proven and the results obtained in animal models are conflicting. We thus tested the hypothesis that tocilizumab and Kineret could improve the resolution of key parameters of non-COVID ARDS. We also hypothesized that two peptides, rytvela and HSJ633, IL-1 and IL-6 receptor antagonists, respectively, which preserve some of the cytoprotective downstream pathways, could potentially be more effective than Kineret and tocilizumab in treating the various parameters of ARDS. The goal of my master thesis was therefore to test these two hypotheses in a mouse model of acute lung injury (ALI) induced by bleomycin instillation, which, during its acute phase, mimics the main parameters of ARDS. My work has shown that none of the antagonists were able to significantly improve the parameters observed on day 7 post-bleomycin (general condition of the mice, alveolar damages, pulmonary edema and inflammation). Thus, my data suggest that in our bleomycin-induced ALI model, the inflammatory response triggered via IL-1R or IL-6R does not appear to be the principal mechanism generating the main damaging outcome, since they are not prevented by the antagonists of these receptors. In addition to contributing to a better understanding of this animal model of ALI, my research has highlighted the fact that targeting inflammation alone is insufficient and that repairing alveolar damages, and secondary resorbing lung edema, are cornerstones for the resolution of ARDS.

Acute Respiratory Distress Syndrome (ARDS) is common in COVID-19 patients and is associated with high mortality. The aim of this observational study was to describe patients’ characteristics and outcome, identifying potential risk factors for in-hospital mortality and for developing Long-COVID symptoms. This retrospective study included all patients with COVID-19 associated ARDS (cARDS) in the period from March 2020 to March 2021 who were invasively ventilated at the intensive care unit (ICU) of the University Hospital Dresden, Germany. Between October 2021 and December 2021 patients discharged alive (at minimum 6 months after hospital discharge—midterm survival) were contacted and interviewed about persistent symptoms possibly associated with COVID-19 as well as the quality of their lives using the EQ-5D-5L-questionnaire. Long-COVID was defined as the occurrence of one of the symptoms at least 6 months after discharge. Risk factors for mortality were assessed with Cox regression models and risk factors for developing Long-COVID symptoms by using relative risk (RR) regression. 184 Patients were included in this study (male: n = 134 (73%), median age 67 (range 25–92). All patients were diagnosed with ARDS according to the Berlin Definition. 89% of patients (n = 164) had severe ARDS (Horovitz-index < 100 mmHg). In 27% (n = 49) extracorporeal membrane oxygenation was necessary to maintain gas exchange. The median length of in-hospital stay was 19 days (range 1–60). ICU mortality was 51%, hospital mortality 59%. Midterm survival (median 11 months) was 83% (n = 55) and 78% (n = 43) of these patients presented Long-COVID symptoms with fatigue as the most common symptom (70%). Extreme obesity (BMI > 40 kg/m2) was the strongest predictor for in-hospital mortality (hazard ratio: 3.147, confidence interval 1.000–9.897) and for developing Long-COVID symptoms (RR 1.61, confidence interval 1.26–2.06). In-hospital mortality in severe cARDS patients was high, but > 80% of patients discharged alive survived the midterm observation period. Nonetheless, most patients developed Long-COVID symptoms. Extreme obesity with BMI > 40 kg/m2 was identified as independent risk factor for in-hospital mortality and for developing Long-COVID symptoms.

No description available.

Le syndrome de détresse respiratoire aiguë (SDRA) est caractérisé par des dommages au niveau de la barrière alvéolo-capillaire, résultant en la formation d’un œdème pulmonaire et une réponse inflammatoire exacerbée. Sans résolution rapide de ces paramètres, le syndrome progresse vers le développement de fibrose menant à l’insuffisance respiratoire. Or, il a été établi que la réparation de l’épithélium alvéolaire est une étape cruciale pour la résolution du SDRA. Une meilleure compréhension des mécanismes de réparation de l’épithélium alvéolaire est donc nécessaire afin de proposer de nouvelles thérapies pour le SDRA, pour lequel aucun traitement efficace n’existe. Il a été montré que les mécanismes de réparation sont régulés par des protéines membranaires, non seulement par les récepteurs aux facteurs de croissance et les intégrines, mais également par les canaux ioniques, en particulier les canaux potassiques. L’objectif principal de cette étude était donc de caractériser l’impact de la modulation des canaux potassiques KCa3.1 et KvLQT1 dans la résolution du SDRA. Dans un premier temps, nos résultats ont montré le rôle coopératif du canal potassique KCa3.1, de la matrice extracellulaire et de l’intégrine-β1 dans les processus de réparation de l’épithélium alvéolaire in vitro. Nous avons montré que la matrice de fibronectine et le KCa3.1 étaient impliqués dans la migration et dans la réparation de monocouches de cellules alvéolaires de cultures primaires de rat. Dans un deuxième temps, nous avons étudié l’impact de la modulation du canal potassique KvLQT1 dans certains aspects physiopathologiques du SDRA à l’aide de modèles in vivo. Nous avons montré que KvLQT1 n’était pas seulement impliqué dans les mécanismes de réparation de l’épithélium alvéolaire, mais également dans la résorption de l’œdème pulmonaire et la résolution de la réponse inflammatoire. Nos résultats démontrent que les canaux potassiques, tels que KCa3.1 et KvLQT1, pourraient être identifiés en tant que cibles thérapeutiques potentielles pour le SDRA. / Acute respiratory distress syndrome (ARDS) is characterized by alveolar-capillary barrier damage, resulting in the formation of pulmonary oedema and an exacerbated inflammatory response. Without rapid recovery of these parameters, there is a gradual development of fibrosis, leading to respiratory failure. It has been established that alveolar regeneration is a critical step for the resolution of ARDS. A better understanding of alveolar epithelial repair mechanisms is hence necessary to identify new therapies for ARDS, for which no effective treatment exist. It has been shown that repair mechanisms are regulated by membrane proteins, not only by growth factor receptors and integrins, but also by ion channels, in particular potassium channels. Therefore, the main objective of this study was to characterize the impact of KCa3.1 and KvLQT1 potassium channels modulation in the resolution of ARDS. First, our results have shown the cooperative role of the potassium channel KCa3.1, the extracellular matrix and the β1-integrin in alveolar epithelial repair processes in vitro. We have shown that the fibronectin matrix and KCa3.1 are involved in the migration and repair of primary cultures of rat alveolar cell monolayers. Our data also revealed a putative relationship between Kca3.1 and the β1-integrin. Second, we studied the impact of KvLQT1 potassium channel modulation on ARDS pathophysiological aspects with in vivo models. We showed that KvLQT1 was not only involved in alveolar epithelial repair, but also in the resolution of pulmonary oedema and inflammatory response. Taken together, our data demonstrate that potassium channels, such as KCa3.1 and KvLQT1, may be identified as potential therapeutic targets for the resolution of ARDS.

Les complications respiratoires restent la première cause des complications postopératoiresen chirurgie thoracique oncologique. Le développement des ces complications sont le plussouvent de nature infectieuse. Leur fréquence reste élevée (30 %) et représente la premièrecause de mortalité hospitalière. Des données récentes suggèrent que ces complicationsrespiratoires soient liées à une colonisation périopératoire des voies aériennes. Plusieurstravaux fondés sur l’analyse phénotypique de mise en culture traditionnelle démontrentl’existence d’une colonisation bronchique proximale chez près de 40 % des malades.Néanmoins, les liens entre colonisation et complications respiratoires restent controversés.Une des principales limites demeure les méthodes de cultures employées qui ne permettentl’identification que d’une faible partie (< 1%) des espèces microbiologiques potentiellementexistantes dans la biosphère. Nous avons formulé l’hypothèse que des techniques debiologie moléculaire d’amplification universelle des ADN présents dans les échantillonssuivies du clonage des produits de PCR et du séquençage de ces clones, appliquées à deséchantillons obtenus des bronches distales et de biopsies pulmonaires, permettraientl’identification de pathogènes bactériens, viraux ou émergents. Nos résultats suggèrent quel’identification précise et exhaustive de ces colonisations ne peut être réalisée que par uneapproche moléculaire moderne, innovante et systématique. Cette approche permetd’envisager, d’une part, un lien plus précis entre colonisation et complications respiratoires etd’autre part, l’identification de pathogènes difficilement cultivables ou émergents. / Postoperative respiratory complications remain the most frequent and seriouscomplications, as well as being the primary cause of hospital death after thoracic oncologicsurgery. Their incidence is relatively high and concern near 30 % of patients submitted forsurgery. These complications are notoriously infectious and airways colonizations (AWC)have been suggested to be an essential first step in the pathogenesis of this respiratorymorbidity. Previous studies have documented that AWC are presents in near 40 % of cases.However, correlation between AWC and respiratory complications remains controversial.One of the limits is the traditional phenotypic methods of cultures that precludes for definitiveconclusions when considering that majority of microbiological species required modern andinnovating techniques of culture to be identified. Recent data have demonstrated that 99% oforganisms seen microscopically are not cultivated by routine techniques and requiredmolecular techniques to be identified. We have postulated that instead of culture test,molecular detection (DNA genes amplification and sequencing of the bacterial 16S ribosomalRNA) applied to distal bronchial samples or to lung biopsies, should allow identifyingbacteria, virus or emerging pathogens. Our results suggest that molecular cultureindependenttechniques applied in the context of AWC will provide in the future a greatopportunity to precise correlation between colonization and respiratory complications and tothe other hand, to discover new and/or emerging pathogens that are currently unknown.

<p>Akutni respiratorni distres sindrom (ARDS) predstavlja klinički sindrom koji se manifestuje te&scaron;kom respiratornom insuficijencijom sa razvojem akutnog edema pluća u odsustvu znakova popu&scaron;tanja leve polovine srca. S obzirom da ovaj sindrom ima heterogenu etiologiju, progresivan tok i visoku stopu mortaliteta, pravovremena i tačna dijagnoza esencijalna je u primeni efektivne i rane terapije, a samim tim i u pobolj&scaron;anju prognoze bolesti. Cilj ove doktorske disertacije bio je da se ispita povezanost kliničke i patohistolo&scaron;ke dijagnoze ovog sindroma, kao i da se analiziraju i uporede vrednosti kliničkih parametara neophodnih za postavljanje dijagnoze ARDS-a sa patohistolo&scaron;kim parametrima o&scaron;tećenja plućnog tkiva. Studija je obuhvatila 67 pacijenata Instituta za plućne bolesti Vojvodine koji su umrli pod kliničkom slikom ARDS-a i/ili kod kojih je na obdukciji patohistolo&scaron;ki dokazan ARDS. Za postavljanje kliničke dijagnoze ARDS-a kori&scaron;ćeni su kriterijumi The American-European Consensus Conference iz 1994. Nakon semikvantitativne analize patohistolo&scaron;kih parametara difuznog alveolarnog o&scaron;tećenja određivan je histolo&scaron;ki stadijum ARDS-a i svi pacijenti podeljeni su u dve grupe: I grupa - pacijenti u eksudativnoj fazi i II grupa - pacijenti u proliferativnoj fazi difuznog alveolarnog o&scaron;tećenja. Formirane grupe pacijenata upoređivane su u odnosu na vrednosti kliničkih parametara 12h pre smrtnog ishoda. U cilju procene prisustva komorbiditeta analizirani su indeks telesne mase (engl. body mass index- BMI) i podaci o prethodno dijagnostikovanoj arterijskoj hipertenziji. Kod svih pacijenata uključenih u studiju upoređivane su kliničke dijagnoze sa obdukcionim nalazom. Za klasifikaciju autopsijskih dijagnoza kori&scaron;ćena je Goldman-ova klasifikacija. Na osnovu provedenog istraživanja, do&scaron;lo se do zaključka da slaganje klinički dijagnostikovanih i patohistolo&scaron;ki potvrđenih slučajeva ARDS-a iznosi 68%. Senzitivnost kliničke dijagnoze ARDS-a iznosi 82%, a pozitivna prediktivna vrednost 80%. Pacijenti sa nalazom eksudativne faze DAD-a u plućnom tkivu su u najvećem procentu imali klinički težak ARDS, dok su se pacijenti sa nalazom proliferativne faze sindroma če&scaron;će manifestovali pod kliničkom slikom srednje te&scaron;kog ARDS-a, odnosno utvrđeno je da postoji statistička povezanost između nižih vrednosti PaO2/FiO2 i teže faze ARDSa. Patohistolo&scaron;kom analizom promena u plućnom tkivu nađeno je da najvažnija obeležja eksudativne faze ARDS-a predstavljaju: hijaline membrane, edem i krvarenje, dok su se kao najvažnija obeležja proliferativne faze ARDS-a izdvojili: proliferacija pneumocita tipa II, intersticijalna i mutilantna fibroza i organizirajuća pneumonija. Kod pacijenata sa kliničkom dijagnozom ARDS-a kod kojih ARDS nije i patohistolo&scaron;ki dokazan, najče&scaron;ći nalaz na plućima bila je fibrinozno-purulentna bronhopneumonija. Analizom etiolo&scaron;kih faktora koji doprinose razvoju ovog sindroma otkriveno je da je ARDS najče&scaron;će nastao kao posledica delovanja direktnih/pulmonalnih činilaca: pneumonije i virusa gripa H1N1. Najzastupljeniji komorbiditeti prisutni kod pacijenata sa ARDS-om bili su sistemska hipertenzija i gojaznost. Najzad, kod svih pacijenata uključenih u istraživanje upoređivane su kliničke dijagnoze sa obdukcionim nalazom i na osnovu Goldman-ove klasifikacije kliničke dijagnoze i obdukcioni nalaz slažu se u 72% slučajeva. Rezultati ove studije mogli bi se upotrebiti u daljim istraživanjima kako bi omogućili bolji dijagnostički pristup ovom problemu, a samim tim i bolji terapijski pristup i smanjivanje stope mortaliteta.</p> / <p>Acute respiratory distress syndrome (ARDS) is a clinical syndrome characterized by severe respiratory failure with development of acute pulmonary edema in the absence of left heart failure signs. Since this syndrome has a heterogeneous etiology, progressive course and high mortality, timely and accurate diagnosis is essential in the implementation of effective and early treatment, and therefore in improving the prognosis of the disease. The aim of this PhD thesis was to examine the association between clinical and pathohistological diagnosis of this syndrome, as well as to analyze and compare the values of clinical parameters necessary for the diagnosis of ARDS with pathohistological parameters of diffuse alveolar damage. The study included 67 patients of the Institute for Lung Diseases who died under clinical picture of ARDS and / or in which, at the autopsy, pathohistological diagnosis of ARDS was set. To set up a clinical diagnosis of ARDS the criteria of the American-European Consensus Conference in 1994 were used. After a semi-quantitative analysis of histopathological parameters of diffuse alveolar damage, all patients were divided into two groups: Group I - patients in the exudative stage and Group II - patients in the proliferative phase of diffuse alveolar damage. Formed groups of patients were compared with respect to clinical parameters values 12 h before death. In order to assess the presence of comorbidities body mass index (BMI) and data on previously diagnosed arterial hypertension were analyzed. In all patients included in the study the clinical diagnosis were compared with autopsy findings according to Goldman&#39;s classification. According to this study, agreement of clinically diagnosed and histologically confirmed cases of ARDS is 68%. The sensitivity of clinical diagnosis of ARDS is 82%, and positive predictive value is 80%. Patients with exudative phase of DAD most frequently had a severe form of ARDS, whereas patients with proliferative phase often manifested with moderate form of ARDS, ie it was found that there is a statistical association between lower values PaO2 / FiO2 and more severe phase of ARDS. Pathological analysis of changes in lung tissue revealed that the most important characteristics of exudative phase of ARDS are: hyaline membrane, edema and bleeding, while the most important features of the proliferative phase of ARDS are: the proliferation of type II pneumocytes, interstitial fibrosis and mutilating and organizing pneumonia. In patients with a clinical diagnosis of ARDS in which ARDS was not pathohistologically proven, the most common finding in the lungs was fibrinous-purulent bronchopneumonia. The analysis of etiological factors that contribute to the development of this syndrome discovered that ARDS usually develop as a result of pulmonary factors: pneumonia and influenza virus H1N1. The most common comorbidities present in patients with ARDS were systemic hypertension and obesity. Finally, in all patients included in the study clinical diagnosis and autopsy findings were compared and based on Goldman&#39;s classification clinical diagnosis and autopsy findings are in agreement in 72% of cases. The results of this study could be used in further research to enable better diagnostic approach to this problem, and therefore a better therapeutic approach and reducing mortality rates.</p>

Des études adultes sur l’œdème pulmonaire lésionnel et le Syndrome de Détresse Respiratoire Aiguë ont mené à l’établissement de recommandations sur les stratégies de ventilation mécanique à employer chez ces patients. Cependant, il n’est pas clair si les recommandations adultes sont également bénéfiques pour l’enfant. Objectif Décrire les stratégies de ventilation mécanique employées chez les enfants atteints d’un œdème pulmonaire lésionnel. Méthodes Étude épidémiologique transversale tenue dans 59 unités de Soins Intensifs Pédiatriques de 12 pays en Amérique du Nord et en Europe. Six jours d’étude ont eu lieu entre juin et novembre 2007. Les enfants atteints d’un œdème pulmonaire lésionnel étaient inclus et des données sur la sévérité de leur maladie, les paramètres de ventilation mécanique et les thérapies adjuvantes employées ont été recueillies. Résultats Des 3823 enfants dépistés, 414 (10.8%) avaient un œdème pulmonaire lésionnel et 165 (40%) ont été inclus dans l’étude (124 étaient sous ventilation mécanique conventionnelle, 27 sous ventilation à haute fréquence par oscillation et 14 sous ventilation non invasive). Dans le groupe sous ventilation conventionnelle, 43.5% étaient ventilés avec un mode contrôlé à pression, le volume courant moyen était de 8.3±3.3 ml/kg et l’utilisation de la PEP et FiO2 était hétérogène. Conclusions Cette étude démontre une hétérogénéité dans les stratégies de ventilation mécanique employées chez les enfants souffrant d’un œdème pulmonaire lésionnel. Celle-ci pourrait être en partie reliée à la robustesse des critères diagnostiques actuellement utilisés pour définir l’ALI/SDRA. Une évaluation rigoureuse de ces stratégies est nécessaire pour guider la standardisation des soins et optimiser l’issue de ces patients. / Acute Lung Injury and Acute Respiratory Distress Syndrome are life-threatening conditions frequently leading to respiratory support with mechanical ventilation. Studies on mechanical ventilation strategies in adult patients have led to lung protective ventilation recommendations. However, there are few pediatric clinical trials on optimal mechanical ventilation management in Acute Lung Injury and it is still unclear if strategies studied in adults are equally beneficial to children. Objective Describe mechanical ventilation strategies in Acute Lung Injury in children. Methods Cross-sectional study for six 24-hour periods from June to November 2007 across 59 Pediatric Intensive Care Units in 12 countries in North America and Europe. We identified children meeting Acute Lung Injury criteria and collected detailed information on illness severity, mechanical ventilation support and use of adjunctive therapies. Results Of 3823 patients screened, 414 (10.8%) were diagnosed with Acute Lung Injury and 165 were included in the study (124 received conventional mechanical ventilation, 27 high frequency oscillatory ventilation, 14 non-invasive mechanical ventilation). In the conventional mechanical ventilation group, 43.5% were ventilated in a pressure control mode, the mean tidal volume was 8.3±3.3 ml/kg and there was no clear relationship between PEEP and FiO2 delivery. Conclusions Our study reveals inconsistent mechanical ventilation practice and use of adjunctive therapies in children with Acute Lung Injury. Rigorous evaluation of ventilator management strategies in children with an Acute Lung Injury are urgently needed to guide standardization of care and optimize clinical outcomes.

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