Doctor Scientiae (Odontology) - DSc(Odont) / Investigations of pathoses of the oral cavity encompass a relatively wide spectrum of diseases, abnormalities, tumours and tumour-like conditions affecting and occurring in the dental hard tissues and supportive structures, the bony skeleton of the face and the soft tissues of the. mouth. It involves a study of the normal - oral biology - and the abnormal - oral pathology. Oral pathology is a relatively new specialized field of dental science and practice. In South Africa, prior to the nineteen-fifties, research in oral pathology was primarily directed towards dental disease. Two people - Julius Staz of the University of the Witwatersrand and Tony Ockerse of the University of Pretoria - were the doyens in this field and made major contributions to dental science. Staz reported on the status of dental caries and tumorous malformations of teeth and Ockerse on the prevalence and severity of fluorosis in South Africa. During the fifties a second generation of dental surgeons, who were interested in soft tissue, bone and tumour pathology, emerged. They ,were Bertie Cohen, George Baikie, Mervyn Shear and John Lemmer who, at that time, were all from the University of the Witwatersrand. Bertie Cohen later joined the Royal College of Surgeons of England. Mervyn Shear led the field with his research on cysts of the oral cavity. The practice of oral pathology, moulded on anatomical pathology, was established in the early sixties and Mervyn Shear and the author, from the University of Pretoria, became known as oral pathologists. Research at that early stage comprised clinical and histological observations of oral lesions, diseases, tumours and tumour-like conditions. Observation techniques became more sophisticated during the sixties and seventies with the advent of histochemistry and electronmicroscopy. The next major development which blossomed in the seventies and early eighties was the application of epidemiological methods in the study of disease. Epidemiological principles enabled the correct recording of profiles of oral pathoses in the community. Much was learnt about the prevalence and distribution of oral conditions. The application and use of experimental models, especially laboratory animals, became popular in the eighties. Amongst others, a germfree animal unit was established in the Faculty of Dentistry of the University of Stellenbosch enabling workers to study the microbiological aetiology of dental and oral disease. Morphological observations of tumours and mucosal lesions were further enhanced during this period with the development of immunocytochemistry Experimental cell studies by means of cell culture techniques, commenced late in the eighties and was established in the early nineties. These models fostered molecular biology techniques which have become useful tools for the investigation of the aetiology of disease at a cellular and molecular level. At present molecular techniques are also popular in other spheres of oral pathology such as microbiological, immunological and oncological research. The author's first contact with oral pathology as a subject, forming an important and interesting part of dentistry, was the prescribed textbook "Oral and Dental Diseases", 2nd ed., 1951., by HH Stone of the University of Liverpool in the United Kingdom. Subsequently an enduring interest in the subject and research was cultivated by three teachers and colleagues, Ivor Kramer, Robert Bradlow and Mervyn Shear. Ivor Kramer, Professor of Oral Pathology in the Eastman Dental Institute of the University of London was a superb postgraduate teacher of oral pathology, and revelled in research. The Dean of the Institute, Professor Sir Robert Bradlow was a clinician and splendid diagnostician. He correlated the clinical and histopathological features of oral diseases. These two teachers set the course in oral pathology for the author during his postgraduate studies. In the sixties, after a spell at the University of Pretoria, the author joined Professor Mervyn Shear at the University of Witwatersrand. It was here that the author could further his skills of presenting lectures and research papers in an orderely manner and strengthen his love of research. The research carried out by the author reflects to a large extent the development of research in oral pathology in South Africa since 1960.. It includes studies of diseases and lesions of the oral mucosa, the dental hard tissues, tumours of the oral cavity and jaws and forensic odonto-stomatology. To date 139 articles have been published and accepted in scientific journals of which I was the first or co-author. The research presented here, however, comprises only those studies related to pathoses of the oral mucosa as it occurs in South Africa. Fifty-four papers and two abstracts are submitted. The papers are grouped into two divisions which include studies on (I) normal human oral and ectocervical mucosa and (II), those related to pathoses of the oral mucosa. The latter is subdivided into sections on: the profile of lesions of the oral mucosa in the community; cytological, clinical and morphological features of lesions of the oral mucosa; and studies on the aetiology of lesions of the oral mucosa. Each division and section is preceded by a declaration as to the contribution of the author or co-authors and a précis of the aims, objects and research findings. In the introduction of the précis statements are made explaining the aims of the study. These statements are not referenced because they appear in the respective articles.

La dégénérescence maculaire liée à l’âge (DMLA) est l’une des principales causes de la perte de vision chez les personnes âgées. Dans la DMLA de forme sèche, le stress oxydatif, l’inflammation et la dysfonction lipidique causent la perte des cellules de l’épithélium pigmentaire rétinien (RPE) qui sont essentielles au maintien des photorécepteurs. Nous avons précédemment démontré qu’un ligand sélectif du CD36 permet de préserver la fonction rétinienne dans un modèle murin de la DMLA. Cependant, l’effet des ligands synthétiques du CD36 dans la protection du RPE n’a jamais été vérifié. L’objectif de cette étude était de caractériser l’effet cytoprotecteur du ligand du CD36 MPE-001 sur le RPE contre le stress oxydatif. Le stress oxydatif a été induit chez la lignée humaine hTERT RPE-1 par le NaIO3. Il a été observé que le MPE-001 diminue la production de superoxydes mitochondriaux et l’apoptose des cellules du RPE sans toutefois affecter le système antioxydant au niveau transcriptionnel. Des essais par immunobuvardage et par immunocytochimie ont montré que le NaIO3 perturbe le flux autophagique, alors que le MPE-001 le rétablit. L’effet protecteur du MPE-001 était complètement aboli par les inhibiteurs de l’autophagie wortmannin et bafilomycine A1. En conclusion, nous avons démontré pour la première fois qu’un ligand du CD36 protège les cellules du RPE contre le stress oxydatif de façon autophagie-dépendante. Nous proposons la modulation du stress oxydatif chez le RPE par l’activation du CD36 comme stratégie potentielle pour traiter la DMLA de forme sèche. / Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the elderly population. The retinal pigment epithelium (RPE) is a monolayer of epithelial cells that are critical in maintaining retinal neurons. Oxidative stress, inflammation and defects in lipid clearance are thought to cause damages to the RPE and the eventual loss of photoreceptors in the dry form of AMD. CD36 is a scavenger receptor that plays an important role in inflammation and lipid homeostasis. We have previously shown that stimulation of CD36 by a selective ligand preserves photoreceptor function in high fat high cholesterol diet-fed Apoe-/- mice, a mouse model of AMD. The effect of CD36 ligands on RPE cells protection from oxidative insults, however, had yet to be investigated. In this study, we aimed to study the cytoprotective effect of the CD36 ligand MPE-001 in RPE cells exposed to oxidative stress. Oxidative stress was induced in the human RPE cell line hTERT RPE-1 using NaIO3. MPE-001 was observed to decrease NaIO3-induced mitochondrial superoxide production and apoptosis, with no transcriptional effect on antioxidant enzymes. Immunoblotting and immunostaining showed that NaIO3 disrupts autophagic flux while MPE-001 co-treatment restores it. The protective effect of MPE-001 was completely abolished by the autophagy inhibitors wortmannin and bafilomycin A1. In conclusion, we report for the first time that a CD36 ligand confers protection to RPE cells under oxidative stress through the improvement of autophagic process. We therefore propose modulation of oxidative stress by CD36 ligands as a potential strategy to treat dry AMD.

Diabetic Peripheral Neuropathy (DPN) is one of the most common types of diabetes that can affect the cornea. An accurate analysis of the corneal epithelium nerve structures and the corneal endothelial cell can assist early diagnosis of this disease and other corneal diseases, which can lead to visual impairment and then to blindness. In this thesis, fully-automated segmentation and quantification algorithms for processing and analysing sub-basal epithelium nerves and endothelial cells are proposed for early diagnosis of diabetic neuropathy in Corneal Confocal Microscopy (CCM) images. Firstly, a fully automatic nerve segmentation system for corneal confocal microscope images is proposed. The performance of the proposed system is evaluated against manually traced images with an execution time of the prototype is 13 seconds. Secondly, an automatic corneal nerve registration system is proposed. The main aim of this system is to produce a new informative corneal image that contains structural and functional information. Thirdly, an automated real-time system, termed the Corneal Endothelium Analysis System (CEAS) is developed and applied for the segmentation of endothelial cells in images of human cornea obtained by In Vivo CCM. The performance of the proposed CEAS system was tested against manually traced images with an execution time of only 6 seconds per image. Finally, the results obtained from all the proposed approaches have been evaluated and validated by an expert advisory board from two institutes, they are the Division of Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar and the Manchester Royal Eye Hospital, Centre for Endocrinology and Diabetes, UK.

La dégénérescence maculaire liée à l’âge (DMLA) est une des premières causes de cécité pour les personnes âgées de plus de 50 ans. Elle existe sous deux formes : sèche et humide. La forme causant les pertes de vision les plus sévères et rapides est DMLA humide où des nouveaux vaisseaux sanguins anormaux se forment dans la rétine; ce processus est appelé la néovascularisation choroïdienne. Celui-ci est causé par la dégradation des différentes membranes de la rétine et de l’augmentation du VEGF stimulant la croissance de ces vaisseaux. L’obésité, l’hypertension, le diabète et la cigarette sont connus pour être des facteurs modifiables et fortement corrélés avec la maladie. Avec l’arrivée des nombreuses diètes tendances, le jeûne intermittent pourrait être une intervention non-pharmacologique impactant l’obésité, l’hypertension et le diabète. En effet, cette diète est reconnue pour améliorer la santé, améliore la sensibilité à l’insuline et la tolérance glucose, diminuer le cholestérol sanguin et exercerait un effet bénéfique sur l’obésité. Ce mémoire a été entrepris dans le but d’évaluer les avantages potentiels du cycle de diète, soit le jeûne intermittent, sur la néovascularisation choroïdienne dans un modèle de DMLA. Nous avons émis l’hypothèse que le jeûne intermittent permet la diminution de la néovascularisation choroïdienne. Nos résultats montrent que les souris sous le régime jeûne intermittent que nous avons utilisé, c’est-à-dire 2 jours d’alimentation pour 1 jour de jeûne, ne perdent pas de poids, et suivent le même schéma de prise de poids que les souris nourries à volonté. De plus, les souris sous jeûne intermittent n’ont pas d’avantage métabolique que ce soit au niveau du glucose et, encore, moins au niveau de l’insuline. Les résultats ne permettent pas de montrer une différence au niveau de la néovascularisation choroïdienne induit par notre modèle. Le modèle de jeûne intermittent choisit ne permet pas d’obtenir des avantages au niveau de la néovascularisation choroïdienne ni pour la sensibilité au glucose et à l’insuline / Age-related macular degeneration (AMD) is one of the most prominent causes of blindness for people over 50 years old. It exists in two forms: dry and wet. The form causing majority of loss of sight is caused by wet AMD from where new abnormal blood vessels form in retina. This process is called choroidal neovascularization. This is caused by degeneration of outer portion of the retina and an increase in VEGF that instigate the growth of the new blood vessels. Obesity, hypertension, diabetes and smoking are known to be modifiable factors and strongly correlated with the disease. The advent of a vast number of trendy diets has introduced the possibility of modulating chronic disease by modifying eating habits. As an example, intermittent fasting can impacting obesity, hypertension, and diabetes. Indeed, this diet has been known to improve health, increase sensitivity of insulin and glucose, lower cholesterol and to have beneficial effect in obesity. The purpose of the research in my master’s thesis is to evaluate the influence of diet cycle, intermittent fasting on choroidal neovascularization in a mouse model of AMD. We hypothesized that the intermittent fasting could be diminish the choroidal neovascularization. There are several experimental paradigms that reproduce intermittent fasting. We selected the intermittent fasting 2 days of eating for one day of fasting (IF 2:1). Our results show that mice on our selected intermittent fasting regimen did not lose weight and follow the same pattern of weight gain as the mice that fed ad libitum. Furthermore, the mice on this intermittent fasting diet paradigm didn’t have metabolic benefits on glucose or insulin tolerance. Our results also did not show any differences in choroidal neovascularization. Hence, the 2:1 paradigm of intermittent fasting didn’t show any benefits on choroidal neovascularization, nor glucose and insulin.

No description available.

Nous avons étudié le transcriptome de neuf échantillons d'ARN extraits de cultures primaires de cellules non tumorales de l’épithélium de surface de l’ovaire (NOSE) provenant de quatre donneuses non porteuses de mutation, deux mutées sur BRCA1 et trois sur BRCA2, ainsi que de quatre échantillons d’ARN extraits de cultures primaires de cellules tumorales de l’ovaire (TOV) provenant de trois donneuses porteuses de mutation sur BRCA1 et une sur BRCA2. Nous avons identifié, pour la première fois, les signatures moléculaires associées à la présence d’une mutation de BRCA1 et BRCA2 dans les cellules NOSEs ainsi que la signature associée à la transformation tumorale des cellules NOSEs en TOVs chez les porteuses de mutation de BRCA1. Nous avons également localisé les domaines chromosomiques comportant des gènes corégulés en association avec la présence d’une mutation de BRCA1 dans les cellules NOSEs. Les allèles sauvage et muté de BRCA2 étaient exprimés dans les cellules TOVs provenant des porteuses de la mutation 8765delAG sur BRCA2. Nous avons observé que le niveau d’expression des transcrits de BRCA2 était plus élevé dans les cellules provenant des tumeurs ovariennes les plus agressives chez les femmes porteuses de la mutation 8765delAG sur BRCA2, les transcrits correspondants à l’allèle muté contribuant avec un pourcentage élevé du niveau d’expression total du gène. Le phénotype tumoral observé chez les Canadiennes Françaises porteuses de cette mutation pourrait résulter d’un effet de dosage de l’allèle muté. / We analyzed the transcriptome of nine primary cultures of non-tumor ovarian surface epithelium cells (NOSE) from four non-carriers, two BRCA1 and three BRCA2 carriers, and four primary cultures of tumor ovarian cells (TOV) from three BRCA1 and one BRCA2 carriers. We identified the first molecular signatures associated with the presence of BRCA1 and BRCA2 mutations in NOSEs and the first molecular signature associated with the transformation from NOSEs to TOVs in French Canadian women carriers of BRCA1 mutation. Moreover, we localized some co-regulated chromosomal domains associated with the presence of a BRCA1 mutation in NOSE cells. Wild-type and mutated BRCA2 allelic transcripts were expressed in tumor cells from 8765delAG BRCA2 mutation carriers, with the highest level of BRCA2 transcript expression and the highest contribution of the mutated allele in cells originating from the most aggressive ovarian tumors. The observed phenotype in BRCA2-mutated cells as well as the aggressiveness of the tumor could result from a dosage effect of the BRCA2 mutated allele.

Introduktion: Ameloblastom (AB), adenomatoid odontogen tumör (AOT), ameloblastiskt fibrom (AF) och odontogent fibrom (OF) är odontogena tumörer som innehåller epiteliala komponenter. Frekvensen av recidiv hos dessa varierar från låg förekomst till relativt hög förekomst. Syftet med denna studie är att undersöka om Ki-67, p53 och BRAF kan användas som prognostiska markörer i recidivmönstret hos dessa tumörer.Material och metod: Studien genomfördes genom immunohistokemi med monoklonala antikroppar av Ki-67, p53 och BRAF på respektive tumör. Tumörerna hämtades från avdelningen för Oral patologi på Malmö högskola. En statistisk analys utfördes med hjälp av Kruskal-Wallis envägs-ANOVA.Resultat: I de tio AB-fallen kunde en hög proliferation och en hög prevalens av muterade p53 ses. I de sju fallen av AOT kunde en måttligt hög proliferation och en generellt hög prevalens av muterade p53, jämförbara med värden för AB, ses. De sju fallen med AF och de fem fallen med OF visade båda en låg proliferation och en låg förekomst av muterade p53. Skillnaden mellan gruppen AB och AOT och gruppen AF och OF visade en signifikant högre infärgningsintensitet för både Ki-67 (p<0.001) och p53(p=0.001) för gruppen med AB och AOT.Konklusion: Proliferations index med Ki-67 och förekomst av p53-mutationer kan användas som en prognostisk markör för recidiv hos AB och AOT. Det är å andra sidan inte tillämpbart för AF och OF. / Introduction: Ameloblastoma (AB), adenomatoid odontogenic tumour (AOT), ameloblastic fibroma (AF) and odontogenic fibroma (OF) are all odontogenic tumours with an epithelial component. The recurrence rate for these odontogenic tumours varies from low frequencies to quite high frequencies. The aim of this study is to evaluate the expression of Ki-67, p53 and BRAF and the possibility of these antibodies acting as prognostic markers in the recurrence pattern of odontogenic tumours.Material and method: An immunohistochemical study using Ki67, p53 and BRAF monoclonal antibodies was performed on 29 paraffin blocks from the respective tumours obtained at the department of Oral Pathology in the Faculty of Odontology at Malmö University. Statistical analysis was performed with Kruskal-Wallis one-way ANOVA.Results: In the series of ten AB cases high proliferation activity and a high prevalence of p53 mutations was observated. In the seven AOT cases a moderately high proliferative activity as well as a generally high prevalence of p53 mutation, comparable to AB, was observed. The seven cases of AF and the five cases of OF demonstrated a low proliferative activity and a low prevalence of p53 mutation. The difference between AB and AOT versus AF and OF as two separate groups, showed a significantly higher staining intensity for both Ki-67 (p < 0.001) and p53 (p = 0.001) in AB and AOT as a group.Conclusion: Ki-67 proliferation index and p53-mutation status can be considered to be a prognostic marker for AB and AOT recurrence. This is, however, not applicable to AF and OF.

No description available.

O epitélio nasal é a primeira porção do sistema respiratório a entrar em contato com o ambiente externo. Partículas da poluição do ar, principalmente os compostos orgânicos absorvidos, podem atuar como liberadores endócrinos. O receptor aril hidrocarboneto (AhR) é um importante competidor dos receptores de estrógeno-beta (ERbeta) que regulam a transcrição do gene para enzimas de metabolização xenobióticas (enzimas do citocromo P450). O objetivo deste estudo é identificar e quantificar ERbeta, AhR, CYP1A1, CYP1A2, CYP1B1 e o perfil de muco no epitélio nasal de camundongos machos e fêmeas em diferentes fases do ciclo estral. Camundongos BALB/c machos (n=32) e fêmeas (n=84) foram expostos ao ar ambiente e ao MP2,5 concentrado a 600 ug.m-³ em um concentrador de partículas ambientais (CPAs). As fêmeas foram divididas de acordo com as fases do ciclo estral: proestro, estro e diestro. O epitélio nasal foi avaliado por RT-PCR e imuno-histoquímica para análise de expressão de ERbeta (proteína), Erbeta-1 e Erbeta-2 (gene), AhR (proteína e gene) e Cyp1a1, Cyp1a2 and Cyp1b1 (gene). A quantificação de muco neutro - Periodic Acid Schiff\'s (PAS+) e ácido - Alcian Blue (AB+) foi avaliada por morfometria. As exposições foram realizadas durante 5 dias/semana, por 45 ± 55 dias. A expressão de Erbeta-2 RNAm apresentou diferenças em resposta à exposição ao CPAs (p=0,016), bem como uma diminuição em fêmeas, quando comparadas aos camundongos machos (p=0,036). A expressão de Cyp1b1 RNAm foi significantemente menor no grupo exposto ao CPAs, em relação ao grupo exposto ao ar ambiente nas fêmeas em diestro (p=0,036). A expressão de Erbeta foi aumentada no epitélio nasal de fêmeas em estro expostas ao CPAs (p=0,005) e a expressão de AhR foi menor em fêmeas em proestro expostas ao CPAs (p=0,048). A exposição ao CPAs levou ao aumento do conteúdo de muco ácido em camundongos machos (p=0,048), o qual diminuiu em fêmeas (p=0,040), quando comparados ao grupo ar ambiente. Este estudo mostrou que houve diferentes respostas à exposição à poluição do ar no epitélio nasal entre machos e fêmeas, e que essas diferenças podem estar relacionadas com a predisposição de fêmeas apresentarem maior suscetibilidade a doenças respiratórias das vias aéreas / The nasal epithelium is the first portion of the respiratory system to reach contact with the external environment. Air pollution particles, mainly the organic compounds absorbed into them, may act as endocrine releasers. The aryl hydrocarbon (AhR) receptor is an important competitor of estrogenic receptors-beta (ERbeta) that regulate transcription of gene coding for xenobiotic-metabolizing enzymes (cytochrome P450 enzymes). The aim of this study is to identify and quantify in the nasal epithelium of male and female mice in different estrous cycle phases related with ERbeta, AhR, CYP1A1, 1A2, 1B1 and the mucus profile. Male (n=32) and female (n=84) BALB/c mice were exposed to ambient air and PM2.5 concentrated at 600 ug.m-³ in an ambient particle concentrator with a particulate matter diameter of 2.5 um (PM2.5). Females were subdivided in three estrous cycles: proestrus, estrus and diestrus. Nasal epithelium was evaluated through RT-PCR and immunohistochemistry for the expression of ERbeta (protein), Erbeta-1 and Erbeta-2 (gene expression), AhR (protein and gene expression) and Cyp1a1, Cyp1a2 and Cyp1b1 (gene expression). Morphometry was applied for evaluation of mucus profile: acid - Alcian Blue (AB+) and neutral - Periodic Acid Schiff\'s (PAS+). Exposure happened for 5 days/week, for 45 ± 55 days. There were differences in Erbeta-2 mRNA in response to exposition to CPAs (p=0.016), and a significant decrease in female compared male mice (p=0.036). Cyp1b1 mRNA was significantly smaller in the CPAs-exposed group compared with the ambient air group in diestrus female mice (p=0.036). The ERbeta expression increased in the nasal epithelium of CPAs-exposed females in the estrus cycle (p=0.005), and the AhR expression decreased in the proestrus cycle of CPAs-exposed females (p=0.048). The exposure to the CPAs led to an increase in the acidic content of mucus in male mice (p=0.048), and decreased in female mice (p=0.040), compared to the ambient air group. This study showed there were different responses in the nasal epithelia of male and female mice exposed to air pollution, which could be related to the predisposition of the females to present more susceptibility to airway respiratory diseases

Le syndrome de détresse respiratoire aiguë (SDRA) est caractérisé par des lésions alvéolaires diffuses menant à un œdème alvéolaire lésionnel et une insuffisance respiratoire aiguë hypoxémique. Malgré les progrès récents dans la prise en charge des patients de réanimation, le SDRA reste un syndrome fréquent et associé à une morbimortalité importante. Deux mécanismes principaux du SDRA semblent associés à une mortalité plus élevée et à des réponses thérapeutiques différentes : la déficience de la clairance liquidienne alvéolaire (AFC, pour alveolar fluid clearance), l’incapacité pour l’épithélium alvéolaire de résorber l’œdème alvéolaire, et la présence d’un phénotype « hyper-inflammatoire ». Les approches pharmacologiques du traitement du SDRA restent limitées et il est nécessaire de poursuivre l’étude des voies biologiques impliquées dans la pathogénie du SDRA et dans sa résolution afin de développer des approches innovantes des prises en charge diagnostique et thérapeutique du SDRA. RAGE, le récepteur des produits de glycation avancée, est un récepteur multi-ligands, exprimé abondamment par les cellules épithéliales alvéolaires du poumon (pneumocytes), qui module de nombreuses voies de signalisation intracellulaire. De nombreuses études récentes suggèrent que sRAGE, la forme soluble principale de RAGE, pourrait servir de marqueur lésionnel du pneumocyte de type I, et que RAGE pourrait jouer un rôle-pivot dans la pathophysiologie du SDRA, en initiant et en entretenant la réponse inflammatoire alvéolaire. Nos objectifs étaient de caractériser les rôles de RAGE au cours du SDRA, grâce à une approche translationnelle combinant études cliniques et précliniques. D’abord, des études cliniques observationnelles et interventionnelles ont été conduites afin de caractériser sRAGE comme un véritable biomarqueur dans le SDRA. Ensuite, des cultures in vitro de cellules épithéliales et de macrophages, ainsi qu’un modèle expérimental in vivo de SDRA murin par instillation trachéale d’acide chlorhydrique ont été utilisés pour décrire les effets de la voie RAGE sur les mécanismes d’AFC et l’inflammation macrophagique médiée par l’inflammasome « Nod-Like Receptor family, Pyrin domain containing 3 » (NLRP3). Enfin, l’effet d’une inhibition de RAGE, par sRAGE recombinant ou par anticorps monoclonal anti-RAGE, était testée en modèle murin. Nos résultats issus des études cliniques suggèrent que sRAGE présente toutes les caractéristiques d’un biomarqueur au cours du SDRA, avec un intérêt dans le diagnostic, le pronostic et la prédiction du risque de développer un SDRA dans une population à risque. Pris ensemble, notre travail suggère que la voie RAGE joue un rôle important dans la régulation de l’atteinte pulmonaire, de l’AFC et de l’activation macrophagique au cours du SDRA. Toutefois, les mécanismes précis de cette régulation restent incertains. La forme soluble de RAGE (sRAGE), lorsqu’elle est dosée dans le plasma, présente toutes les caractéristiques d’un biomarqueur pouvant être utile en pratique clinique, mais son intérêt dans la sélection de sous-groupes (ou « phénotypes ») de patients pouvant bénéficier de traitements ciblés reste à étudier. La voie RAGE pourrait enfin représenter une cible thérapeutique prometteuse. Bien que des études de validation restent nécessaires, ces résultats pourraient ouvrir de nouvelles perspectives dans la prise en charge des patients atteints de SDRA. / The acute respiratory distress syndrome (ARDS) is associated with diffuse alveolarinjury leading to increased permeability pulmonary edema and hypoxemic respiratory failure. Despite recent improvements in intensive care, ARDS is still frequent and associated with high mortality and morbidity. Two major features of ARDS may contribute to mortality and response to treatment: impaired alveolar fluid clearance (AFC), i.e. altered capacity of the alveolar epithelium to remove edema fluid from distal lung airspaces, and phenotypes of severe inflammation. Pharmacological approaches of ARDS treatment are limited and further mechanistic explorations are needed to develop innovative diagnostic and therapeutic approaches. The receptor for advanced glycation endproducts (RAGE) is a multiligand pattern recognition receptor that is abundantly expressed by lung alveolar epithelial cells andmodulates several cellular signaling pathways. There is growing evidence supporting sRAGE (the main soluble isoform of RAGE) as a marker of epithelial cell injury, and RAGE may be pivotal in ARDS pathophysiology through the initiation and perpetuation of inflammatory responses. Our objectives were to characterize the roles of RAGE in ARDS through a translational approach combining preclinical and clinical studies. First, observational and interventional clinical studies were conducted to test sRAGE as a biomarker during ARDS.Then, cultures of epithelial cells, macrophages and a mouse model of acidinduced lung injury were used to describe the effects of RAGE pathway on AFC and inflammation, with special emphasis on a macrophage activation through NodLikeReceptor family, Pyrindomain containing 3 (NLRP3) inflammasome. Acidinjured mice were treated with an antiRAGE monoclonal antibody or recombinant sRAGE to test the impact of RAGE inhibition on criteria of experimental ARDS. Results from clinical studies support a role of sRAGE as a biomarker of ARDS, withdiagnostic, prognostic and predictive values. In addition, plasma sRAGE is correlated with a lung imaging phenotype of nonfocal ARDS and could inform on therapeutic response. Herein, we also describe in vivo and in vitro effects of RAGE activation on transepithelial fluid transport and expression levels of epithelial channels (aquaporin 5, αNa,KATPaseandαENaC) and on macrophage activation through NLRP3 inflammasome. Finally, RAGE inhibition improves AFC and decreases lung injury in vivo. Taken together, our findings support a role of RAGE pathway in the regulation of lung injury, AFC and macrophage activation during ARDS, albeit precise regulatory mechanisms remain uncertain. sRAGE has most features of a validated biomarker that could be used in clinical medicine, but whether it may help to identify subgroups (or phenotypes) of patients that would benefit from tailored therapy remains underinvestigated. Modulation ofRAGE pathway may be a promising therapeutic target, and though validation studies are warranted, such findings may ultimately open novel diagnostic and therapeutic perspectivesin patients with ARDS.