O uso de diferentes tipos de medicação intracanal para o controle do processo infeccioso, principalmente nos casos em que há presença de microrganismos resistentes às manobras de desinfecção, tem sido alvo de muitas pesquisas. A proposta deste estudo foi avaliar, in vitro, o efeito antimicrobiano de bacteriófagos específicos diante de cinco cepas de Enterococcus faecalis e a ação de um lisado híbrido polivalente na eliminação da infecção causada por essas cinco cepas da mesma espécie. Foram utilizados 37 dentes unirradiculares humanos, recentemente extraídos e de proporções aproximadas. As coroas foram removidas e os canais instrumentados até a lima tipo K de número 45. Os espécimes foram, então, esterilizados e utilizados em dois experimentos distintos. O primeiro experimento utilizou 25 raízes divididas em cinco grupos de cinco espécimes. Três espécimes de cada grupo foram inoculados com uma das culturas bacterianas e seus fagos correspondentes na proporção 1:1, por um período de três horas a 37 °C, enquanto os outros dois, receberam a cultura de microrganismos ou somente meio de cultura (controle positivo e negativo, respectivamente). No segundo experimento, 11 espécimes receberam um inóculo formado pelas cinco cepas por um período de 10 dias de incubação a 37 °C, com o propósito de manter condições apropriadas para a penetração das bactérias no interior dos túbulos dentinários, e um outro espécime recebeu apenas meio de cultura (controle negativo). Essa penetração foi confirmada empregando-se microscopia ótica e eletrônica realizada em dois espécimes. Após o período de incubação, o lisado polivalente, preparado com os cinco fagos, foi aplicado por 24 horas a 37 °C em 8 espécimes, e os demais preenchidos com meio de cultura (controle positivo e negativo). Alíquotas do interior de todos os canais foram colhidas antes e depois do contato com os fagos e no segundo experimento, também 24 e 48 horas depois, para semeadura e contagem de unidades formadoras de colônia. Os resultados do primeiro experimento mostraram 100% de redução do crescimento bacteriano nos espécimes que receberam a suspensão de fagos específicos, em comparação a seus respectivos controles positivos, em todos os grupos. No segundo experimento, foi comparado o crescimento obtido após os 10 dias de infecção com aquele posterior a aplicação dos fagos, redução que variou entre 50% e 100%. Diante desses resultados, conclui-se que os bacteriófagos foram eficazes na diminuição dos microrganismos presentes no interior de canais radiculares e nos túbulos dentinários de dentes humanos. / Many studies have investigated different intracanal medications to control infection processes, especially in cases of microbial resistance to disinfection procedures. The purpose of this study was to evaluate the in vitro antimicrobial effect of specific bacteriophages on five isolates of Enterococcus faecalis, as well as the activity of a lysate cocktail in eliminating the infection caused by these bacteria. Thirty-seven recently extracted human teeth of approximately equal size and with single roots were used. The crowns were removed and each canal was prepared using K files,up to # 45, and sterile physiological saline. Specimens were then sterilized and used in two separate studies. The first study utilized 25 individual roots divided into five groups of five specimens each. Three specimens of each group were inoculated with one of the bacterial cultures and the corresponding bacteriophage in a proportion of 1:1, and incubated for three hours at 37°C; the other two specimens were inoculated with only the bacterial culture or only the culture medium (positive and negative controls, respectively). In the second study, 11 specimens were inoculated with all five strains and incubated for ten days at 37°C in order to allow bacteria to penetrate the interior of the dental tubules, and another one, received just the culture medium (negative control). Penetration into the tubules was confirmed by optical and electron microscopy of two specimens. Following incubation, the lysate cocktail prepared using all five bacteriophages was applied to the other 8 specimens for 24 hours at 37°C, and 2 specimens were filled with the culture medium (positive and negative controls). In the first study, samples were taken from the lumen of all canals before and after contact with bacteriophages; in the second, aliquots were also taken 24 and 48 hours after the bacteria were exposed to the phages. All samples were diluted and plated and the number of colony forming units was counted. In the first study, there was a 100% reduction in bacterial growth in specimens that received the specific bacteriophage suspension compared to the positive controls within each group. In the second study, after ten days the number of bacteria was reduced by 50% to 100% following the bacteriophage application. These results suggest that bacteriophages are effective in reducing the number of bacteria inside the root canal and in the dental tubules of human teeth.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / A intensificaÃÃo das relaÃÃes entre os mercados globalizados tem reflexo relevante nas organizaÃÃes, de forma que, para permanecerem no mercado, elas necessitam preservar e aprimorar sua imagem perante seus stakeholders. Nesse sentido, emerge o conceito de reputaÃÃo, frequentemente discutido no contexto das organizaÃÃes, e que pode ser entendido como o conjunto de atributos organizacionais desenvolvidos ao longo do tempo, que influencia na forma pela qual os stakeholders percebem as empresas no mercado. No presente estudo, a reputaÃÃo corporativa à analisada na perspectiva da sustentabilidade e de sua influÃncia no desempenho superior e persistente das empresas, sob a fundamentaÃÃo da teoria da sinalizaÃÃo. EvidÃncias empÃricas revelam que as aÃÃes socialmente responsÃveis por parte das empresas lhes conferem reputaÃÃo favorÃvel, na medida em que emitem sinais positivos ao mercado, propiciando maior atratividade aos stakeholders, uma vez que estes percebem maior confianÃa e menor risco (FOMBRUN; SHANLEY, 1990; FOMBRUN; RINDOVA, 1996; FOMBRUN; VAN RIEL, 1997; SCHULTZ; NIELSEN; BOEGE, 2002; GARDBERG; FOMBRUN, 2002; ROBERTS; DOWLING, 2002; CAIXETA et al. 2011). Ao atrair e firmar suas relaÃÃes com os vÃrios stakeholders, garante-se a conquista da vantagem competitiva sustentÃvel, ou do desempenho superior e persistente, das empresas no mercado (BARNEY, 1991; TIERGARTEN; ALVES, 2008; SARAIVA JUNIOR; ALCALDE; COSTA, 2009). A abrangÃncia de estudos anteriores sobre o tema nÃo permitiram anÃlise da longevidade dos benefÃcios conquistados pela boa reputaÃÃo corporativa e nem em contextos mercadolÃgicos diferenciados. Nesse contexto, o presente estudo tem o objetivo de investigar a relaÃÃo entre a reputaÃÃo corporativa e o desempenho superior e persistente das companhias de capital aberto que publicam relatÃrios de sustentabilidade, segundo a listagem do Global Reporting Initiative (GRI). Para tanto, trata-se de uma pesquisa descritiva e explicativa, de natureza quantitativa, utilizando-se os procedimentos bibliogrÃfico e documental, com a aplicaÃÃo das ferramentas estatÃsticas AnÃlise de CorrespondÃncia (Anacor), Teste de MÃdia, AnÃlise fatorial e AnÃlise em painel, no perÃodo de 2008 a 2011. O estudo se justifica na medida em que busca contribuir para ampliaÃÃo da discussÃo sobre a reputaÃÃo corporativa na perspectiva da sustentabilidade. AlÃm disso, apresenta uma anÃlise diferenciada, por tratar do tema relacionando-o com o desempenho superior e persistente, verificando se a reputaÃÃo corporativa se relaciona com a conquista e preservaÃÃo da vantagem competitiva sustentÃvel. A Anacor aponta que as empresas com mais elevados nÃveis de reputaÃÃo figuram no grupo de empresas com maior desempenho. AlÃm disso, o teste de mÃdia realizado demonstra que as empresas com desempenho superior e persistente possuem reputaÃÃo estatisticamente diferente das empresas sem desempenho superior e persistente, sendo que aquelas apresentaram mÃdia de Ãndice de reputaÃÃo corporativa maior do que estas. A anÃlise de dados em painel preliminarmente realizada indicou que nÃo hà associaÃÃo entre a reputaÃÃo corporativa e o desempenho superior e persistente, refutando a hipÃtese da pesquisa. PorÃm, ao transformar as variÃveis em fatores e utilizar estes na anÃlise de dados em painel, identificou-se relaÃÃo de dependÃncia do desempenho para com os fatores porte (representado pelo tamanho) e credibilidade (representado pelo endividamento e reputaÃÃo). Logo, conclui-se que, para a amostra considerada, a reputaÃÃo sozinha nÃo à capaz de influenciar o desempenho empresarial, mas levando em conta o endividamento, o fator credibilidade (constituÃdo pelos fatores endividamento e reputaÃÃo) pode ser explicativo do desempenho. Assim, conforme a Teoria da SinalizaÃÃo, a reputaÃÃo representa sinais emitidos ao mercado capaz de influenciar o comportamento dos stakeholders, impactando seu desempenho. / The intensification of relations between the global markets presents a relevant reflection on organizations, so as to remain in the market, they need to further preserve and improve their image in front of their stakeholders. In this sense, the concept of reputation emerges, being often discussed in the context of organizations and moreover can be understood as the set of organizational attributes developed over time, which influences the way stakeholders perceive companies within the market. In this study, corporate reputation is examined from the perspective of sustainability and of its influence in the companiesâ superior and persistent performance under the theory of signalingâs foundation. Empirical evidence reveals that socially responsible actions taken by companies provide them a favorable reputation, as they issue positive signals to the market, offering greater attractiveness to stakeholders since they perceive higher reliability and lower risks (Fombrun, Shanley 1990; Fombrun; RINDOVA, 1996; Fombrun, Van Riel 1997, SCHULTZ, Nielsen; BOEGE, 2002; GARDBERG; Fombrun, 2002; ROBERTS & Dowling, 2002; CAIXETA et al. 2011). By attracting and establishing their relationships with various stakeholders, the achievement of either sustainable competitive advantage or the superior persistent performance is assured in the market companies (Barney, 1991; TIERGARTEN; ALVES, 2008; HAIL JUNIOR; ALCALDE; COSTA, 2009). The scope of these previous studies on the topic did not allow analysis of the longevity of the benefits gained by neither good corporate reputation nor in differentiated market contexts. Within this context, this study aims at investigating the relationship between corporate reputation and superior persistent performance of public companies that publish sustainability reports, according to Global Reporting Initiative (GRI)âs listing. It is a descriptive and explanatory research of quantitative nature, using bibliographic and documentary procedures with the application of statistical tools Correspondence Analysis, Average Testing and Panel Analysis. The studyâs justification is to seek to contribute on expanding the discussion on corporate reputation in the perspective of sustainability. Moreover, it presents a differentiated analysis for dealing with the issue relating to the superior persistent performance and checking whether corporate reputation relates to the achievement and maintenance of a competitive advantage for a long period of time. Anacor points out that companies with higher levels of reputation are included in the group of companies with higher performance. Moreover, the conducted average testing shows that companies with superior persistent performance regard a statistically different reputation from their counterparts without superior persistent performance, being that the former presented an average index of corporate reputation greater than the latter. The preliminarily performed panel data analysis indicated no association between corporate reputation and superior persistent performance, disproving the research hypothesis. However, by transforming the variables into factors and using them in the panel data analysis, a performance dependency relationship was identified regarding size (represented by its size) and credibility (represented by its debt and reputation) factors. Therefore, it is concluded that, for the sample considered in this research, reputation alone is not able to influence business performance, but taking debt into account; the credibility factor (grouping the reputation and debt factors) may provide further explanations about performance. Thus, according theory of signaling, the reputation represents signals to the market and it is able to influence the behavior of stakeholders, impacting their performance.

Orientador: Hélio Pedrini / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Computação / Made available in DSpace on 2018-08-24T00:14:20Z (GMT). No. of bitstreams: 1 Silva_RicardoDutrada_D.pdf: 13549105 bytes, checksum: 3d49e5116a70a72601ba4cc3b3c85762 (MD5) Previous issue date: 2013 / Resumo: A Teoria de Morse é importante para o estudo da topologia em funções escalares como elevação de terrenos e dados provenientes de simulações físicas, a qual relaciona a topologia de uma função com seus pontos críticos. A teoria contínua foi adaptada para dados discretos através de construções como os complexos de Morse-Smale e o complexo discreto de Morse. Complexos de Morse têm sido aplicados em processamento de imagens, no entanto, ainda existem desafios envolvendo algoritmos e considerações práticas para a computação e modelagem dos complexos para imagens. Complexos de Morse podem ser usados como um meio de definir a conexão entre pontos de interesse em imagens. Normalmente, pontos de interesse são considerados como elementos independentes descritos por informação local. Tal abordagem apresenta limitações uma vez que informação local pode não ser suficiente para descrever certas regiões da imagem. Pontos de mínimo e máximo são comumente utilizados como pontos de interesse em imagens, os quais podem ser obtidos a partir dos complexos de Morse, bem como sua conectividade no espaço de imagem. Esta tese apresenta uma abordagem dirigida por algoritmos e estruturas de dados para computar o complexo de Morse discreto em imagens bidimensionais. A construção é ótima e permite fácil manipulação do complexo. Resultados teóricos e experimentais são apresentados para mostrar que o método é eficaz. Experimentos realizados incluem a computação de homologia persistente e hierarquias de complexos sobre dados de elevação de terrenos. Outra contribuição é a proposição de um operador topológico, chamado Contexto Local de Morse, computado sobre complexos de Morse, para extrair vizinhanças de pontos de interesse para explorar a informação estrutural de imagens. O contexto local de Morse é usado no desenvolvimento de um algoritmo que auxilia a redução do número de casamentos incorretos entre pontos de interesse e na obtenção de uma medida de confiança para tais correspondências. A abordagem proposta é testada em pares de imagens sintéticas e de imagens subaquáticas, para as quais métodos existentes podem obter muitas correspondências incorretas / Abstract: The Morse theory is important for studying the topology of scalar functions such as elevation of terrains and data from physical simulations, which relates the topology of a function to critical points. The smooth theory has been adapted to discrete data through constructions such as the Morse-Smale complexes and the discrete Morse complex. Morse complexes have been applied to image processing, however, there are still challenges involving algorithms and practical considerations for computation and modeling of the complexes. Morse complexes can be used as means of defining the connectedness of interest points in images. Usually, interest points are considered as independent elements described by local information. Such an approach has its limitations since local information may not suffice for describing certain image regions. Minimum and maximum points are widely used as interest points in images, which can be obtained from Morse complexes, as well as their connectivity in the image space. This thesis presents an algorithmic and data structure driven approach to computing the discrete Morse complex of 2-dimensional images. The construction is optimal and allows easy manipulation of the complex. Theoretical and applied results are presented to show the effectiveness of the method. Applied experiments include the computation of persistent homology and hierarchies of complexes over elevation terrain data. Another contribution is the proposition of a topological operator, called Local Morse Context (LMC), computed over Morse complexes, for extracting neighborhoods of interest points to explore the structural information in images. The LMC is used in the development of a matching algorithm, which helps reducing the number of incorrect matches between images and obtaining a confidence measure of whether a correspondence is correct or incorrect. The approach is tested in synthetic and challenging underwater stereo pairs of images, for which available methods may obtain many incorrect correspondences / Doutorado / Ciência da Computação / Doutor em Ciência da Computação

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Le syndrome de fragilité est devenu le concept le plus étudié ces dix dernières années par les gériatres, de par le vieillissement rapide de la population Française et mondiale et pour l'intérêt en terme de prévention globale que ce syndrome pourrait représenter. L’ intérêt qu’ apporte ce nouveau concept de plus en plus consensuel est en effet sa capacité à définir une personne âgée comme étant une entité fonctionnelle et multidimensionnelle (cognitive, thymique et sociale) pouvant être réversible. A partir de la, l’élaboration d'une stratégie par les médecins, afin de dépister les patients les plus fragiles pourrait permettre d’éviter les stades irréversibles de la perte d’autonomie, l’institutionnalisation et la surmortalité. Cela aurait probablement des conséquence s possibles en matière de santé publique. Un des facteurs de risque possible de la fragilité est la douleur chronique qui a toujours été considérée à tord comme un simple symptôme prévalent chez les personnes âgées et non pas comme une maladie soit une entité clinico - pathologique complexe pouvant interagir avec la fragilité. Dans ce travail, nous avons étudié les mécanismes physiopathologiques communs qui lient le syndrome de fragilité à la douleur chronique , leur interaction et l’ intérêt que peut susciter l’optimisation du dépistage de la douleur chronique chez les personnes âgées dans l’évaluation des personnes les plus fragiles. Nous proposons à travers de nouveaux projets de recherche clinique prospectifs , de démontrer au - delà d e la relation possible entre la fragilité et la douleur persistante, le rôle que pourrait jouer les médicaments essentiellement analgésiques dans la réversibilité de ce syndrome / The frailty concept has become the most studied one over the past decade , by the rapid aging of French and the world population and for the interest in terms of overall prevention that this syndrome could represent. The advantage brought by this ne w concept increasingly consensual relies on its ability to define elderly as a m ultidimensional functional entity (cognitive, social and mood) being reversible. Caregivers have to start before to tailor a care plan by screening for the frailest patients in order to avoid irreversible stages of frailty, ( institutionalization and mortal ity ) . This probably would have possible consequences for public health. One of the possible risk factors for fragility is persistent pain which has always been wrongly considered as a mere prevalent symptom in o lder people and not as a clinical and patholo gical entity that can interact with the complex fragility syndrome. In this work, we studied the common pathophysiological mechanisms that link frailty to pain, their interaction and the interest that may lead to optimize screening of pain in older adults within frailty evaluation. We offer through new clinical research projects looking to demonstrate beyond the possible relationship between fragility and persistent pain, the potential role of analgesic drugs mainly in the reversibility of this syndrome

L’être humain est exposé quotidiennement et simultanément à des dizaines de polluants environnementaux, pourtant il n’existe encore que peu ou pas d’études sur les effets de ces mélanges. Des études épidémiologiques et transcriptomiques montrent que les polluants peuvent perturber le métabolisme glucidique et lipidique. Le lien entre métabolisme et cancer a été démontré depuis plusieurs décennies, en effet, une dérégulation du métabolisme oxydatif, appelée effet Warburg, et commune à presque toutes les cellules tumorales se caractérise par une déviation du métabolisme oxydatif mitochondrial vers une glycolyse anaérobie entrainant une augmentation de la production de lactate. Pour ce travail les effets d’un mélange de deux polluants organiques persistants ayant des voies de signalisation différentes sont étudiés. Le mélange associe la TCDD, une substance cancérigène, à un pesticide l’α-endosulfan, afin d’évaluer les effets combinés de ces deux polluants sur le métabolisme énergétique de cellules cancéreuses coliques humaines Caco2. Le traitement des cellules pendant 48 heures par la TCDD (25 nM) et l’α-endosulfan (10µM) conduit à une diminution de l’oxydation du glucose, corrélée à une augmentation de la production de lactate, alors que chaque polluant seul exerce un effet peu significatif. Le mélange diminue l’activité globale de la mitochondrie caractérisée par une diminution de la respiration cellulaire, et de la production d’ATP sans toutefois modifier l’intégrité mitochondriale. L’étude des mécanismes impliqués dans ces effets indique l’implication de l’AMPK et du complexe PDH, deux enzymes clés régulant de façon très importante la glycolyse cellulaire ; en effet l’inhibition de l’AMPK abolit les effets des polluants. Des modifications du calcium intracellulaire qui régule entre autre l’activité de ces deux enzymes sont observées et l’inhibition du calcium abolit également les effets des polluants. Ces travaux montrent que le mélange induit une aggravation de la dérégulation du phénotype métabolique des cellules Caco2 à l’état prolifératif. Cela pourrait signifier une synergie de l’activité de ces polluants qui pourrait accentuer ce phénotype dans un contexte tumorale via un mécanisme impliquant le calcium. / During tumorigenesis most of cancer cells exhibit an altered metabolism that is characterized by an elevated uptake of glucose and an increased glycolytic rate; this phenomenon is known as the Warburg effect. Compelling recent evidences suggest that alteration of cellular metabolism is critical during cancer development and constitutes a major feature of aggressive tumour. Considering the recent observations on the impact of persistent organic pollutants (POPs) on cell metabolism, we hypothesize that POPs could exert their carcinogenic effects by promoting metabolic alterations that could converge to a metabolic shift supporting a tumoral phenotype. Proliferating colon cancer cells (Caco2) were treated with TCDD (25 nM) or/and α-endosulfan (10 µM), two environmental pollutants mainly produced by human activities and designated by the International Agency for Research on Cancer as probably or well-established carcinogenic to humans. A significant decrease of glucose and glutamine oxidation (60%) was observed after a treatment for 48 hours with the two pollutants while each pollutant alone had no significant effect. These observations are correlated with an increased lactate production by two fold. These effects are maintained in the presence of antioxidative NAC (10 mM), suggesting that they are independent of the oxidative status of the cell. We also observed a decreased incorporation of glucose in total lipids (50%). The ATP production and the cell respiration level were significantly decreased by the mixture by about 50% and 80%, respectively. In the same conditions, the glycogen production and the NADPH/NADPH,H+ ratio were unchanged. Taken together, these results suggest that POPs could worsen the metabolic phenotype of cancer cells. The molecular mechanisms underlying the POPs-induced metabolic reprograming are under investigation and should provide a better understanding of the signalling pathways involved in POPs action on the regulation of the energetic metabolism balance and their consequence on cancer.

La colonisation nasale à Staphylococcus aureus est un important facteur de risque d’infection par cette bactérie chez l’homme. Le rôle de la colonisation extra-nasale dans la physiopathologie des infections liées à la souche de colonisation est incertain. Contrairement aux porteurs intermittents et aux non porteurs, les porteurs persistants ont un risque accru d’infection à S. aureus notamment chez les patients dialysés. Nous avons développé et proposé une nouvelle stratégie applicable aux soins courants pour prédire rapidement le statut de portage nasal persistant de S. aureus dans l’optique de faire bénéficier les porteurs les plus à risque d’infection à S. aureus de mesures de prévention ciblées. Nous avons montré, à travers l’étude des réservoirs pharyngé et digestif, qu’il existe une grande diversité génétique des souches de S. aureus isolées des muqueuses. Enfin, différentes hypothèses ont été investiguées pour déterminer les facteurs microbiologiques associés à la persistance du portage nasal de S. aureus. Ces résultats préliminaires suggèrent que les souches isolées de colonisation nasale persistante et intermittente ont des caractéristiques très similaires / Staphylococcus aureus nasal carriage is a major risk factor of infection with this bacterium in humans. The role of S. aureus extra-nasal carriage in endogenous infections remain elusive. By contrast to intermittent carriers and noncarriers, persistent carriers have a higher risk of S. aureus infection, especially in dialysis patients. We have developed and validated an algorithm to predict the nasal carriage state in clinical practice for proposing decolonization to carriers having the highest risk of S. aureus infection. We found a high diversity between S. aureus strains colonizing the nose, the throat and the rectum, suggesting that extra-nasal carriage could be an additional risk factor of S. aureus infection. Finally, we studied several bacterial determinants of persistent nasal carriage. Our preliminary results suggest that S. aureus isolated in persistent and intermittent carriers harboured similar features

La dysplasie broncho-pulmonaire (DBP), complication fréquente de la prématurité, atteint 30% des nouveau-nés de faible poids de naissance. L’hypertension artérielle pulmonaire persistante du nouveau-né (HTAPP), associé ou non à la DBP, résulte d’une mauvaise adaptation à la vie extra-utérine et survient dans diverses situations pathologiques (prématurité, sepsis, inhalation de méconium, hernie diaphragmatique congénitale…). Ces 2 pathologies sont grevées d’une morbidité et d’une mortalité importante en période périnatale. En effet, certaines situations d’HTAPP ou de DBP sévères restent réfractaires aux thérapeutiques actuelles.Les acides gras polyinsaturés oméga 3 (AGPI ω-3) sont des nutriments aux propriétés bénéfiques sur le système circulatoire et pulmonaire, mais également sur le développement fœtal, démontrés par de nombreuses études expérimentales et cliniques. La déhydroépiandrostérone (DHEA) est une hormone stéroïdienne dont le taux de sécrétion chez l’homme diminue avec l’âge. Des études récentes ont démontré un effet cardio-protecteur mais également un effet vasodilatateur pulmonaire et préventif de lésions de DBP dans des modèles expérimentaux.Les buts de notre travail étaient 1) d’étudier l’effet d’une supplémentation en AGPI ω-3 dans un modèle expérimental de DBP induite par hyperoxie chez le raton, 2) d’étudier l’effet circulatoire d’injection d’AGPI ω-3 (in vivo) dans un modèle d’étude de la circulation pulmonaire chez le fœtus de brebis chroniquement instrumenté, et d’étudier les mécanismes d’action AGPI ω-3 (anneaux vasculaires isolés) , enfin 3) d’étudier l’effet circulatoire de la DHEA (in vivo) dans le modèle de fœtus de brebis et d’étudier les mécanismes d’actions de la DHEA sur la circulation pulmonaire fœtale (in vivo)._x000D_Nous avons démontré que la supplémentation par voie orale en AGPI ω-3 de rates gestantes à la fin de la gestation et après la naissance permettait de prévenir, chez les ratons nouveau-nés, les lésions de DBP induites par une exposition chronique à l’hyperoxie. Ces lésions étaient retrouvées dans les groupes contrôles (eau et AGPI ω-6). Cette étude n’avait pas retrouvée d’effet bénéfique des AGPI ω-3 sur le remodelage vasculaire induit.L’injection d’acide eicosapentaènoique (EPA) chez le fœtus de brebis a révélé un effet vasodilatateur pulmonaire puissant avec une baisse significative et prolongée des résistances vasculaires pulmonaires (RVP), en comparaison à l’injection d’acide docosahéxaènoique (DHA) ou de l’excipient (faible dose d’éthanol). L’effet vasorelaxant de l’EPA sur des anneaux isolés pré-contractés était plus important que celui du DHA à dose équivalente, et il était dose- et endothélium-dépendent. Enfin, cet effet impliquait la voie de production du NO puisqu’il était diminué lors du traitement des anneaux par le L-Nitro-Arginine (LNA), inhibant la NO synthase.L’étude de perfusion en bolus de DHEA dans le lit pulmonaire vasculaire chez le fœtus de brebis instrumenté mettait en évidence un effet vasodilatateur bref. Cet effet était dose-dépendant avec une baisse plus prononcée des RVP et une durée plus importante pour des doses de DHEA plus importantes. Enfin l’étude des mécanismes d’action retrouvait une inhibition de l’effet de la DHEA par le LNA, démontrant une action vasodilatatrice par activation de production du NO.L’ensemble de ces travaux permet de suggérer que les AGPI ω-3 représentent des nutriments intéressants en période périnatale (grossesse, allaitement et per os), notamment en traitement préventif dans les situations à risque de DBP, ou curatif en cas d’HTAPP. La DHEA reste une piste dans le traitement de l’HTAP, mais semble pour l’instant plus difficile à instaurer en clinique humaine. / Bronchopulmonary dysplasia (BPD), a common complication of prematurity, reached in 30% of newborns with very low birth weight. Persistent pulmonary hypertension of the newborn (PPHN), with or without BPD, results in poor adaptation to extrauterine life and occurs in various pathological conditions such as prematurity, sepsis, inhaled meconium, or diaphragmatic hernia Congenital. The mortality and morbidities of these two diseases are high in the perinatal period. Severe PPHN or BPD are refractory to current treatment.Polyunsaturated fatty acids omega-3 (ω-3 PUFA) are nutrients with beneficial properties on the circulatory and pulmonary system, but also on fetal development, demonstrated by many experimental and clinical studies. Dehydroepiandrosterone (DHEA) is a steroid hormone whose secretion levels in humans decreases with age. Recent studies have demonstrated a cardio-protective effect of diet DHEA supplementation but also a pulmonary vasodilator and preventive effect of DBP injury in experimental models.The aims of our study were : 1) to study the effect of PUFA ω-3 supplementation in an experimental model of hyperoxia-induced DBP in pups; 2) to study effect on pulmonary circulation of infusion of ω-3 PUFAs (in vivo) in model of chronically instrumented fetal sheep, and to analyze the mechanisms of action of ω-3 PUFA (isolated vascular rings); and finally 3) to study the in vivo effect of DHEA in fetal pulmonary circulation in the same model of fetal sheep and to understand the mechanisms of action of DHEA._x000D_We have demonstrated that supplementation with diet PUFA ω-3 on pregnant rats at the end of gestation and after birth prevent BPD injuries induced by chronic exposure to hyperoxia in pups. These lesions were found in the control groups (water and ω-6 PUFA). ω-3 PUFA supplementation did not prevent vascular remodeling.Infusion of eicosapentaenoic acid (EPA) in sheep fetus showed a potent pulmonary vasodilator effect as compared to docosahexaenoic acid (DHA) or excipient (low dose of ethanol). Vasorelaxant effect of EPA on pre-contracted isolated rings was more important than DHA at equivalent dose, and was dose- and endothelium-dependent. This effect involves NO production.Bolus DHEA perfusion in the pulmonary vascular bed study on instrumented fetal sheep highlighted an acute vasodilator effect. This effect was dose-dependent with a more pronounced and sustained decrease in PVR at highest doses of DHEA. Finally, mechanisms of action study found an inhibition of the effect of DHEA by the LNA, indicating that DHEA-induced vasodilation is NO dependant.Taken together, our results suggest that supplementation with ω-3 PUFAs and DHEA within the perinatal period may prevent BPD and PPHN in high risk conditions including preterm birth, premature rupture of the membrane or intrauterine growth restriction.

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