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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.

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Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

O desenvolvimento do câncer cervical depende da exposição ao HPV, fator necessário, mas não suficiente. Outras bactérias, tais como ureaplasmas, têm sido associadas como cofatores. O objetivo deste estudo foi avaliar a presença de ureaplasmas em mulheres com lesão cervical, e observar alterações em PHK causadas pela infecção por ureaplasmas. 140 swabs vaginais foram coletados. O material foi submetido a PCR para a detecção de HPV, Mollicutes, U. urealyticum, U. parvum e seus sorotipos, e outras bactérias de importância ginecológica; e qPCR para U. urealyticum e U. parvum. Também foi realizada a infecção de ureaplasmas em PHK transformados com HPV. As células foram contadas e realizou-se a dosagem das citocinas IL1-β, IL-6 e TNF-α. HPV, Mollicutes, U. parvum, sorotipos 1 e 6 de U. parvum, T. vaginalis e G. vaginalis, além de alguns fatores socioeconômicos, foram associados com lesão cervical. Verificou-se maior carga de U. parvum entre mulheres com lesão. Houve diminuição do número de células e maior liberação de IL-6 e TNF-α nos grupos infectados. Com os resultados obtidos neste estudo, foi possível verificar uma associação entre os ureaplasmas e HPV no início das lesões cervicais, contudo mais estudos precisam ser realizados para aprimorar essa hipótese. / The development of cervical cancer depends on the exposure to HPV, necessary factor, but not enough. Other bacteria, such as ureaplasmas, have been associated as cofactors. The aim of this study was to evaluate the presence of ureaplasmas in women with cervical injury, and observe changes in PHK infected by ureaplasmas. 140 vaginal swabs were collected. The material was subjected to PCR for detection of HPV, Mollicutes, Ureaplasma urealyticum, U. parvum (and serotypes) and other bacteria gynecological importance; qPCR for U. urealyticum and U. parvum was made. PHK transformed by HPV was infected by ureaplasma. Cells were counted and it was done titration of IL1-β, IL-6 and TNF-α. HPV, Mollicutes, U. parvum, serotypes 1 and 6 U. parvum, T. vaginalis and G. vaginalis, and some socioeconomic factors were associated with cervical injury. Besides this, it was detected higher load U. parvum among women with injury. There was decrease in cell number and increased release of IL-6 and TNF-α in infected groups. With the results of this study, we found an association among HPV and ureaplasmas at the beginning of cervical lesions, but more studies are needed to enhance this hypothesis.

O desenvolvimento do câncer cervical depende da exposição ao HPV, fator necessário, mas não suficiente. Outras bactérias, tais como ureaplasmas, têm sido associadas como cofatores. O objetivo deste estudo foi avaliar a presença de ureaplasmas em mulheres com lesão cervical, e observar alterações em PHK causadas pela infecção por ureaplasmas. 140 swabs vaginais foram coletados. O material foi submetido a PCR para a detecção de HPV, Mollicutes, U. urealyticum, U. parvum e seus sorotipos, e outras bactérias de importância ginecológica; e qPCR para U. urealyticum e U. parvum. Também foi realizada a infecção de ureaplasmas em PHK transformados com HPV. As células foram contadas e realizou-se a dosagem das citocinas IL1-β, IL-6 e TNF-α. HPV, Mollicutes, U. parvum, sorotipos 1 e 6 de U. parvum, T. vaginalis e G. vaginalis, além de alguns fatores socioeconômicos, foram associados com lesão cervical. Verificou-se maior carga de U. parvum entre mulheres com lesão. Houve diminuição do número de células e maior liberação de IL-6 e TNF-α nos grupos infectados. Com os resultados obtidos neste estudo, foi possível verificar uma associação entre os ureaplasmas e HPV no início das lesões cervicais, contudo mais estudos precisam ser realizados para aprimorar essa hipótese. / The development of cervical cancer depends on the exposure to HPV, necessary factor, but not enough. Other bacteria, such as ureaplasmas, have been associated as cofactors. The aim of this study was to evaluate the presence of ureaplasmas in women with cervical injury, and observe changes in PHK infected by ureaplasmas. 140 vaginal swabs were collected. The material was subjected to PCR for detection of HPV, Mollicutes, Ureaplasma urealyticum, U. parvum (and serotypes) and other bacteria gynecological importance; qPCR for U. urealyticum and U. parvum was made. PHK transformed by HPV was infected by ureaplasma. Cells were counted and it was done titration of IL1-β, IL-6 and TNF-α. HPV, Mollicutes, U. parvum, serotypes 1 and 6 U. parvum, T. vaginalis and G. vaginalis, and some socioeconomic factors were associated with cervical injury. Besides this, it was detected higher load U. parvum among women with injury. There was decrease in cell number and increased release of IL-6 and TNF-α in infected groups. With the results of this study, we found an association among HPV and ureaplasmas at the beginning of cervical lesions, but more studies are needed to enhance this hypothesis.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

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