Добірка наукової літератури з теми "Balb/cJRj mice"

AbstractThe mouse model of 2,4-dinitrochlorbenzene (DNCB)-induced human-like atopic dermatitis (hlAD) has been widely used to test novel treatment strategies and compounds. However, the study designs and methods are highly diverse, presenting different hlAD disease patterns that occur after sensitization and repeated challenge with DNCB on dorsal skin. In addition, there is a lack of information about the progression of the disease during the experiment and the achieved pheno- and endotypes, especially at the timepoint when therapeutic treatment is initiated. We here examine hlAD in a DNCB-induced BALB/cJRj model at different timepoints: (i) before starting treatment with dexamethasone, representing a standard drug control (day 12) and (ii) at the end of the experiment (day 22). Both timepoints display typical AD-associated characteristics: skin thickening, spongiosis, hyper- and parakeratosis, altered cytokine and gene expression, increased lipid mediator formation, barrier protein and antimicrobial peptide abnormalities, as well as lymphoid organ hypertrophy. Increased mast cell infiltration into the skin and elevated immunoglobulin E plasma concentrations indicate a type I allergy response. The DNCB-treated skin showed an extrinsic moderate sub-acute hlAD lesion at day 12 and an extrinsic mild sub-acute to chronic pheno- and endotype at day 22 with a dominating Th2 response. A dependency of the filaggrin formation and expression in correlation to the disease severity in the DNCB-treated skin was found. In conclusion, our study reveals a detailed classification of a hlAD at two timepoints with different inflammatory skin conditions and pheno- and endotypes, thereby providing a better understanding of the DNCB-induced hlAD model in BALB/cJRj mice.

Food allergy is associated with alterations in the gut microbiota, epithelial barrier, and immune tolerance. These dysfunctions are observed within the first months of life, indicating that early intervention is crucial for disease prevention. Preventive nutritional strategies with prebiotics are an attractive option, as prebiotics such as galacto-oligosaccharides and inulin can promote tolerance, epithelial barrier reinforcement, and gut microbiota modulation. Nonetheless, the ideal period for intervention remains unknown. Here, we investigated whether galacto-oligosaccharide/inulin supplementation during gestation could protect offspring from wheat allergy development in BALB/cJRj mice. We demonstrated that gestational prebiotic supplementation promoted the presence of beneficial strains in the fecal microbiota of dams during gestation and partially during mid-lactation. This specific microbiota was transferred to their offspring and maintained to adulthood. The presence of B and T regulatory immune cell subsets was also increased in the lymph nodes of offspring born from supplemented mothers, suggestive of a more tolerogenic immune environment. Indeed, antenatal prebiotic supplementation reduced the development of wheat allergy symptoms in offspring. Our study thus demonstrates that prebiotic supplementation during pregnancy induces, in the offspring, a tolerogenic environment and a microbial imprint that mitigates food allergy development.

ABSTRACT Macrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to β-lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in treating Gram-negative bacterial airway infections, e.g., those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular, motility-stimulating activity in the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities but with retained anti-inflammatory properties, was used as an adjunct treatment for experimental P. aeruginosa lung infection, in combination with a conventional antibiotic. Airway infections in BALB/cJRj mice were induced by nasal instillation of P. aeruginosa; this was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infections. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the numbers of leukocytes in bronchoalveolar lavage fluid, and reduced the numbers of neutrophils present in lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study.

The gut microbiota is influenced by environmental factors such as food. Maternal diet during pregnancy modifies the gut microbiota composition and function, leading to the production of specific compounds that are transferred to the fetus and enhance the ontogeny and maturation of the immune system. Prebiotics are fermented by gut bacteria, leading to the release of short-chain fatty acids that can specifically interact with the immune system, inducing a switch toward tolerogenic populations and therefore conferring health benefits. In this study, pregnant BALB/cJRj mice were fed either a control diet or a diet enriched in prebiotics (Galacto-oligosaccharides/Inulin). We hypothesized that galacto-oligosaccharides/inulin supplementation during gestation could modify the maternal microbiota, favoring healthy immune imprinting in the fetus. Galacto-oligosaccharides/inulin supplementation during gestation increases the abundance of Bacteroidetes and decreases that of Firmicutes in the gut microbiota, leading to increased production of fecal acetate, which was found for the first time in amniotic fluid. Prebiotic supplementation increased the abundance of regulatory B and T cells in gestational tissues and in the fetus. Interestingly, these regulatory cells remained later in life. In conclusion, prebiotic supplementation during pregnancy leads to the transmission of specific microbial and immune factors from mother to child, allowing the establishment of tolerogenic immune imprinting in the fetus that may be beneficial for infant health outcomes.

Bien qu'une diminution conséquente de la pollution atmosphérique soit constatée depuis les années 1990, cette dernière demeure un problème de santé publique majeur, à l'origine de plus de 4,2 millions de décès prématurés par an dans le monde. À l'heure actuelle, l'attention des experts se concentre sur les particules ultrafines (PM0,1 ou PUF) en raison de leur capacité à transloquer dans la circulation systémique pour atteindre les organes périphériques où elles seront alors susceptibles d'avoir un impact néfaste. Néanmoins, les connaissances en termes de mécanismes cellulaires et moléculaires impliqués dans la toxicité de ces particules restent encore très parcellaires et demeurent, le plus souvent, centrées sur leur cible principale qu'est le poumon. Ainsi, ce projet de thèse avait pour objectifs principaux d'apporter des éléments novateurs sur la toxicocinétique (i.e., distribution/persistance) et la toxicodynamique (i.e., mécanismes physiopathologiques, voies de signalisation associées) de PUF prélevées en milieu urbain, d'une part, et les effets organo-spécifiques des PUF et l'utilisation des miARN circulants comme indicateurs d'exposition chronique et/ou cumulées aux PUF dans un modèle murin, d'autre part. Afin de répondre à ces interrogations, des souris Balb/cJRj ont été exposées durant 3 mois à différentes doses de PUF prélevées dans la zone urbaine de Lille, puis des analyses ont été réalisés au sein de différents organes-cibles richement vascularisés, et par conséquent directement exposés aux PUF lors de leur phase de translocation et de distribution systémique. Les résultats obtenus ont démontré que, dans l'ensemble des organes cibles, le potentiel oxydant intrinsèque des PUF induisait indéniablement la production d'espèces pro-oxydantes et l'activation de défenses antioxydantes en quantité suffisante pour rétablir un état d'homéostasie redox mais ne parvenant pas, cependant, à éviter l'apparition d'une réponse inflammatoire au niveau pulmonaire, cardiaque et cérébral. Des approches transcriptomiques réalisés au sein des poumons, organes cibles présentant les effets délétères les plus marqués, ont suggéré la dérégulation de nombreuses voies de signalisation en relation avec les réponses oxydante et inflammatoire, qui constituent les mécanismes centraux de toxicité des PUF mais aussi avec des mécanismes de toxicité plus originaux tels que la dysfonction mitochondriale, la transition épithélio-mésenchymateuse et le remodelage tissulaire, dont la modulation a également été validée d'un point de vue fonctionnel. Ces données prometteuses pourraient à terme contribuer à une meilleure prise de décision quant à la réduction des émissions des PUF de même qu'à la réactualisation des normes réglementaires actuellement en vigueur
Although there has been a significant reduction in air pollution since the 1990s, it remains a major public health problem, responsible for over 4.2 million premature deaths worldwide every year. At present, experts' attention is focused on ultrafine particles (PM0.1 or UFP) because of their ability to translocate into the systemic circulation and reach peripheral organs, where they are likely to have a harmful impact. Nevertheless, the knowledge of the cellular and molecular mechanisms involved in the toxicity of these particles is still very patchy, and most often remains focused on their main target, the lung. Thus, the main objectives of this thesis project were to provide innovative insights into the toxicokinetics (i.e., distribution/persistence) and toxicodynamics (i.e., pathophysiological mechanisms, associated cell signaling pathways) of UFP collected in urban environments, on the one hand, and the organospecific effects of UFP and the use of circulating miRNA as indicators of chronic and/or cumulative exposure to UFP in a mouse model, on the other hand. To answer these questions, Balb/cJRj mice were exposed for 3 months to various doses of UFP collected in the urban area of Lille, then analyzed in various target organs richly vascularized, and therefore directly exposed to UFP during their translocation and systemic distribution phase. The results showed that, in all target organs, the intrinsic oxidative potential of UFP undeniably induced the production of oxidative oxygen species and the activation of antioxidant defenses in sufficient quantities to restore a state of redox homeostasis, but were unable to prevent the onset of an inflammatory response in the lungs, heart and brain. Transcriptomic approaches carried out in the lungs, the target organ with the most marked deleterious effects, have suggested the deregulation of numerous signaling pathways in relation to oxidative and inflammatory responses, which constitute the central mechanisms of UFP toxicity, but also with more original toxicity mechanisms such as mitochondrial dysfunction, epithelial-mesenchymal transition and tissue remodeling, whose modulation has also been validated from a functional point of view. These promising data could ultimately contribute to better decision-making on the reduction of UFP emissions, as well as to the updating of current regulatory standards