Ataxia telangiectasia (AT), caused by mutations in the gene encoding ataxia telangiectasia mutated kinase (ATM), is a rare autosomal recessive disorder. AT individuals exhibit neuronal degeneration and are predisposed to cancer. Carriers of this disorder are predisposed to cancer and ischemic heart disease. Heart disease, mostly due to myocardial infarction (MI), is a leading cause of death in the US. Following MI, release of catecholamines in the heart stimulates β- adrenergic receptors (β-AR). Our lab has shown that β-AR stimulation increases ATM expression in the heart and myocytes, and ATM plays an important role in β-AR-stimulated myocardial remodeling with effects on function, fibrosis and apoptosis. Using wild-type (WT) and ATM heterozygous knockout (hKO) mice, this study investigated the role of ATM in the inflammatory, proliferative and maturation phases of infarct healing post-MI. During the inflammatory phase, 1 and 3 days post-MI, a deficiency of ATM resulted in decreased left ventricular dilation as measured by echocardiography. It decreased the number of neutrophils and macrophages in the heart 1 day post-MI. Myocardial fibrosis, expression of alpha-smooth muscle actin (α-sma) and apoptosis were higher in the infarct region of ATM deficient hearts. Akt activation (anti-apoptotic) was lower, while Bax expression (pro-apoptotic) was higher in the infarct region of ATM deficient hearts. During the proliferative phase, 7 days post-MI, ATM deficiency attenuated cardiac dysfunction as measured by echocardiography. ATM deficient hearts exhibited increased fibrosis and expression of α-sma in the infarct region with increased myocyte apoptosis in the border area. During the maturation phase, 14 and 28 days post-MI, ATM deficiency resulted in exaggerated cardiac function. It associated with increased fibrosis, expression of α-sma and decreased cardiac cell apoptosis in the infarct region 28 days post-MI. Myocyte hypertrophy was greater in the non-infarct region during ATM deficiency. ATM deficiency decreased expression of p16 (marker of cell senescence) and activation of proapoptotic protein, GSK-3β. Thus, ATM modulates the remodeling processes of the heart including function, fibrosis, apoptosis and hypertrophy post-MI. ATM (1) delays the inflammatory response post-MI, (2) decreases dilative remodeling during inflammatory and proliferative phases and (3) exaggerates dysfunction during the maturation phase.

La Galanine est un peptide ubiquitaire de 29 acides aminés chez les mammifères (30 chez l'homme) qui contrôle de nombreuses fonctions biologiques: (I) secrétions endocrines (insuline, somatostatine, glucagon); (II) comportement (prise alimentaire, nociception, apprentissage, mémoire); (III) tonicité musculaire dans le tractus digestif. Ce peptide a particulièrement été étudié dans le système nerveux central où il joue un rôle dans l'évolution de certaines maladies neurodégénératives telles que les maladies de Parkinson et d'Alzheimer. La galanine agit en se fixant sur 3 récepteurs connus, GalR1-2-3 qui appartient à la grande famille des récepteurs couplés aux protéines G (GPCR). Bien que la Galanine et ses trois récepteurs soient fortement exprimés au niveau périphérique, leur rôle dans les effets périphériques et leur implication en pathologie ont été très peu étudié. L'objectif de mon travail de thèse a été d'identifier le rôle de la galanine dans le remodelage myocardique, qui constitue un déterminant majeur dans la progression de l'insuffisance cardiaque. Dans un premier temps, nous avons démontré que la galanine possède des propriétés anti-apoptotiques et anti-oxydantes in vitro dans les cardiomyocytes. En effet, le traitement de cellules par la galanine entraîne une diminution de l'apoptose et de la production de radicaux libres oxygénés en réponse à l'hypoxie. En accord avec ces effets bénéfiques au niveau cellulaire, les études in vivo réalisées dans un modèle d'ischémie-reperfusion cardiaque, ont montré que le traitement à la galanine dans la phase précoce de reperfusion réduit l'apoptose et la nécrose myocardique. De plus, nous avons confirmé in vivo l'importance de la galanine dans la défense contre le stress oxydant associé aux lésions mitochondriales post-ischémiques. Dans un deuxième temps, nous avons mis en évidence le rôle important de la galanine dans le contrôle de l'activité des fibroblastes cardiaques in vitro. Nous avons montré que la galanine inhibe des étapes clés d'activation de la cascade pro-fibrotique dans les fibroblastes cardiaques. Les propriétés anti-fibrotiques de la galanine ont également été confirmées in vivo dans un modèle de surcharge en pression par constriction aortique chez la souris. Dans ce modèle, nos résultats montrent que le traitement chronique à la galanine s'accompagne d'une amélioration de la fonction cardiaque. Ces données nous ont permis de démontrer que la galanine joue un rôle clé dans le remodelage cardiaque et de proposer la galanine comme un candidat potentiel dans le traitement de l'insuffisance cardiaque. / Galanin is an ubiquitous 29 amino acid peptide in mammals (30 in humans) that controls many biological functions: (I) endocrine secretions (insulin, somatostatin, glucagon); (II) behavior control (food intake, nociception, learning, memory, pain); (III) muscle tonicity in the digestive tract. This peptide has been particularly studied in the central nervous system where it plays a role in the evolution of neurodegenerative diseases such as Parkinson's and Alzheimer's. Although Galanin and its three receptors (GalR1, GalR2, GalR3) are strongly expressed at the peripheral level, their role in peripheral effects and their involvement in the pathology have been poorly studied. The objective of my thesis work was to identify the role of galanin in myocardial remodeling, which is a major determinant in the progression of heart failure. Firstly, we demonstrated that galanin has anti-apoptotic and anti-oxidant properties in vitro in cardiomyocytes. Indeed, the treatment of cells with galanin causes a dose-dependent decrease in apoptosis and reactive oxygen species in response to hypoxia. In line with these beneficial effects at the cellular level, using in vivo model of cardiac ischaemia-reperfusion we showed that galanin treatment reduces apoptosis and necrosis in the early phase of reperfusion. In addition, we confirmed in vivo the importance of galanin in the defense against oxidative stress associated with post-ischemic mitochondrial lesions. Secondly, we demonstrated the important role of galanin in controlling the activity of cardiac fibroblasts. Using in vitro models, we have shown that galanin inhibits activation of key steps of the pro-fibrotic cascade in cardiac fibroblasts. The anti-fibrotic properties of galanin were also confirmed in vivo in a mouse model of pressure overload-induced heart failure. This observation is accompanied by an improvement of cardiac function. These data reveal that galanin plays a key role in cardiac remodeling and suggest galanin as a potential candidate in the treatment of heart failure.

Research in the biomedical sciences is incredibly diverse and often involves the interaction of specialists in a variety of fields. In particular, quantitative, mathematical, and computational methods are increasingly playing significant roles in studying problems arising in biomedical science. This is particularly exciting for mathematical modeling as the complexity of biological systems poses new challenges to modelers and leads to interesting mathematical problems. On the other hand mathematical modeling can provide considerable insight to laboratory and clinical researchers. In this thesis we develop mathematical representations for three biological processes that are of current interest in biomedical science. A deeper understanding of these processes is desirable not only from the standpoint of basic science, but also because of the connections these processes have with certain diseases. The processes we consider are collective cell motility, bone remodeling, and injury response in articular cartilage. Our goals are to develop mathematical representations of these processes that can provide a conceptual framework for understanding the processes at a fundamental level, that make rigorous the intuition biological researchers have developed about these processes, and that help to translate theoretical and experimental work into information that can be used in clinical settings where the primary concern is in treating diseases associated with the process.

In cases of compromised bone remodeling like osteoporosis, insufficient osseointegration occurs and results in implant failure. Implant retention relies on proper secondary fixation, which is developed during bone remodeling. This process is disrupted in metastatic bone diseases like osteoporosis. Osteoporosis is characterized low bone mass and bone strength resulting from either accelerated osteoclast-mediated bone resorption or impaired osteoblast-mediated bone formation. These two processes are not independent phenomena. In fact, osteoporosis can be viewed as a breakdown of the cellular communication connecting bone resorption to bone formation. Because bone remodeling occurs at temporally generated specific anatomical sites and at different times, local regulators that control cross-talk among the cells of the BRU are important. Previous studies show Ti implant surface characteristics like roughness, hydrophilicity, and chemistry influence the osteoblastic differentiation of human MSCs and maturation of OBs. Furthermore, microstructured Ti surfaces modulate the production of factors shown to be important in the reciprocal communication necessary for the maintenance of healthy bone remodeling. Semaphorin signaling proteins are known to couple the communication of osteoblasts to osteoclasts and are capable of stimulating bone formation or bone resorption depending on certain cues. Implant surface properties can be optimized to exploit these effects to favor rapid osseointegration in patients with osteoporosis.

Le rétrécissement aortique (RAo) est la valvulopathie la plus fréquente dans les pays industrialisés. Il entraine une augmentation chronique de la postcharge imposée au ventricule gauche (VG) se caractérisant par une hypertrophie ventriculaire gauche (HVG), une ischémie et une fibrose myocardique, une dysfonction diastolique et à long terme une insuffisance cardiaque. Indépendamment de la sévérité de la valvulopathie, plusieurs facteurs comme l’obésité, le diabète, l’insulinorésistance semblent influencer le remodelage ventriculaire dans cette condition. Ces troubles métaboliques sont associés à un état pro-inflammatoire, notamment du tissu adipeux, impliquant des médiateurs également associés à l’hypertrophie cardiomyocytaire et la fibrose myocardique. A l’heure actuelle, le remplacement valvulaire aortique (RVAo) chirurgical est le seul traitement ayant montré son impact sur la diminution de la morbi mortalité dans le RAo. Cette chirurgie est devenue peu risquée de nos jours et permet une diminution conséquente de la masse ventriculaire gauche (MVG) dans la première année. Néanmoins certains facteurs, en particulier un remodelage important en préopératoire et l’existence d’un mismatch patient-prothèse (PPM), semblent influencer le remodelage inverse après la chirurgie pouvant expliquer la persistance d’une fibrose myocardique ou de symptômes après l’opération. Nous avons émis les hypothèses suivantes : a) un état pro inflammatoire médié par le tissu adipeux épicardique (TAE) et les leucocytes circulants serait associé à un remodelage pathologique dans l’histoire naturelle du RAo, b) l’existence d’un PPM après RVAo serait associé à un moins bon pronostic indépendamment du poids corporel, c) l’horloge biologique jouerait un rôle dans la modulation de la réponse myocardique à un stimulus hypertrophique et à l’ischémie myocardique, d) l’apparition d’une dysfonction ventriculaire droite (VD) postopératoire, serait associée à un mauvais pronostic après RVAo. Nous avons donc inclus prospectivement les patients porteurs d’un RAo serré sans dysfonction VG, sans autre valvulopathie, adressés depuis 2009 au Centre des Valvulopathies du CHRU de Lille pour un premier RVAo. Une évaluation clinique, biologique ainsi qu’une échocardiographie transthoracique (ETT) pré et postopératoire (avant la sortie) ont été réalisées. Pour une partie de la population, différents prélèvements biologiques (sang et TAE) ont été effectués au moment du bloc opératoire afin de réaliser des analyses de transcriptomique sur le TAE et de cytométrie en flux sur les cellules sanguines circulantes. Une partie de la population a également été revue en ETT à 1 an et tous les patients ont été suivis à distance. Nous avons pu montrer que : a) la quantité de TAE était indépendamment associée à un remodelage VG plus sévère dans le RAo mais n’était pas associée à l’importance du remodelage inverse après RVAo. D’après nos premiers résultats, ce remodelage VG plus sévère semble associé à une dysrégulation de gènes impliqués dans la réponse immunitaire adaptative, dans la régulation de la réponse immunitaire et dans l’activation des cellules lymphocytaires T et également à un nombre de leucocytes et de monocytes circulants plus important, b) une surface fonctionnelle indexée de la prothèse aortique implantée lors du RVAo de moins de 0,85 cm²/m² était le paramètre valvulaire le plus puissant pour prédire les évènements cardiovasculaires à distance de l’opération chez les patients non obèses. De manière surprenante, chez les patients obèses aucune association n’était retrouvée entre cette surface fonctionnelle et le devenir des patients après RVAo, c) il existe une variation circadienne de la tolérance à l’ischémie-reperfusion imposée lors du RVAo [...] / Aortic stenosis (AS) is the most common valvular heart disease (VHD) in Western countries. It causes a chronic increase in left ventricular (LV) afterload characterized by left ventricular hypertrophy (LVH), ischemia and myocardial fibrosis, diastolic dysfunction and long-term heart failure. Regardless of the severity of stenosis, several factors such as obesity, diabetes, insulin resistance seems to impact the LV remodeling in this condition. These metabolic disorders are associated with a pro-inflammatory state, including adipose tissue, involving mediators perceived in cardiomyocyte hypertrophy and myocardial fibrosis. To date, surgical aortic valve replacement (SAVR) is the only option that has shown an impact on mortality. This surgery has become less risky and leads to a significant decrease in the left ventricular mass (LVM) in the first year. Nevertheless, some factors, including the existence of a patient-prosthesis mismatch (PPM), seem to influence this reverse remodeling after surgery, which may explain the persistence of myocardial fibrosis or symptoms after the surgery. We have made the following hypotheses: a) a pro-inflammatory state mediated by epicardial adipose tissue (EAT) and circulating leukocytes would be associated with pathological remodeling in the natural history of AS, b) the existence of a PPM after SAVR would be associated with a poorer prognosis regardless of body weight status, c) the circadian clock would play a role in modulating the myocardial response to a hypertrophic stimulus and myocardial ischemia, d) the onset of postoperative right ventricular (RV) dysfunction, would be associated with poorer prognosis after SAVR. We therefore prospectively included patients with severe AS without LV dysfunction, or another VHD, referred to our Heart Valve Center in Lille University Hospital since 2009 for a first SAVR. Clinical and biological evaluation and pre- and postoperative (before discharge) trans-thoracic echocardiography (TTE) were performed for all patients. In a sub-group of patients, biological samples (blood and TAE) were collected at the time of surgery to perform transcriptomic analysis on EAT and flow cytometry on the circulating blood cells. TTE was also performed 1-year after SAVR in a sub-group and all patients were followed-up for cardiovascular events. We found that: a) the amount of EAT was independently associated with worse LV remodeling in AS but not with the magnitude of reverse remodeling after SAVR. According to our first results, this more severe LV remodeling seems to be associated with dysregulation of genes involved in the adaptive immune response, in the regulation of the immune response and in the activation of T lymphocyte cells and also with a number of circulating leukocytes and monocytes more important, b) the indexed effective orifice area of the aortic prosthesis calculated by TTE with the unique cut-off of 0.85cm²/m² showed the best accuracy to predict major events after SAVR in lean or overweight patients but not in obese, c) perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing SAVR, with poorer tolerance in patients operated on in the morning, d) heart failure is more frequently observed in patients operated on in the morning, unrelated to the occurrence of acute kidney injury after SAVR, e) the early and severe post-operative decline in RV longitudinal function reverses within a year and is not predictive of long-term outcomes after SAVR. Subsequently, we will continue to explore the link between adipose tissue and the natural course of LV remodeling, cardiovascular events after SAVR in particular the impact of circadian variations on the occurrence of heart failure and the RV function after SAVR.

Orientador: Maria Aparecida Neves Jardini / Banca: Fabio da Silva Matuda / Banca: Andréa Carvalho de Marco / Banca: Mariéllen Longo Vilas Boas / Banca: Cibelle Barbosa Lopes / Resumo: A doença periodontal (DP) resulta de uma infecção polimicrobiana complexa, levando à destruição dos tecidos periodontais, como consequência da perturbação da homeostase entre a microbiota subgengival e os mecanismos de defesas do hospedeiro em indivíduos suscetíveis. A deficiência estrogênica (DE) é a causa mais comum de osteoporose. A osteoporose é definida como uma doença crônica, multifatorial, provenientes de uma desordem esquelética que promove fragilidade óssea pela redução de sua massa. Vários estudos experimentais têm demonstrado que a estimulação com Campo Eletromagnético Pulsátil (CEMP) pode promover a osteogênese e potencialmente aumentar a mineralização óssea e também, reduzir a inflamação aguda e crônica em tecidos moles e duros. Frente a isso, este estudo teve como objetivo, avaliar por meio da histomorfometria, imunoistoquímica e microtomografia computadorizada (MicroCT), a influência do CEMP na DP induzida em ratas ovariectomizadas e Sham. Para a pesquisa, foram utilizadas 60 ratas adultas (Rattus norvegicus, variação albinus, Wistar) com 3 meses de idade, pesando em torno de 300 gramas e em todos os animais a DP foi induzida. As ratas foram randomizadas em dois grupos experimentais, contendo 30 animais cada, classificados em ovariectomia simulada (Sham) e Ovariectomizada (Ovz), respectivamente. Os grupos foram divididos em dois subgrupos com 15 animais cada: Sham-S (n=15): não receberam terapia com CEMP e este foi nosso grupo controle. Sham-CEMP (n=15): receb... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract : Periodontal disease (PD) results from a complex polymicrobial infection, leading to the destruction of periodontal tissues as a consequence of the disturbance of homeostasis between the subgingival microbiota and the host defense mechanisms in susceptible individuals. Estrogen deficiency is the most common cause of osteoporosis. Osteoporosis is defined as a chronic, multifactorial disease from a skeletal disorder that promotes bone fragility by reducing its mass. Several experimental studies have shown that Pulsed Electromagnetic Field (PEMF) stimulation can promote osteogenesis and potentially increase bone mineralization and also reduce acute and chronic inflammation in soft and hard tissues. The aim of this study was to evaluate, through histomorphometry, immunohistochemistry and computerized microtomography (MicroCT), the influence of PEMF on PD induced in ovariectomized and Sham rats. For the research, 60 adult rats (Rattus norvegicus, albinus variant, Wistar) at 3 months of age, weighing around 300 grams were used and in all animals PD was induced. The rats were randomized into two experimental groups, containing 30 animals each, classified as simulated ovariectomy (Sham) and Ovariectomized (Ovz), respectively. The groups were divided into two subgroups with 15 animals each: Sham-S (n = 15): did not receive PEMF therapy and this was our control group. Sham-PEMF (n = 15): received PEMF therapy. Ovz-O (n = 15): did not receive PEMF therapy. Ovz-PEMF (n = 15): received PEMF therapy. The histomorphometric and MicroCT analyzes were performed and the data were submitted to analysis of variance (ANOVA) and Tukey's test, both with a 95% significance level and did not present any statistically significant difference. In the semiquantitative analysis for RANKL and OPG biomarkers, the Ovz-O subgroup showed higher expression of the RANKL biomarker and lower expression...(Complete abstract click electronic access below) / Doutor

A remodelação do processo alveolar após a exodontia é um fenômeno fisiológico que resulta em alterações das dimensões ósseas e que podem interferir na reabilitação protética. Para minimizar a perda óssea, estratégias de preservação do rebordo vêm sendo empregadas e a terapia por fotobiomodulação (TFBM) se destaca como uma opção de baixo custo e morbidade. Estudos prévios evidenciaram o impacto positivo da TFBM no reparo ósseo. O objetivo do presente trabalho foi avaliar o efeito TFBM no reparo alveolar. Vinte pacientes com indicação clínica de exodontia dos primeiros ou segundos molares bilateralmente foram selecionados e os lados direito e esquerdo de cada paciente distribuídos em um dos grupos experimentais: (1) TFBM, tratado com laser de baixa frequência, e (2) Controle, que recebeu o mesmo tratamento com o equipamento desligado; a aplicação foi realizada no pós-operatório imediato, 1, 2, 3, 4, 7 e 15 dias. Aos 45 dias pós-exodontia, espécimes de tecido do interior dos alvéolos foram coletados para análise microtomográfica e histológica. Os dados foram comparados utilizando o Teste-t pareado e o nível de significância foi de 5%. A análise morfométrica evidenciou diferenças estatisticamente significante entre os grupos para os seguintes parâmetros: superfície óssea (p=0,029), superfície óssea/volume total (p=0,028), número de trabéculas (p=0,025) e densidade de conectividade (p=0,029), maiores no grupo TFBM em relação ao Controle. O volume ósseo, volume ósseo/total, espessura e separação trabecular não apresentaram diferenças estatisticamente significantes (p=0,054; p=0,082; p=0,598 e p=0,109, respectivamente). Esses dados foram confirmados na análise histológica, onde foi identificado maior quantidade de tecido trabecular no grupo TFBM, enquanto no Controle fica evidente maior quantidade de tecido conjuntivo. Os resultados evidenciaram que a terapia de fotobiomodulação tem efeito positivo no reparo de alvéolos humanos. / The process of bone repair after tooth extraction is a physiological phenomenon which results in alterations of the bone dimensions and could interfere in prosthetic rehabilitation. To minimize bone loss, strategies for border preservation have been used and photobiomodulation therapy (TFBM) stands out as a low cost option and morbidity. Previous studies have shown the positive impact of TFBM on bone repair. The aim of this study was to evaluate the effect of TFBM on alveolar repair. Twenty patients with exodontia indication of the first or second molar bilaterally were chosen, right and left sides were distributed in one of the following experimental groups: (1) TFBM, treated with low frequency laser, and (2) Control group, who received the same treatment with the equipment off; besides, laser application was applied right after the post-operatory, after 1, 2, 3, 4, 7 and 15 days. After 45 days from the extraction, tissue samples from the alveoli were collected for micro-tomographic and histological analysis. Data were compared using the paired t-test and the accuracy level was 5%. A morphometric analysis showed statistically significant differences between the groups regarding the following parameters: bone surface (p = 0.029), bone surface / total volume (p = 0.028), trabeculae number (p = 0.025) and connectivity density (p = 0.029), higher in the TFBM group than in Control. The bone volume, bone / total volume, trabecular thickness and separation did not present statistically significant differences (p = 0.054, p = 0.082, p = 0.598 and p = 0.109, respectively). These data were confirmed in the histological analysis, where a greater amount of trabecular tissue was identified in the TFBM group, while in control group, a high amount of connective tissue was evident. The results showed that photobiomodulation therapy has a positive effect on the repair of human alveoli.

Histone modifying enzymes and chromatin remodeling complexes play an important regulatory role in chromatin dynamics that dictate the interaction of regulatory factors involved in processes such as DNA replication, recombination, repair and transcription, with DNA template. The CHD (Chromodomain Helicase DNA Binding Protein) family of proteins is known to be involved in the regulation of gene expression, recombination and chromatin remodeling via their chromatin specific interactions and activities. Phenotypic analysis of the Chd2 mutant mouse model developed by our laboratory indicates that the Chd2 protein plays a critical role in tumor suppression as the heterozygous mutant mice develop spontaneous lymphomas. In this study we demonstrate that mutation of Chd2 renders cells susceptible to inefficient DNA repair and genomic instability. Homozygous and heterozygous Chd2 mutant mouse embryonic fibroblast accumulates higher levels of gamma-H2AX after DNA damage. Chd2 mutant cells show inefficiency in DNA repair of DNA lesions induced by X-rays and UV irradiation as assessed by single cell gel electrophoresis assays. These cells also exhibit increased chromosomal aberrations after treatment with low doses of X-ray irradiation (2 Gy) and show increased radiosensitivity in a clonogenic survival assay. At the molecular level, endogenous CHD2 protein level is induced after exposure to X-ray radiation. In addition, we have also demonstrated in this study that CHD2 is phosphorylated after DNA damage and is a potential substrate for phosphoinositide 3-kinase-related kinases (PIKK) - ATM/ATR. Additionally, mass spectrometric analysis showed possible association of CHD2 with the paraspeckle family of proteins known to be involved in an array of cellular processes specifically in RNA processing and DNA repair. An in vivo splicing assay demonstrated that CHD2 played a role in modulation of pre-mRNA splicing event. Collectively, our findings suggest that CHD2 is a multi-functional protein working with the paraspeckle protein complex to facilitate both the pre-mRNA splicing process and the initial DNA repair process. CHD2 may also be involved in the later stages of DNA damage response pathway by influencing p53’s transcriptional activity.

Thesis (M.S.)--University of Florida, 2003. / Title from title page of source document. Includes vita. Includes bibliographical references.

Lasthme est une pathologie inflammatoire caractérisée par une inflammation, une hyperréactivité et un remodelage bronchique. Des études menées sur des souris déficientes en MMP-8 et en MMP-19 nous ont permis de démontrer que ces deux protéases jouaient un rôle protecteur vis-à-vis du développement de l'inflammation dans la pathologie asthmatique. En effet, suite à la sensibilisation et à l'exposition par inhalation à lallergène (Ovalbumine),les souris déficientes en MMP-8 en MMP-19 développent respectivement une inflammation neutrophilique et éosinophilique significativement plus importante comparativement aux souris wild-type. Dans une seconde partie de ce travail, nous avons évalué les effets de deux inhibiteurs synthétiques des MMPs administrés en inhalation sous une formulation adéquate dans notre modèle murin dasthme. Suite à ladministration de ces deux inhibiteurs, nous avons observé une diminution de linflammation au sein du lavage bronchoalvéolaire. De plus, nous observons une diminution de linfiltration du tissu pulmonaire par les cellules inflammatoires. Lhyperréactivité bronchique observée suite à linhalation de doses croissantes de méthacholine est également significativement diminuée. Ces résultats sont comparables à ceux obtenus après linhalation de Fluticasone, stéroïde inhalé utilisé très largement en clinique humaine et utilisé dans nos expériences comme médicament de référence. Afin dobserver les modifications morphologiques bronchiques, nous avons mis au point un modèle murin dasthme permettant une exposition de longue durée (90 jours) aux allergènes. En plus de développer une inflammation pulmonaire, les souris traitées vont voir la structure de leurs bronches se modifier. L'inhalation de doxycycline diminue significativement l'inflammation, la réactivité bronchique et diverses caractéristiques du remodelage bronchique telles que l'hyperplasie des cellules à mucus, le dépôt de collagène péribronchique, l'épaisseur de la membrane basale sous-épithéliale et l'épaisseur de la couche de cellules musculaires lisses. Au cours de ces travaux, nous avons caractérisé des modèles murins dasthme. Nous avons démontré que linhibition de certaines MMPs est délétère, nous incitant à les considérer comme des « anti targets ». Nous avons, dans une seconde partie, pu apporter la démonstration que linhibition de certaines MMPs précises (MMP-2, -9 et -14) par des inhibiteurs relativement spécifiques administrés en inhalation améliore le phénotype asthmatique. Par ces travaux, nous avons contribué à la compréhension globale des mécanismes impliquant les MMPs dans la pathologie asthmatique et nous suggérons que de nouvelles voies thérapeutiques, basées sur linhibition de certaines MMPs, pourraient faire lobjet de développements futurs.