Estudos sugerem que o exercício de força e a suplementação de aminoácidos de cadeia ramificada apresentam potencial anabólico e anti-proteolítico, exercendo de forma sinérgica efeitos positivos sobre o remodelamento muscular. Diante disso, esse estudo teve como objetivo comparar os efeitos da suplementação de aminoácidos de cadeia ramificada (BCAA) e leucina isolada sobre as vias de síntese proteica muscular após uma sessão de exercício de força. Foi conduzido um estudo transversal, randomizado, duplo-cego e controlado por placebo. Dezoito sujeitos do gênero masculino, sedentários e com idade entre 18-30 anos foram divididos em três grupos experimentais: BCAA (BCAA: 3,3 g leucina + 2,4 g de isoleucina + 2,4 g de valina), leucina (LEU: 3,2 g de leucina + 4,8 g de alanina) e placebo (PLA: 8 g de alanina). Os grupos foram submetidos a uma sessão exercício de força (extensão de joelho) composta por 8 séries de 8-10 repetições (85% de 1RM ) com 2 minutos de intervalo entre as séries e receberam intervenção nutricional imediatamente após o término da sessão. Imediatamente antes, imediatamente após, 30, 60, 90 e 120 minutos após o término da sessão os voluntários realizaram coletas de sangue. Os voluntários foram submetidos a biópsias musculares para análises de expressão proteica proteica (p-p70S6KThr389, p-4E-BP1Thr37/46, p-peIF4E Ser209) no período basal (pré), 1 e 2 horas após o término da sessão de exercício. As amostras de sangue foram utilizadas para medir os níveis plasmáticos de insulina, glicose, perfil lipídico e citocinas (TNF-, IL-1, IL-4, IL-6 e IL-10). Não foram encontradas diferenças significativas entre os grupos para o perfil lipídico e os níveis plasmáticos de glicemia. A concentração plasmática de insulina aumentou significativamente nos grupos BCAA e LEU 60 minutos após a ingestão em comparação ao PLA. Para os valores de citocinas musculares, foi encontrada diferença significativa entre BCAA e Estudos sugerem que o exercício de força e a suplementação de aminoácidos de cadeia ramificada apresentam potencial anabólico e anti-proteolítico, exercendo de forma sinérgica efeitos positivos sobre o remodelamento muscular. Diante disso, esse estudo teve como objetivo comparar os efeitos da suplementação de aminoácidos de cadeia ramificada (BCAA) e leucina isolada sobre as vias de síntese proteica muscular após uma sessão de exercício de força. Foi conduzido um estudo transversal, randomizado, duplo-cego e controlado por placebo. Dezoito sujeitos do gênero masculino, sedentários e com idade entre 18-30 anos foram divididos em três grupos experimentais: BCAA (BCAA: 3,3 g leucina + 2,4 g de isoleucina + 2,4 g de valina), leucina (LEU: 3,2 g de leucina + 4,8 g de alanina) e placebo (PLA: 8 g de alanina). Os grupos foram submetidos a uma sessão exercício de força (extensão de joelho) composta por 8 séries de 8-10 repetições (85% de 1RM ) com 2 minutos de intervalo entre as séries e receberam intervenção nutricional imediatamente após o término da sessão. Imediatamente antes, imediatamente após, 30, 60, 90 e 120 minutos após o término da sessão os voluntários realizaram coletas de sangue. Os voluntários foram submetidos a biópsias musculares para análises de expressão proteica proteica (p-p70S6KThr389, p-4E-BP1Thr37/46, p-peIF4E Ser209) no período basal (pré), 1 e 2 horas após o término da sessão de exercício. As amostras de sangue foram utilizadas para medir os níveis plasmáticos de insulina, glicose, perfil lipídico e citocinas (TNF-, IL-1, IL-4, IL-6 e IL-10). Não foram encontradas diferenças significativas entre os grupos para o perfil lipídico e os níveis plasmáticos de glicemia. A concentração plasmática de insulina aumentou significativamente nos grupos BCAA e LEU 60 minutos após a ingestão em comparação ao PLA. Para os valores de citocinas musculares, foi encontrada diferença significativa entre BCAA e Estudos sugerem que o exercício de força e a suplementação de aminoácidos de cadeia ramificada apresentam potencial anabólico e anti-proteolítico, exercendo de forma sinérgica efeitos positivos sobre o remodelamento muscular. Diante disso, esse estudo teve como objetivo comparar os efeitos da suplementação de aminoácidos de cadeia ramificada (BCAA) e leucina isolada sobre as vias de síntese proteica muscular após uma sessão de exercício de força. Foi conduzido um estudo transversal, randomizado, duplo-cego e controlado por placebo. Dezoito sujeitos do gênero masculino, sedentários e com idade entre 18-30 anos foram divididos em três grupos experimentais: BCAA (BCAA: 3,3 g leucina + 2,4 g de isoleucina + 2,4 g de valina), leucina (LEU: 3,2 g de leucina + 4,8 g de alanina) e placebo (PLA: 8 g de alanina). Os grupos foram submetidos a uma sessão exercício de força (extensão de joelho) composta por 8 séries de 8-10 repetições (85% de 1RM ) com 2 minutos de intervalo entre as séries e receberam intervenção nutricional imediatamente após o término da sessão. Imediatamente antes, imediatamente após, 30, 60, 90 e 120 minutos após o término da sessão os voluntários realizaram coletas de sangue. Os voluntários foram submetidos a biópsias musculares para análises de expressão proteica proteica (p-p70S6KThr389, p-4E-BP1Thr37/46, p-peIF4E Ser209) no período basal (pré), 1 e 2 horas após o término da sessão de exercício. As amostras de sangue foram utilizadas para medir os níveis plasmáticos de insulina, glicose, perfil lipídico e citocinas (TNF-, IL-1, IL-4, IL-6 e IL-10). Não foram encontradas diferenças significativas entre os grupos para o perfil lipídico e os níveis plasmáticos de glicemia. A concentração plasmática de insulina aumentou significativamente nos grupos BCAA e LEU 60 minutos após a ingestão em comparação ao PLA. Para os valores de citocinas musculares, foi encontrada diferença significativa entre BCAA e LEU comparado ao PLA para a concentração de IL-10 entre o momento 60 e 120 minutos após. Nesse mesmo período de tempo, também foi encontrada diferença significativa entre LEU e BCAA para a concentração de IL-1. Para os valores de citocinas plasmáticas, não foram encontradas diferenças significativas entre os grupos em todos momentos analisados. A suplementação de BCAA e LEU aumentou significativamente a expressão p-4E-BP1Thr37/46 120 minutos após comparado ao PLA no mesmo tempo. A expressão de p-p70S6kThr389 foi significativamente aumentada nos grupos BCAA e LEU 60 e 120 minutos após quando comparado com o PLA no mesmo tempo. A expressão de p-eIF4ESer209 encontrou-se significativamente aumentada após 60 minutos apenas no grupo LEU quando comparado ao PLA. Porém, 120 minutos após encontrou-se significativamente elevada em ambos grupos comparado ao PLA. Por meio dos resultados, podemos concluir que a suplementação de BCAA e leucina associadas ao exercício de força possuem efeitos semelhantes sobre o balanço inflamatório e sobre as vias de sinalização de síntese proteica muscular aumentando a fosforilação de efetores da cascata de sinalização da via Akt/mTOR / Studies suggest that resistance exercise and branched chain amino acids supplementation have potential anabolic and anti-proteolytic, synergistically exerting positive effects on muscle remodeling. Therefore, this study aimed to compare the effects of branched chain amino acids (BCAA) and leucine isolated supplementation on muscle remodeling pathways after a resistance exercise. A cross-sectional, a randomized, double-blind, placebo-controlled trial was conducted. Eighteen male sedentary subjects were aged 18-30 years were divided into three experimental groups: BCAA (BCAA: leucine + 3.3 g 2.4 g 2.4 g isoleucine + valine), leucine (LEU : 3.2 g of leucine + alanine 4.8 g) and placebo (PLA: 8 g of alanine). Both groups underwent a session of resistance exercise (knee extension) that consists of 8 sets of 8-10 repetitions (85% of 1RM) with 2 minutes rest between sets and received nutritional intervention immediately after the session. Immediately before, immediately after, 30, 60, 90 and 120 minutes after the end of the session the blood samples were assessed. Muscle biopsies were collected for analysis of protein expression (p-p70S6KThr389, p-4E-BP1Thr37/46, p-peIF4ESer209, MAFbx and MURF-1) at baseline (pre), 1 and 2 hours after end of the exercise session. The blood samples were used to measure serum levels of insulin, glucose, lipid and cytokine (TNF-, IL-1, IL-4, IL-6 and IL-10). No significant differences between groups were observed for the lipid profile and plasma glucose. The plasma insulin increased significantly in the groups BCAA and leucine 60 minutes after ingestion compared to PLA. For values of muscular cytokines, significant difference was found between BCAA and LEU compared to PLA for the concentration of IL-10 between the time 60 and 120 minutes after. In that same time period, also found significant differences between LEU and BCAA for the concentration of IL-1. For values of plasma cytokines, no significant differences between groups were observed at all time points analyzed. BCAA and LEU supplementation significantly increased the expression of p-4E-BP1Thr37/46 120 minutes after the resistance exercise compared to PLA at the same time point. The expression of p-p70S6KThr389 was significantly increased in BCAA and LEU groups 60 and 120 minutes after resistance exercise compared to PLA at the same time point. The expression of p-peIF4ESer209 p70S6KThr389 was significantly increased after 60 minutes only on LEU group compared to PLA at the same time point. However, 120 minutes after the expression was significantly elevated in both groups compared to PLA. Through the results, we can conclude that the BCAA and leucine supplementation associated with strength exercise have similar effects on the balance of inflammatory and signaling pathways of muscle protein synthesis by increasing the phosphorylation of effectors of the signaling cascade of Akt / mTOR

Introdução: A disfunção cardíaca relacionada à cirrose acomete pacientes com insuficiência hepática avançada e pode estar associada a complicações como a síndrome hepatorrenal. Diferente do que ocorre na insuficiência cardíaca, em que o tratamento farmacológico com betabloqueadores é reconhecidamente eficaz em reverter o remodelamento cardíaco e aumentar a sobrevida, ainda não foi testada nenhuma modalidade terapêutica que possa bloquear o efeito remodelador e a progressão da disfunção cardíaca nos pacientes com cirrose. Formulamos a hipótese que o uso de betabloqueador poderia ter efeito benéfico sobre as alterações cardíacas morfológicas e funcionais observadas em pacientes com cirrose. Objetivos: O objetivo primário foi avaliar a eficácia do metoprolol na reversão da disfunção cardíaca em pacientes com cirrose não alcoólica. Os objetivos secundários compreenderam: reversão das alterações ecocardiográficas, biomarcadores da ativação neuro-humoral, eletrofisiológicas, eventos clínicos e efeitos adversos. Avaliou-se também o impacto da resposta inotrópica anormal no prognóstico da cirrose. Material e métodos: Conduzimos um estudo prospectivo, randomizado, duplo-cego, placebo-controlado, fase II, com análise \"por intenção de tratar\". Os critérios de inclusão foram cirrose de etiologia não alcoólica, escore MELD entre 10 e 20 pontos e idade entre 18 e 60 anos. Os critérios de exclusão foram doença cardiovascular prévia, doenças sistêmicas com acometimento cardíaco e contraindicação ao uso de betabloqueadores. No momento da inclusão e após 180 dias de tratamento, realizamos avaliação clínica, dosagem de biomarcadores (noradrenalina, troponina, peptídeo natriurético tipo B e atividade da renina plasmática), mensuração indireta da atividade simpática (ECG dinâmico de 24 horas) e ecocardiograma sob estresse com dobutamina. A disfunção cardíaca foi caracterizada pela resposta inotrópica anormal ao eco-estresse (incremento do débito cardíaco <= 30% após o estresse em relação ao basal, medido pela integral velocidadetempo na via de saída do ventrículo esquerdo). O desfecho primário foi definido como o aumento >=30% da resposta inotrópica ao estresse. Os eventos clínicos avaliados como desfecho foram: ascite, síndrome hepatorrenal, encefalopatia, infecções, hemorragia digestiva varicosa, internações e mortalidade. Considerando a possibilidade de erro alfa de 0,05, erro beta de 0,2 e diferença de proporções na melhora da VTI ( >= de 30%) entre os grupos, o tamanho amostral foi estimado em 72 pacientes. O protocolo foi aprovado pela Comissão de ética institucional e registrado na base de dados internacional ClinicalTrials.gov (NCT01676285, acrônimo \"Cardiac Remodeling in cirrhosis - CARE cirrhosis\"). Resultados: No período de junho de 2011 a dezembro de 2013, 478 pacientes com cirrose foram prospectivamente avaliados e 190 preencheram os critérios de elegibilidade, sendo incluídos 125 pacientes. Desses, 78 (62%) apresentaram resposta inotrópica anormal ao estresse farmacológico. Os demais 47 (38%) pacientes com resposta inotrópica normal foram seguidos sem intervenção farmacológica. Os pacientes com resposta anormal foram randomizados para receber tratamento (succinato de metoprolol, n=41 ou placebo, n=37). Três (7,3%) dos pacientes no grupo metoprolol e 9 (24,3%) no grupo placebo apresentaram normalização da resposta inotrópica ao estresse, diferença não estatisticamente significante (p=0,057). Não houve diferença entre os grupos metoprolol e placebo em relação à reversão das alterações ecocardiográficas, laboratoriais e eletrofisiológicas. Não houve diferença quanto aos desfechos clínicos isolados ou combinados na comparação entre metoprolol e placebo: síndrome hepatorrenal n=1 (2,4%) versus n=0, p=0,99; ascite n= 4 (12%) versus n=2 (5,4%), p=0,27; infecções bacterianas n= 2 (4,8%) versus n=2 (5,4%), p=0,94; encefalopatia hepática n= 5 (12,1%) versus n=6 (16.2%), p=0,59, hemorragia varicosa n=0 em ambos os grupos; internações n=6 (14,6%) versus n=8 (21,6%), p=0,45; morte n=5 (12,1%) versus n= 2 (5,4%), p=0,94; respectivamente. Não houve diferença entre metoprolol e placebo em relação ao surgimento de efeitos adversos n=4 (9,7%) versus n=6 (16,2%), respectivamente, p=0,5. Os pacientes no grupo com resposta inotrópica anormal apresentaram maiores taxas de desfechos combinados (26 (33,3%) versus 8 (17,0%), p=0,03) em relação àqueles com resposta inotrópica normal. Conclusão: embora seguro, o metoprolol não foi eficaz na reversão da disfunção cardíaca em pacientes com cirrose não alcoólica. Não houve benefício na terapia com metoprolol em relação aos desfechos ecocardiográficos, laboratoriais, eletrofisiológicos e clínicos, incluindo mortalidade. Os pacientes com resposta inotrópica normal tiveram melhor evolução em relação àqueles com resposta inotrópica anormal / Background: Cardiac dysfunction is found in patients with end-stage liver disease and is implicated in complications such as hepatorenal syndrome. Unlike heart failure, in which beta-blockers are admittedly effective in reversing cardiac remodeling and improving survival, the effect of beta-blockade on the cardiac dysfunction of patients with cirrhotic cardiomyopathy is unknown. We hypothesized that beta-blockers could have a beneficial effect on the morphological and the functional cardiac changes seen in patients with cirrhosis. Aim: To assess the efficacy of metoprolol in the reversal of the cardiac dysfunction in patients with non-alcoholic cirrhosis. Methods: We conducted a prospective, randomized, double-blind, placebocontrolled, with an \"intention to treat\" analysis, phase II study. Inclusion criteria were cirrhosis of non-alcoholic etiology, MELD score between 10 and 20 points and age between 18 and 60 years old. Exclusion criteria were previous cardiovascular disease, systemic diseases with cardiac involvement and contraindications to beta-blockers. Clinical assessment, measurements of biomarkers (norepinephrine, troponin, B-type natriuretic peptide and plasma renin activity), 24-hours Holter and stress echocardiography with dobutamine were performed at inclusion and after 180 days of treatment. Cardiac dysfunction was defined by an abnormal inotropic response to stress echo (an increasing in cardiac output <= 30% during peak stress in relation to baseline values, as measured by the left ventricular outflow tract velocity-time integral). Primary end-point was an increase of 30% in the inotropic response. The frequency of ascites, hepatorenal syndrome, encephalopathy, bacterial infections, variceal bleeding, hospitalization and mortality were also assessed. Considering an alpha error of 0.05, a beta error of 0.2, a difference between proportions of improvement of VTI between the groups of 20%, and an anticipated dropout rate of 10%, the sample size was estimated in 72 patients. The protocol was approved by the institutional ethics board and registered in the database ClinicalTrials.gov (NCT01676285 acronym \"Cardiac Remodeling in cirrhosis - cirrhosis CARE\"). Results: From June 2011 to December 2013, 478 patients with cirrhosis were prospectively evaluated. 190 were eligible to participate in the study. From these, 125 met the inclusion criteria and 78 had abnormal inotropic response to pharmacological stress. These 78 patients, who comprise the present series, were randomly assigned to receive treatment (metoprolol succinate, n = 41 or placebo, n = 37). The remaining 47 (38%) patients with normal inotropic response were followed without pharmacological intervention. Three (7.3%) patients in the metoprolol group and 9 (24.3%) in the placebo group achieved normalization of the inotropic response to stress (p = 0.057). There was no difference between metoprolol or placebo with respect to the reversal of the echocardiographic, electrophysiological and laboratory changes. There was no difference in clinical outcomes between the groups: hepatorenal syndrome n = 1 (2.4%) versus n = 0, p = 0.99; ascites n = 4 (12%) versus n = 2 (5.4%), p = 0.27; bacterial infections n = 2 (4.8%) versus n = 2 (5.4%), p = 0.94; hepatic encephalopathy n = 5 (12.1%) versus n = 6 (16.2%), p = 0.59), variceal bleeding n = 0 in both groups; admissions n = 6 (14.6%) versus n=8 (21.6%), p = 0.45; death n=5 (12.1%) versus n=2 (5.4%), p = 0.94; for metoprolol and placebo, respectively. Adverse effects were similar in both groups: metoprolol n = 4 (9.7%) versus placebo n = 6 (16.2%), p = 0.5. Patients in the group with abnormal inotropic response showed higher rates of combined outcomes (26 (33.3%) versus 8 (17.0%), p = 0.03) compared to those with normal inotropic response. Conclusion: Although safe, metoprolol was not effective in reversing the cardiac dysfunction in patients with nonalcoholic cirrhosis. There was neither improvement in echocardiographic, laboratory, and electrophysiological parameters nor in clinical outcomes, including mortality. Abnormal inotropic response was associated with a higher incidence of clinical events

L’infarctus du myocarde (IDM), responsable du remodelage ventriculaire, peut conduire, s’il est délétère, à l’insuffisance cardiaque (IC), principale cause de mortalité à travers le monde. Les récentes découvertes ont montré l’implication des ARNs non codants, microARNs (miARNs) et les longs ARNs non codants (lncARNs), dans les processus physiologiques et pathologiques et notamment dans les maladies cardiovasculaires. L’objectif de ce travail a été d’étudier le potentiel des miARNs et des lncARNs en tant que biomarqueurs pronostiques et diagnostiques ainsi qu’en tant que cibles thérapeutiques dans l’IDM et le remodelage ventriculaire. Dans un premier temps, nous avons évalué le pouvoir diagnostique des miARNs sur une cohorte de patients présentant des douleurs thoraciques. Le miR-208b et le miR-499 ont montré une bonne capacité diagnostique de l’IDM, ne dépassant toutefois pas celle des troponines. Nous avons ensuite observé que le miR-150 présente une plus faible concentration dans le sang de patients avec un remodelage ventriculaire post-IDM par rapport aux patients sans remodelage, le positionnant comme un biomarqueur intéressant dans le pronostic de l’IC. Enfin, nous avons montré une régulation importante de plusieurs lncARNs dans le cœur de souris, 24 heures après IDM et 2 lncARNs, MIRT1 et MIRT2, ont été mis en avant pour leur association avec le remodelage. En conclusion, nos études ont montré l’utilité des ARNs non codants pour améliorer l’identification des patients à risque de développer une IC après IDM et ont permis également de mettre en évidence de nouvelles cibles thérapeutiques qui pourraient prévenir le remodelage ventriculaire post-IDM / Myocardial infarction (MI responsible for left ventricular remodeling which can be deleterious and the development of heart failure (HF). HF is one of the leading causes of mortality worldwide and despite many improvements, it remains a major challenge in clinical practice. Recent discoveries in genomics have showed the involvement of non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in physiological and pathological processes and notably linked to cardiovascular diseases. The goal of this work was to study the potential of miRNAs and lncRNAs as prognostic and diagnostic biomarkers and as therapeutic targets in MI and left ventricular remodeling leading to HF. First, we evaluated the diagnostic value of miRNAs in patients with chest pain. MiRNA-208b and miR-499 have shown a good diagnostic capacity for MI. However, these miARNs failed to improve the diagnosis of MI by troponins. MiRNA-208b could also predict patient mortality after MI but this capacity was modest. Then, we observed that miR-150 was present at a low level in the blood of patients with left ventricular remodeling post-MI compared to patients without remodeling. Therefore, miRNA-150 is an interesting prognostic biomarker. Finally, we have shown a significant regulation of several lncRNAs in mouse heart, 24 hours after MI, and 2 lncRNAs, MIRT1 and MIRT2, have been demonstrated for their association with left ventricular remodeling. In conclusion, our studies have shown the utility of non-coding RNAs to improve the identification of patients at risk of developing HF after MI and also allowed to identify potential therapeutic targets to prevent left ventricular remodeling

L’IRM cardiaque a une capacité unique d’étudier le remodelage ventriculaire gauche (VG) après infarctus du myocarde. Les objectifs principaux de ce travail étaient de caractériser le tissue de l’infarctus par IRM et d’évaluer les facteurs associés au remodelage du VG. Nous avons étudié prospectivement 114 patients présentant un premier infarctus du myocarde avec sus-décalage du segment ST et ayant subi une angioplastie primaire. Des IRM cardiaques ont été réalisées dans les 2 à 4 jours et à 6 mois suivant la revascularisation. Premièrement, nous avons réalisé une analyse comparative de différentes méthodes de segmentation de l’infarctus sur l’imagerie de rehaussement tardive (RT). Deuxièmement, nous avons étudié l’évolution des différentes composantes de la zone RT au cours des six mois, et observé que la réduction de la zone RT (33,8%) était représentée par l’extension de la zone grise initiale. Troisièmement, nous avons évalué le rôle clinique de la zone grise. Elle s’est révélée protectrice vis-à-vis du remodelage délétère. Quatrièmement, nous avons étudié l’influence de l’obstruction microvasculaire (OMV) sur le remodelage local du VG. Différents motifs ont été observés entre les patients atteints de l’OMV et ceux ne présentant pas d’OMV: un rétrécissement uniforme à travers le VG chez les patients sans OMV lorsque les sujets avec OMV présentaient une dilatation globale significative, ainsi qu’une dilatation plus importante dans les régions atteint d’OMV / Cardiac MRI (CMR) has the unique ability to study left ventricular remodeling after myocardial infarction. The main objectives of this work were to characterize infarct tissue by CMR and to evaluate factors associated with LV remodeling. We prospectively studied 114 patients with a first ST-segment elevation myocardial infarction (STEMI) undergoing primary angioplasty. CMR was performed within 2-4 days and at 6 months after the revascularization. First, we compared different methods for the segmentation of myocardial infarcts on late gadolinium enhancement (LGE) imaging. Second, we described the evolution of different components of LGE area during 6 months. We found that the decrease of LGE area (33.8%) matched the extent of initial gray zone. Third, we studied the clinical role of gray zone. The gray zone was found to be a protective factor for adverse remodeling. Fourth, we studied the influence of microvascular obstruction (MVO) on local LV remodeling and observed distinct remodeling patterns in patients with and without MVO: equally-distributed shrinkage throughout the LV cavity in patients without MVO whereas significant dilation occurring in those with MVO, tending to be greater in myocardial regions containing MVO

La rigidité artérielle et la fibrose ont une valeur prédictive dans le développement des maladies cardiovasculaires (CV). Ces 2 phénotypes impliquent les cellules musculaires lisses vasculaires (CMLVs) notamment des récepteurs membranaires et les protéines du cytosquelette. Les objectifs ont été d’étudier : (i) l’influence du récepteur minéralocorticoïde (MR) sur la réactivité vasculaire, (ii) le rôle de l’intégrine αvβ3 dans le développement de la rigidité artérielle et la fibrose vasculaire, et (iii) l’impact de la vimentine et la synémine sur la structure et la fonction artérielle. Ces trois études ont utilisées des souris avec invalidation génétiques des protéines d’intérêt. Résultats : l’absence du MR diminue la réactivité vasculaire en altérant le couplage contraction/relaxation des CMLVs via des mécanismes Ca2+- et NO-dépendants (une diminution de la vasoconstriction en réponse au Ca2+ extracellulaire et une altération de la vasorelaxation endothélium-dépendante en réponse à l’acétylcholine). L’invalidation de la sous-unité αv prévient la fibrose en réponse à l’administration d’angiotensine II. L’absence de la vimentine et non celle de la synémine augmente la rigidité artérielle via des changements des adhésions focales des CMLVs mais aussi des cellules endothéliales. En conclusion, les récepteurs membranaires et protéines intracellulaires étudiées influencent la fonction et la structure des artères grâce à des actions spécifiques sur le tonus musculaire, la mécanotransduction et l’organisation ultra-structurale des CMLVs. Ces études montrent au niveau cellulaire et moléculaire le déterminisme plurifactoriel des phénotypes de rigidité-fibrose de la paroi artérielle. Ces résultats nécessitent des travaux plus mécanistiques pour affirmer l’implication de ces protéines dans les maladies CV liées au vieillissement / Arterial stiffness and fibrosis have a predictive value in the development of cardiovascular diseases (CV). These two phenotypes involve vascular smooth muscle cells (VSMCs) including membrane receptors and cytoskeletal proteins. The objectives were to examine: (i) the influence of the mineralocorticoid receptor (MR) on vascular reactivity, (ii) the role of avb3 integrin in the development of arterial stiffness and vascular fibrosis, and (iii) the impact of vimentin and synemin on arterial structure and function. The mice with genetic invalidation of the proteins of interest were used in these three studies. Results: the absence of MR decreased vascular reactivity by altering the contraction/relaxation coupling of VSMC through Ca2+- and NO-dependent mechanisms (a decrease of vasoconstriction in response to extracellular Ca2+ and impaired endothelium-dependent vasorelaxation in response to acetylcholine). The invalidation of the αv subunit prevented fibrosis in response to the administration of angiotensin II. The absence of vimentin, and not that of the synemin, increased arterial stiffness via changes in focal adhesions of VSMCs as well as endothelial cells. In conclusion, the studied membrane receptors and intracellular proteins that influenced the structure and function of arteries through specific actions on muscle tone, the mechanotransduction and the ultra-structural organization of VSMCs. These studies show the multifactorial dependency of the stiffness-fibrosis phenotypes of the arterial wall at the cellular and molecular levels. These results require more mechanistic work to determine the role of these proteins in CV diseases related to aging

Chez les patients mucoviscidosiques (CF), l'épithélium des voies aériennes est souvent lésé et remodelé. Que le remodelage soit lié à l'infection et/ou l'inflammation inhérentes à la pathologie ou à un processus de régénération dérégulée reste à déterminer. Le premier objectif de cette thèse a été de déterminer le rôle de l'inflammation dans le remodelage et la régénération de l'épithélium bronchique CF. Grâce à un modèle in vitro de culture en interface air-liquide, nous avons montré qu'en absence d'infection et d'inflammation exogènes, la régénération épithéliale CF est anormale et retardée, et que l'épithélium régénéré est remodelé, en comparaison d'un épithélium régénéré non-CF. En outre, en générant une inflammation chronique dans les cultures CF et non-CF, nous avons pu attribuer un rôle pour l'inflammation endogène (mémoire inflammatoire) des cellules CF dans l'augmentation de la hauteur épithéliale et dans le développement de l'hyperplasie des cellules basales, un rôle essentiel de l'inflammation exogène dans le développement de l'hyperplasie des cellules mucipares, et l'absence d'influence de l'inflammation dans le retard de différenciation des cellules ciliées épithéliales CF. Le second objectif de cette thèse a été d’identifier une molécule susceptible d’être anti-remodelage et/ou pro-régénératrice. Les résultats obtenus montrent qu’une molécule issue des agro-ressources régionales régule l'augmentation de la hauteur épithéliale et l'hyperplasie des cellules basales et sécrétoires, favorise la différenciation des cellules ciliées, et réduit l'inflammation et de synthèse de la mucine MUC-5AC, tant dans les cultures CF quand dans les cultures non-CF soumises à une inflammation chronique. Enfin, la molécule restaure la sécrétion des ions chlorure CFTR-dépendante dans les cultures CF. Cette molécule semble donc être un candidat médicament prometteur pour le traitement de la CF. / The airway epithelium of cystic fibrosis (CF) patients is frequently injured and remodeled. Whether these alterations are related to infection and/or inflammation or to a dysregulated regeneration process remains to be elucidated. The first objective of this study was to determine the involvement of inflammation in remodeling and regeneration of the CF airway epithelium. Using an in vitro model of airway epithelial cell culture at the air-liquid interface, we demonstrated that, in absence of exogenous infection and inflammation, the CF airway epithelium regeneration was abnormal, delayed, and led to the reconstitution of a remodeled epithelium, in comparison to a non-CF regenerated airway epithelium. Moreover, by inducing a chronic inflammation in non-CF and CF cultures, we were able to attribute a role of the endogenous inflammation of CF cells (inflammatory memory) in the airway epithelium height increase as well as in the basal cell hyperplasia development, an essential involvement of exogenous inflammation in the development of goblet cell hyperplasia, and the absence of implication of inflammation in the ciliated cell differentiation delay. The second objective of this study was to identify an anti-remodeling and/or pro-regenerative molecule. The results we obtained showed that a molecule derived agro-resources regulated the increase in the airway epithelium height as well as the basal and goblet cell hyperplasia development, favored the ciliated cell differentiation, decreased the inflammation and the production of the MUC5-AC mucin, in the CF cultures an in the chronically inflamed non-CF cultures. Finally, this molecule restored chloride secretion through CFTR in CF cultures. In conclusion, the chosen molecule seems to be a promising therapeutics for cystic fibrosis.

Das Ziel der Studien, die im Rahmen dieser Arbeit vorgestellt werden, war es neue Informationen über die elementare Zusammensetzung des mineralisierten Knochens zu gewinnen. In einer ersten Studie wurden zwei Parameter verglichen, die beide eng mit der Knochenmineralisierung verknüpft sind. So zeigte die Gegenüberstellung des mineral/matrix Raman-Wertes und der Kalziumkonzentration gute Übereinstimmung mit theoretischen Überlegungen. Diese Methoden wurden auch verwendet um Knochengewebe von Mäusen zu charakterisieren bei denen ein genetischer Defekt zu einem Mangel von Sclerostin führte. So war es möglich nachzuweisen, dass eine hierdurch verstärkte Knochenneubildung zu einer veränderten Mineralisationskinetik des Knochens führen kann. Nachdem zukünftig Sclerostinantikörper für die Behandlung von Knochenkrankheiten eingesetzt werden sollen, haben diese Erkenntnisse große medizinische Bedeutung. Es wurde auch die Mineraldichteverteilung eines Mausmodells mit fragilem Knochen (Osteogenesis Imperfecta, OI) untersucht. Die Mäuse wurden mit Sclerostinantikörpern behandelt. Es zeige sich ein signifikanter Knochenzuwachs doch die Mineraldichteverteilung veränderte sich gleichermaßen für gesunde und für OI Mäuse. In einer Studie am humanen Knochen konnten der Zusammenhang zwischen Osteozytennetzwerk und Knochenzusammensetzung untersucht werden. Elemente wie Na, Mg und S wiesen typische Konzentrationsverteilungen auf. Die Routinen wurden auch verwendet um Mineralisationsfronten zu charakterisieren. Es zeigte sich, dass die Konzentrationen von K, Mg, Na und Cl abhängig von dem analysierten anatomischen Ort, stark voneinander abweichen. Abschließend kann gesagt werden, dass durch die Entwicklung neuer Routinen zusätzliche Erkenntnisse über die Knochenmineralisierung und Zusammensetzung gewonnen werden konnten. Die Resultate sind von medizinischer und biologischer Bedeutung und tragen zu aktuellen Debatten über die Knochenentwicklung bei. / The purpose of the presented work was to gain new insight into the elemental composition of mineralized bone matrix at different sites of human bone tissue, and in mouse models linked to human genetic diseases. Using novel tools and routines, human (femur cross sections from healthy adults and children) and murine samples (femur long-and cross sections of two mouse models) were analyzed with focus on the elemental composition. In a methodological study the consistency of matrix mineralization measured by Raman microspectroscopy (e.g. the mineral/matrix ratio) and the Calcium content (wt%Ca) as measured by qBEI was proved. Both methods were applied to a mouse model exhibiting induced bone overgrowth due to a genetic defect causing a lack of Sclerostin, which is a negative regulator for bone formation. We found changes in the mineralization kinetics depending on the anatomical site. This result is of clinical importance since Sclerostin antibodies are suggested for future treatment of diseases characterized by fragile bone. Hence, also a mouse model of a brittle bone disease (Osteogenesis Imperfecta) was analyzed with and without Sclerostin antibody treatment. A significant increase in bone mass was documented while the mineralization pattern revealed no interaction between genotype and treatment. The correlation between OLCN and the composition of the mineralized matrix was examined in the same regions of human compact bone. Characteristic distributions of the minor elements (Mg, Na, S) were found. The developed tools were also used to investigate mineralization fronts, reflecting a critical stage of bone development. Differences in the Ca/P ratio and in the concentrations of K, Mg, Na and Cl depending on the anatomical site were revealed. In conclusion, using newly developed measurement routines, it was possible to gain novel information of bone mineralization and composition. The results contribute to actively debated issues of biological and medical importance.

Gesteigerter oxidativer Stress ist ein typisches Zeichen in der Pathogenese der Herzinsuffi-zienz. Anhand von 2 Rattenmodellen sollen charakteristische Veränderungen des enzymatischen antioxidativen Systems, repräsentiert durch die Glutathionperoxidase (GSH-Px) und Superoxiddismutase (SOD) sowie Änderungen im Hitzeschockproteinsystem (Hsp) untersucht werden, für das stellvertretend Hsp25 und Hsp72 bestimmt wurden. Daneben wurde die Lipidperoxidation durch die Konzentration von Thiobarbitursäure-reaktiven Substanzen (TBARS) quantifiziert. Im ersten Rattenmodell, der Hypertonie-induzierten Herzinsuffizienz durch permanente Renin-Angiotensin-System-Aktivierung in doppelt transgenen Ratten konnte eine linksventrikuläre Hypertrophie mit CK-Isoenzym-Shift mit vermehrter Expression von CK-MB und -BB beobachtet werden. Es kam in beiden Ventrikeln der transgenen Tiere zu einer Zunahme der Lipidperoxidation begleitet von einer Erniedrigung der Serum-Vitamin E-Konzentration durch Verbrauch. SOD und Hsp72 blieben unverändert. Durch die biventrikuläre Zunahme der GSH-Px-Aktivität bei linksventrikulär erhöhtem Hsp25-Gehalt konnte die Toleranz gegenüber Hypoxie/Reoxygenierungsstress erhöht werden. In der 2. Teilstudie - der Myokardinfarkt-induzierten Herzinsuffizienz - wurden die Parameter oxidativer Schädigung und antioxidativen Schutzes im Akutstadium (14-16h) und 3, 6 und 9 Wochen nach experimentellem Infarkt (MI) bestimmt. In der Akutphase zeigten sich in beiden Ventri-keln und im Papillarmuskel gesteigerte GSH-Px- und SOD-Aktivitäten, ohne dass kardiale Hypertrophie vorlag. Hsp72 und Hsp25 waren während der Akutphase nach MI im Papillar-muskel und im linken Ventrikel erhöht. In der Folge resultiert eine verbesserte kontraktile Funktion bei experimentellem Hypoxie/Reoxygenierungsstress. Damit gelang es erstmals eine Selbstprotektion des Myokards während eines akuten MI nachzuweisen. Erst ab der 6. Woche trat kardiale Hypertrophie auf, begleitet vom charakteristischen CK-Isoenzym-Shift. Während die SOD und die Hitzeschockproteine nach der akuten Phase auf das Niveau der Kontrollen absanken, blieb die hohe GSH-Px-Aktivität im linken Ventrikel über den gesamten Untersuchungszeitraum bestehen, bei zunehmender Toleranz des Herzens gegenüber Hypoxie/Reoxygenierungsstress. Die vorgelegten tierexperimentellen Untersuchungen zeigen, dass das Herz sowohl unter akut als auch unter chronisch gesteigertem oxidativen Stress Mechanismen zur Selbstprotektion aktivieren kann, die eine Prävention bzw. Minimierung von Schädigungsreaktionen durch Sauerstoffradikale ermöglichen. / Elevated oxidative stress is typical in the pathogenesis of heart failure. Characteristical changes in antioxidant enzyme status, represented by glutathionperoxidase (GSH-Px) and superoxide dismutase (SOD), and changes in heat shock protein status (Hsp), denoted by Hsp25 and Hsp72, have been revealed in two different rat-models. Lipidperoxidation was quantified by the concentration of thiobarbituric acid reactive substances (TBARS). In the first model of heart failure caused by permanent activation of renin-angiotensin system in double transgenic rat, leftventricular hypertrophy accompanied by a shift of creatine kinase (CK) isoenzyme pattern to higher concentration of fetale CK-MB an -BB-isoforms was found. Higher TBARS concentrations and lower alpha-tocopherol levels caused by consumption have been measured. SOD and Hsp72 remained unchanged. The tolerance against experimental hypoxia/reoxygenation was improved by higher levels of GSH-Px and Hsp25 in both right and left ventricular tissue. In the second study of heart failure caused by experimental myocardial infarction (MI) the parameters of oxidant demolishing and antioxidant defence were evaluated under acute condi-tions (14-16h) and 3, 6 and 9 weeks after infarction. In the acute period higher activities of GSH-Px and SOD in non-hypertrophied left and right ventricular tissue and papillary muscle have been reported. Leftventricular and papillary muscle Hsp25 and Hsp72 content showed higher levels 14-16 hours after MI compared with controls, improving the contractile function in hypoxia/reoxygenation experiments. These findings suggest for the first time a myocardial self-protection after acute myocardial infarction. 6 and 9 weeks after MI leftventricular hyper-trophy occurred attended by the characteristic CK-isoenzymeshift. While SOD-activity and Hsp-content decreased to the levels of the controls, GSH-Px remained on higher altitude in leftventricular tissue in all examined periods after MI. This was accompanied by better toler-ance against hypoxia/reoxygenation stress. These findings of experimental-induced heart failure show the activation of myocardial self protecting mechanisms under acute and chronic oxidative stress conditions, minimizing or even preventing demolishing reactions of oxygen radicals.

INTRODUÇÃO: Os distúrbios minerais e ósseos (DMO) da doença renal crônica (DRC) estão associados ao aumento do risco de fratura, estudos relatam cerca de 3% de fraturas neste grupo de pacientes, e as mesmas ocorrem mais precocemente quando comparadas à população geral, ou seja, 16 e 13 anos antes para homens e mulheres, respectivamente. A melhora no tratamento do DMO ainda não impactou na diminuição das fraturas, assim a melhor compreensão da fisiopatologia das mesmas provavelmente contribuiria para novas abordagens terapêuticas. OBJETIVOS: avaliar informes de fraturas, de ossos longos, de um banco de biopsias ósseas de pacientes com DRC em hemodiálise, e comparar, as características clínicas, bioquímicas e os resultados da análise histomorfométrica do osso trabecular e cortical desses pacientes com o de outros sem fraturas, pareados para idade, sexo e tempo de hemodiálise. Avaliamos também, por imunohistoquimica, a expressão de proteínas envolvidas na formação (SOST) e na mineralização óssea (DMP1, MEPE) de ambos os grupos. MÉTODOS: dezessete pacientes com fratura e igual número de controles foram estudados. RESULTADOS: A prevalência de fraturas foi de 5,5 fraturas/1000 pacientes ano a maioria deles tinha menos de 60 anos e tempo em hemodiálise inferior a 10 anos. Quanto a analise dos dados bioquímicos somente os níveis de fósforo sérico foram significativamente mais baixos nos pacientes com fratura comparada aos controles. Os resultados da análise histomorfométrica revelaram que a totalidade dos pacientes com e sem fratura apresentava doença de alta remodelação e nos fraturados detectamos menor volume e espessura trabecular, maior superfície osteóide, menor superfície de reabsorção além de menor superfície mineralizante, taxa de formação e maior tempo de intervalo para mineralização óssea quando comparados aos controles. Não encontramos diferenças na análise da espessura e porosidade cortical entre os dois grupos e a expressão da DMP1 no osso cortical foi menor e da SOST no osso trabecular foi maior nos pacientes fraturados comparados aos controles além de se associarem com parâmetros estruturais, de formação, de reabsorção e de mineralização. CONCLUSÕES: No banco de informes de biópsias ósseas analisado, encontramos alta prevalência de pacientes com fratura. Os pacientes com e sem fratura apresentavam doença de alta remodelação, porém os fraturados apresentavam maior comprometimento da microarquitetura óssea assim como menor formação e maior defeito de mineralização quando comparados aos pacientes sem fratura. A expressão de proteínas ósseas envolvidas na formação e mineralização óssea se correlacionaram com parâmetros envolvidos na remodelação óssea / INTRODUCTION: Mineral and bone disorders (BMD) of chronic kidney disease (CKD) are associated with increased risk of fracture. Studies report about 3% of fractures in this group of patients, and these occur earlier than in the general population, namely 16 and 13 years earlier for men and women, respectively. Improvement in BMD treatment has not yet impacted reduction of fractures, therefore a better understanding of the pathophysiology of fractures would probably contribute to new therapeutic approaches. OBJECTIVES: evaluate report of long bone fractures from a bank of bone biopsies from patients with CKD on hemodialysis, and compare clinical and biochemical characteristics as well as the results of the histomorphometric analysis of trabecular and cortical bone of these patients with that of others without fractures, paired for age, gender, and time on hemodialysis. We also evaluated the expression of proteins involved in formation (SOST) and bone mineralization (DMP1, MEPE) of both groups by immunohistochemistry. METHODS: seventeen patients with fracture and an equal number of controls were studied. RESULTS: The prevalence of fractures was 6%, the majority of the patients were less than 60 years old, and the time on hemodialysis was less than 10 years. Regarding the analysis of the biochemical data, only serum phosphorus levels were significantly lower in patients with fracture compared to controls. Results of the histomorphometric analysis revealed that all the patients with and without fracture had high turnover disease, and in the fractured ones we detected a smaller trabecular volume and thickness, greater osteoid surface, and smaller surface of resorption in addition to smaller mineralizing surface, formation rate and longer time interval for bone mineralization when compared to controls. We did not find differences in the analysis of thickness and cortical porosity between the two groups; the DMP1 expression in the cortical bone was smaller and the SOST in the trabecular bone was higher in the fractured patients compared to that of controls, besides being associated with structural parameters, formation, reabsorption and mineralization. CONCLUSIONS: In the database of analyzed bone biopsies, we found low prevalence of patients with fracture. Patients with and without fracture had high turnover disease, but the fractured ones presented more impaired bone microarchitecture as well as lower formation and greater mineralization defect when compared to the patients without fracture. The expression of bone proteins involved in bone formation and mineralization correlated with parameters involved in bone remodeling

Introdução: As citocinas desenvolvem papel importante na fisiopatologia da DPOC. Estudos sugerem que a IL-17 modula respostas inflamatórias e infecciosas, podendo ser alvo para o tratamento da inflamação pulmonar. Objetivos: Avaliar os efeitos preventivos e terapêuticos do anti IL-17 num modelo de lesão pulmonar induzida pela elastase em camundongos C57Bl6. Métodos: Foram utilizados 32 camundongos C57Bl6, machos, com idade entre 6 e 8 semanas e peso médio de 20-28 gramas, divididos em 4 grupos: 1. GRUPO SAL: os animais receberam solução salina intra-peritoneal (IP) 3 horas antes de serem submetidos à instilação intra-traqueal (IT) de salina, e salina IP nos dias 25, 26 27 e 28 pós instilação IT de salina; 2. GRUPO ELASTASE CONTROLE (EC): receberam salina IP 3 horas antes de receberem elastase IT, e salina IP nos dias 25, 26, 27 e 28 pós instilação de elastase; 3. GRUPO ELASTASE + ANTI IL-17 PREVENTIVO (EP): receberam anti IL-17 IP 3 horas antes de receberem elastase IT, e salina IP nos dias 25, 26, 27 e 28 pós instilação de elastase; 4. GRUPO ELASTASE + ANTI IL-17 TERAPÊUTICO (ET): receberam salina IP 3 horas antes de receberem elastase IT, e anti IL-17 IP nos dias 25, 26, 27 e 28 pós instilação de elastase. No 29º dia, os animais foram anestesiados, traqueostomizados, conectados ao aparelho FlexiVent (Scireq, Montreal, Canadá), e foram avaliados: resistência do sistema respiratório (Rrs), elastância do sistema respiratório (Ers), resistência de vias aéreas (Raw), resistência do parênquima pulmonar (Gtis), elastância do parênquima pulmonar (Htis), óxido nítrico exalado (NOex), e obtida a contagem das células totais do fluido do lavado broncoalveolar (FLBA). Depois, os animais foram exsanguinados, coração e pulmão foram retirados em bloco. Os pulmões foram fixados com formaldeído 4% a uma pressão constante de 20 cmH2O, por 24 horas. Após esse período, os pulmões foram mantidos em álcool 70% por até 36 horas, e em seguida foram preparados para o processamento histológico para avaliação de MMP9, MMP12, TIMP-1, TGF-beta, lumican, biglicano, decorina, fibronectina, iNOS, eNOS, isoprostano 8-iso-PGF-2alfa, NF-Kb, IL-17, IL-1beta, IL-8, TNF-alfa, neutrófilos, e fibras colágenas e elásticas em vias aéreas e septos alveolares. Foi analisado também o intercepto linear médio (Lm). Resultados: Em relação aos parâmetros Rrs, Ers, Raw, Htis, NOex e número de células totais no FLBA houve aumento no grupo EC em comparação ao grupo SAL (p < 0,05). O tratamento preventivo e terapêutico com anti IL-17 diminuiu os valores de Rrs, Ers, Raw e Htis (p < 0,05). Não houve diferença entre os grupos em relação ao Gtis. Em ambos os tratamentos houve redução do NOex comparados ao grupo EC (p < 0,05). Quanto ao número de células totais no FLBA, houve redução no grupo ET em relação ao EC e EP (p < 0,05), porém não houve diferença entre os grupos EC e EP. Ao realizar a contagem do diferencial de células do FLBA, houve redução apenas no número de macrófagos no grupo ET (p < 0,05). O tratamento preventivo e terapêutico com anti IL-17 também diminuiu o número de células positivas para NF-kb, iNOS, MMP9, MMP12, TGF-beta, isoprostano 8-iso-PGF-2alfa, TNF-alfa,IL-8, IL-1beta e IL-17, e contagem de neutrófilos em vias aéreas e nos septos alveolares quando comparados do grupo EC (p < 0,05), assim como a fração de volume de fibras colágenas, decorina e lumican em vias aéreas, e fibras elásticas e fibronectina no parênquima pulmonar (p < 0,05). Houve aumento do intercepto linear médio no grupo EC comparado ao SAL, e o tratamento com anti IL-17 diminuiu esses valores nos grupos EP e ET (p < 0,05). Houve redução de fibras colágenas em septos alveolares e biglicano em vias aéreas no grupo EP, e redução de células positivas para eNOS em vias aéreas somente no grupo ET em relação ao grupo EC (p < 0,05). Não houve diferença entre os grupos EC, EP e ET nos resultados de TIMP-1, fibronectina em vias aéreas e lumican nos septos alveolares. Conclusão: O anticorpo monoclonal anti IL-17 neste modelo de tratamento, tanto administrado de forma preventiva (atuando no bloqueio imediato da ação da elastase) quanto de forma terapêutica (depois das alterações estabelecidas pelas lesões iniciais), contribuiu para melhora da maioria dos parâmetros funcionais avaliados na mecânica pulmonar, inflamação, remodelamento da matriz extracelular e a resposta ao estresse oxidativo nos septos alveolares e nas paredes das vias aéreas neste modelo de lesão pulmonar induzida pela elastase administrada por via intra-traqueal / Introduction: Cytokines play an important role in the pathophysiology of COPD. Studies suggest that IL-17 modulates inflammatory and infectious responses and may be targeted for treatment of pulmonary inflammation. Objectives: To evaluate preventive and therapeutic effects of antiIL-17 in a model of lung injury induced by elastase in C57Bl6 mice. Methods: Thirtytwo male C57Bl6 mice, aged 6 to 8 weeks and mean weight of 20-28 grams, were divided into 4 groups: 1. SAL GROUP: animals received intra-peritoneal saline (IP) 3 hours before being submitted to intra tracheal (IT) instillation of saline, and IP saline on days 25, 26, 27 and 28 after saline IT instillation; 2. ELASTASE CONTROL (EC) GROUP: received IP saline 3 hours prior to IT elastase, and IP saline on days 25, 26, 27 and 28 post elastase instillation; 3. ELASTASE + PREVENTIVE ANTI IL-17 (EP) GROUP: received anti IL-17 IP 3 hours before receiving IT elastase, and IP saline on days 25, 26, 27 and 28 post elastase instillation; 4. ELASTASE + THERAPEUTIC ANTI IL-17 (ET) GROUP: received IP saline 3 hours before receiving elastase IT, and anti IL- 17 IP on days 25, 26, 27 and 28 post elastase instillation. On 29th day, the animals were anesthetized, tracheostomized, connected to FlexiVent apparatus (Scireq, Montreal, Canada), and evaluated: respiratory system resistance (Rrs), respiratory system elastance (Ers), airway resistance (Raw), pulmonary parenchyma resistance (Gtis), pulmonary parenchyma elastance (Htis), exhaled nitric oxide (NOex), and total bronchoalveolar lavage fluid (FLBA) cell count. Afterwards, the animals were exsanguinated, heart and lung were removed in block. The lungs were fixed with 4% formaldehyde at a constant pressure of 20 cmH2O for 24 hours, maintained in 70% alcohol for up to 36 hours and then prepared for histological processing for MMP9, MMP12, TIMP-1, TGF-Beta, lumican, biglycan, decorin, fibronectin, iNOS, eNOS, isoprostane 8-iso-PGF-2Alpha, NF-kb, IL-17, IL-1Beta, IL- 8, TNF-Alpha, neutrophils, and collagen and elastic fibers in airways and alveolar septa. The mean linear intercept (Lm) was also analyzed. Results: In relation to the parameters Rrs, Ers, Raw, Htis, NOex and number of total cells in FLBA, there was an increase in EC group compared to SAL group (p < 0.05). Preventive and therapeutic treatment with anti IL-17 decreased the values of Rrs, Ers, Raw and Htis (p < 0.05). There was no difference between groups regarding to Gtis. In both treatments there was NOex reduction compared to EC group (p < 0.05). Regarding the number of total cells in FLBA, there was reduction in ET group in relation to EC and EP (p < 0.05), but there was no difference between EC and EP groups. When counting the FLBA cell differential, there was reduction only in number of macrophages in ET group (p < 0.05). Preventive and therapeutic treatment with anti IL-17 also decreased the number of positive cells for NF-kb, iNOS, MMP9, MMP12, TGF-Beta, isoprostane 8-iso-PGF-2Alpha, TNF-Alfa, IL-8 , IL-1Beta and IL-17, and number of neutrophils, in airways and alveolar septa when compared to EC group (p < 0.05), as well as the volume fraction of collagen fibers, decorin and lumican in airways, and elastic fibers and fibronectin in alveolar septa (p < 0.05). There was increase in mean linear intercept in EC group compared to SAL, and treatment with anti IL-17 decreased the values of Lm in EP and ET groups (p < 0.05). There was reduction of collagen fibers in alveolar septa and biglycan in airways in EP group, and reduction of positive cells for eNOS in airways only in ET group in relation to EC group (p < 0.05). There was no difference between EC, EP and ET groups in results of TIMP-1, fibronectin in airways and lumican in alveolar septa. Conclusion: Anti IL-17 monoclonal antibody in this treatment model, both administered as a preventive way (acting on the immediate block of elastase action) and therapeutically (after changes established by the initial lesions), contributed to improvement of most functional parameters evaluated in pulmonary mechanics, inflammation, remodeling of extracellular matrix and response to oxidative stress in alveolar septa and airways in this model of lung injury induced by intratracheal elastase.