Introdução: A avaliação dos riscos a saúde da população associados a exposição aos poluentes de origem veicular é, ainda, um importante desafio para pesquisadores e formuladores de políticas públicas de saúde e ambiente. Objetivos: Estudar a associação espacial das internações por doenças respiratórias e a poluição relacionada ao tráfego no município de São Paulo. Método: Dados de internações hospitalares por doenças respiratórias do sistema público e privado, no periodo de 2004-2006, foram georreferenciados por endereço do paciente. Foram selecionados os CIDs J20-J22 e J40-J47 para crianças menores de 5 anos e os diagnósticos J40-J47 para idosos com idade superior a 64 anos. A área urbana do município foi dividida em uma grade com células de 500mx500m e calculada a densidade de tráfego. Variáveis populacionais, socioeconômicas e o IDH foram convertidos da base de setor censitários para a grade, usando o ArcGIS ArcInfo 9.3. Análise de clusters foi realizada usando o modelo discreto de Poisson para o cálculo do risco esperado para cada grupo etário, com o uso do Software SaTScan v8.0. Para estudo da dependência espacial entre a taxa de internação por respiratórias em cada subgrupo e a densidade de tráfego total foram empregados o índice de Moran (I) e o Local Indicator for Spatial Autocorrelation (LISA), utilizando o software OpenGeoDa 1.2.0. A análise de regressão espacial entre a taxa de internação em cada grupo e a densidade de tráfego foi realizada utilizando o Pacote R R Core Team (2012). Resultados: Foi encontrada associação espacial significativa entre o risco de internação por doenças respiratórias em crianças menores de 5 anos e a densidade de tráfego no município de São Paulo. Para idosos, com idade superior a 64 anos, os resultados não foram significativos. As análises de cluster e de autocorrelação espacial mostraram padrões espaciais diferenciados para crianças e idosos. A análise de autocorrelação (I de Moran) evidenciou maior associação entre internações por doenças respiratórias e densidade veicular para crianças do que para idosos. Os resultados da análise de regressão espacial mostrou associação positiva entre a taxa de internações em crianças e a densidade de tráfego, quando controlado pelo IDH-M. No caso de idosos, o coeficiente de regressão foi negativo. Conclusão: A poluição relacionada ao tráfego configura-se como importante fator de risco à saúde de crianças na cidade de São Paulo e medidas de redução das exposições bem como de redução dos fatores de vulnerabilidade devem ser priorizadas / Introduction: The assessment of population health risks associated with exposure to vehicular pollutants source is, still, a major challenge for researchers and policymakers to health and environment. Objectives: Studying the spatial association of hospitalization for respiratory diseases and air pollution related to traffic in São Paulo. Methods: Data on hospital admissions for respiratory diseases from the public and private sectors, for the period 2004-2006, were geocoded by patient address. We selected CIDs J20-J22 and J40-J47 for children under 5 years and the diagnoses J40-J47 for elderly over the age of 64 years. The urban area was divided into a grid of cells with 500mx500m and calculated the density of traffic. Population variables, socioeconomic and HDI were converted base census sector to the grid, using ArcGIS ArcInfo 9.3. Cluster analysis was performed using the discrete Poisson model to calculate the expected risk for each age group, using the software SaTScan v8.0. To study the spatial dependence between the rate of hospitalization for respiratory in each subgroup and traffic density were employed full index Moran (I) and Local Indicator for Spatial autocorrelation (LISA) using the software OpenGeoDa 1.2.0. Spatial regression analysis between the rate of hospitalization for each group and the traffic density was performed using the package R \"R Core Team (2012). Results: We found significant spatial association between the risk of hospitalization for respiratory diseases in children under 5 years and the traffic density in the city of São Paulo. For elderly people, aged over 64 years, the results were not significant. The cluster analysis and spatial autocorrelation showed distinct spatial patterns for children and elderly. The analysis of autocorrelation (Moran\'s I) showed greater association between hospital admissions for respiratory and vehicular density for children than for older people. The results of the spatial regression analysis showed a positive association between the rate of hospital admissions in children and traffic density when controlled by HDI. In the case of the elderly, the regression coefficient was negative. Conclusion: The traffic- related air pollution configured as an important risk factor to the health of children in the city of São Paulo and measures to reduce exposures and reduction of vulnerability factors should be prioritized

Background: This systematic review evaluates the oral health-related quality of life (OHRQoL) of patients with chronic respiratory diseases. Methods: A systematic literature search was performed based on the PubMed, Medline, Web of Science, and Scopus, using the search terms: “oral health-related quality of life” and “respiratory disease” or “lung” and “oral health-related quality of life.” Full-text articles published until June 30, 2021 and reporting any OHRQoL measurement in children or adults with a chronic respiratory disease or condition were included and analyzed qualitatively. Results: A total of seven out of 44 studies were included, of which four studies examined adults and three studies investigated children. The respective diseases were chronic obstructive pulmonary disease (COPD) (n = 2), sleep apnea (n = 2), severe asthma (n = 1), cystic fibrosis (n = 1), and lung transplantation (n = 1). Four studies confirmed a worse OHRQoL in the respiratory diseased group compared to healthy controls. The overall OHRQoL was reduced in the included studies. Oral health, healthrelated quality of life, and disease-related parameters were rarely examined with regard to OHRQoL. Conclusion: Patients with chronic respiratory diseases show a reduced OHRQoL. Oral health should be fostered in these individuals to support their OHRQoL.

No description available.

Doctor of Philosophy / Department of Diagnostic Medicine/Pathobiology / Daniel U. Thomson / A series of studies were conducted in order to develop, test, implement, and utilize an objective and comprehensive gross pathology scoring system for cattle at slaughter. Individual lung, liver, and rumen gross pathology data was collected from 19,229 head of cattle and corresponding individual pre-harvest and carcass data for a subset of 13,226 head.. Across the entire population 22.6% and 9.8% of cattle displayed mild and severe lesions, respectively. Severe lung lesions at the time of slaughter were associated with a decreased ADG of 0.07 kg/ day and a carcass weight 7.1 kg less than that of their cohorts with no visible signs of pulmonary BRDC lesions (P < 0.01). Overall, 68.6 % of cattle observed had normal livers, free from abscesses and other abnormalities. Cattle with a severe liver abscess at the time of slaughter were associated with a 0.10 kg/day during the feeding period (P < 0.01). Of cattle severely affected by liver abscesses (A+, 4.6%), 14.9% also displayed severe BRDC lung lesions and 28.3 % of cattle displayed mild BRDC lung lesions. Rumenitis lesions were observed in 24.1% of the overall study population. Severe rumenitis lesions were associated with a significant decrease in average daily gain and carcass weight (0.03kg/day and 2.20 kg, respectively, P < 0.01). The system was also implemented on a population of cull cows at a commercial abattoir in the Great Lakes region of the U.S. (n=1,461; 87% Holstein, 13% other cows). Severe liver abscesses, were observed in 18.5% of cull cows at slaughter. Severe rumenitis lesions or rumenitis scars were observed in 10% and severe BRDC lesions were observed in 10.3% o of the population. A prospective study of a commercially available, direct fed microbial oral drench of Megasphaera elsdenii (NCIMB 41125) was conducted in 4,863 head of yearling feeder cattle. No significant effects of treatment were detected for final live weight (599 vs. 601 kg; P=0.79) or hot carcass weight (386 vs. 387 kg P=0.81) for Con and M.e., respectively. Fourteen point two percent and 14.0% of Con and M.e., respectively displayed a liver abscess of varying severity at the time of slaughter. Overall, 8.27 and 7.96% % of Con and M.e. cattle were observed with an altered rumen epithelial health status. The ordinal odds ratio of a M.e. treated animal having a more severe liver abscess score or rumen health score was not significant (Estimate: 0.96, 95% C.L. 0.733-1.259, P=0.771; Estimate: 1.01, 95% C.L. 0.625-1.63 P=0.96, respectively.) Comprehensive monitoring of gross pathology at slaughter is commercially plausible and provides valuable data for veterinarians, nutritionists and management personnel.

Master of Veterinary Biomedical Sciences / Department of Clinical Sciences / Bradley White / Objective- To compare serologic response and viral replication following intranasal administration of a modified-live bovine rhinotracheitis (IBR) parainfluenza-3 (PI-3) vaccine in high (32°C) and moderate (21°C) ambient temperatures. Animals- 28 heifers (mean body weight, 206.8 kg) Procedures- Heifers randomly allocated to treatment groups: High Ambient Temperature (HAT, n=10): received vaccine, housed outdoors, Moderate Ambient Temperature (MAT, n=10): received vaccine, housed indoors, High Ambient Control (HAC, n=4): no vaccine, housed outdoors, Moderate Ambient Control (MAC, n=4): no vaccine, housed indoors. Rectal and nasal mucosal temperatures were recorded every 2 hours from 8am to 8pm on trial days 0 and 1. Nasal swabs were collected on trial days 0 through 7 for virus isolation. Serum samples were collected for serology on trial days 0, 7, 14, and 28. Results- Rectal temperatures did not differ among treatment groups over the study period, but nasal temperatures were higher in the HAT calves compared to MAT group at study hours: 6, 24, 30, 32, and 38. Two weeks post-vaccination, IBR titers were significantly greater in vaccinates (HAT,MAT) relative to non-vaccinates (HAC, LAC), but no differences were identified among HAT and MAT. Viable IBR virus was recovered via virus isolation from all vaccinated calves (HAT,MAT) on trial days 1 through 6. Conclusions and Clinical Relevance- The ability to isolate IBR and stimulate the calf immune response following administration of a modified-live IBR-PI3 intranasal vaccine did not differ in calves housed in temperature-controlled and high ambient temperature environments.

O Vírus Sincicial respiratório (HRSV) é um patógeno de grande importância para crianças. É o maior causador de infecções respiratórias agudas e também um dos principais causadores de internações e mortes de crianças menores de 5 anos. Cepas de HRSV com mutações no sítio de ligação do Palivizumab vêm apresentando resistência ao medicamento. Pouco se sabe sobre a prevalência destas mutações em amostras clínicas, apesar de sua potencial importância na patogênese viral. Além disso, existem poucos dados sobre a evolução molecular da proteína F do HRSV, sobretudo no Brasil. O presente estudo tem como objetivo caracterizar fenotipicamente através de ensaios de microneutralização in vitro, cepas oriundas de crianças não tratadas com Palivizumab circulantes em 2013 apresentando mutações na proteína F, mais especificamente relacionadas a potencial resistência nos epítopos de ligação do Palivizumab. Como resultado deste trabalho todas as amostras testadas foram neutralizadas pelo Palivizumab, concluindo-se que as mutações encontradas não conferem resistência ao monoclonal. / Respiratory Syncytial Virus (HRSV) is a pathogen of great importance for children. It is the major cause of acute respiratory infections and also one of the main causes of hospitalizations and deaths of children under 5 years. Strains of HRSV with mutations in the binding site of Palivizumab have been showing resistance to the drug. Little is known about the prevalence of these mutations in clinical samples, despite their potential importance in viral pathology. In addition, there is little data on the molecular evolution of HRSV F protein, especially in Brazil. The present study aims to characterize phenotypically by in vitro microneutralization assays, strains from children not treated with Palivizumab circulating in 2013 showing mutations in F protein, more specifically related to potential resistance in the binding epitopes of Palivizumab. As result of this study all samples tested were neutralized by Palivizumab, concluding that the mutations found did not confer resistance to the monoclonal.

O vírus influenza A (IAV) é um agente zoonótico de grande relevância tanto para saúde humana como animal. A influenza suína teve seu primeiro reconhecimento clínico em 1918, em suínos do Meio Oeste dos EUA, coincidindo com a pandemia de influenza em humanos. Desde então, o IAV permanece como um importante patógeno para a indústria suinícola em todo o mundo. A grande variabilidade genética destes vírus é causada por dois principais mecanismos genéticos: mutações pontuais e recombinações genéticas. A influenza é endêmica em muitos países e a emergências de recombinantes tem desafiado o controle e o diagnóstico desta enfermidade. No Brasil, a infecção pelo IAV em suínos (swIAV) não está bem caracterizada; poucos relatos evidenciam a prevalência deste agente antes do ano de 2009, especialmente no Estado do Rio Grande do Sul, que alberga um dos maiores rebanhos de suínos do Brasil. Em vista disso, este trabalho teve como objetivo investigar ocorrência de swIAV em alguns rebanhos suínos comerciais do Estado do Rio Grande do Sul, Brasil, no período de 2013-2014, e determinar os tipos e subtipos de vírus circulantes naquelas propriedades. O primeiro capítulo deste estudo reporta os aspectos clínicos, patológicos e virológicos da ocorrência de influenza suína e co-infecções identificadas em seis propriedades suinícolas selecionadas na região do Vale do Taquari. Neste estudo foram analisados suabes nasais coletados de 66 animais e 6 amostras de tecido pulmonar de suínos com sinais de infecção respiratória. A detecção viral foi feita através de uma PCR de triagem e confirmada através do isolamento viral em células MDCK. A identificação dos subtipos virais foi feita através de uma PCR em Tempo Real (rRT-PCR) para o subtipo A(H1N1)pdm09 ou através de uma PCR multiplex (RT-PCR) para outros subtipos de swIAV. A detecção de agentes bacterianos foi realizada apenas nas amostras de tecido pulmonar, através da pesquisa de genomas bacterianos por PCR. O subtipo A(H1N1)pdm09 foi identificado em 4/6 granjas e o subtipo H1N2 em 2/6 granjas. Além disso, agentes envolvidos no complexo respiratório dos suínos foram identificados em todas as granjas; Pasteurella multocida foi identificada em 5/6 granjas e Mycoplasma hyopneumoniae em 3/6 granjas. Actinobacillus pleuropneumoniae (1/6), Haemophilus parasuis (1/6) e PCV2 (1/6) também foram detectados. O segundo capítulo deste estudo teve como objetivo o sequenciamento do genoma completo de um novo recombinante H1N2 de origem humana, detectado em suínos. O genoma completo foi gerado através de uma RT-PCR. Os produtos foram purificados e submetidos ao sequenciamento utilizando a plataforma MiSeq (illumina). A análise filogenética revelou que as sequencias dos genes HA e NA correspondem a genes de IAV de origem humana, enquanto que as sequencias dos genes que codificam as proteínas internas do vírus (PB1, PB2, PA, NP, M e NS) correspondem a genes de amostras do vírus A(H1N1)pdm09. O terceiro capítulo reporta o sequenciamento completo dos genomas de 8 amostras de vírus influenza identificados nas populações de suínos amostradas. Foram identificados dois subtipos virais de origem humana (H1N2 e H3N2), além do vírus A(H1N1)pdm09. Os subtipos de origem humana possuem os genes HA e NA similares a vírus sazonais de humanos e os genes internos são estreitamente relacionados com o vírus A(H1N1)pdm09. / Influenza A virus (IAV) is a zoonotic agent of great relevance to human and animal health. Swine influenza was first recognized clinically in pigs in the Midwestern U.S., in 1918, coinciding with the human influenza pandemic. Since that time swine influenza has remained of importance to the swine industry throughout the world. The great genetic variability of influenza viruses is caused by two main genetic mechanisms: point mutations (antigenic drift) and gene reassortment (antigenic shift). Influenza is endemic in pigs in many countries and the emergence of new viruses has been challenging its control and diagnostics. Influenza virus (swIAV) infection in Brazilian swine population is not well characterized, and little evidence existed of swIAV circulation before 2009, especially in Rio Grande do Sul State, which hosts one of the largest swine populations in Brazil. Thus, this study aimed to investigate the occurrence of IAV in commercial swine herds in the state of Rio Grande do Sul, Brazil, between 2013-2014 and to know the types and subtypes of swine influenza viruses that are circulating in these herd. The first chapter of this study reports the clinical, pathological and virological aspects of the occurrence of swine influenza and related co-infections in six pig properties of the Taquari Valley region. In this study were analyzed nasal swabs collected from 66 animals and six lung tissue samples from pigs showing clinical signs of respiratory disease. IAV detection was performed by PCR screening and confirmed by virus isolation in MDCK cells and hemagglutination (HA). Influenza A subtyping was performed by real-time reverse transcription PCR (rRT-PCR) to detect the 2009 H1N1pandemic A(H1N1)pdm09; other swIAV subtypes were identifieded by multiplex RT-PCR. Bacterial infections were identified through detection of bacterial genomes by PCR, only in lung samples. Influenza A was detected by screening PCR in 46/66 swab samples and from 5/6 lungs. Virus was recovered from pigs of the six herds. Subtype A(H1N1)pdm09 was detected in 4/6 herds and H1N2 in the other 2/6 herds. In lung tissues, further agents involved in porcine respiratory disease complex were detected in all cases; Pasteurella multocida was identified in 5/6 samples and Mycoplasma hyopneumoniae in 3/6. Actinobacillus pleuropneumoniae (1/6), Haemophilus parasuis (1/6) and PCV2 (1/6) were also detected. The aim of the second chapter was to sequence the whole-genome of a novel human-like H1N2 swine influenza virus. Wholegenome sequences were generated by RT-PCR. Amplicons were purified followed by sequencing in the MiSeq sequencing platform (Illumina). Phylogenetic analyses revealed that the HA and NA genes clustered with influenza viruses of human lineage, whereas the internal genes (PB1, PB2, PA, NP, M and NS) clustered with the A(H1N1)pdm09. The third chapter reports the genetic sequencing of the full genomes of eight swine influenza viruses circulating in the sampled pig population. Two swine human-like subtypes (H1N2 and H3N2) and the A(H1N1)pdm09 virus were identified. The human-like subtypes have the HA and NA genes similar to the human seasonal strains and the internal genes are closely related to the virus A(H1N1)pdm09.

A hemorragia pulmonar induzida por exercício (HPIE) é caracterizada pela presença de sangue no trato respiratório anterior e posterior, sendo considerada por muitos autores como a principal causa na redução do desempenho atlético, acarretando prejuízos econômicos significativos. Processos inflamatórios e obstrutivos das vias aéreas anteriores têm sido propostos como fatores desencadeadores da HPIE, contudo, a literatura tem sido conflitante na determinação desta correlação. O objetivo do presente estudo foi a avaliação da correlação entre HPIE e alterações das vias aéreas anteriores e traquéia em eqüinos da raça PSI que competiram no hipódromo da Cidade Jardim do Jockey Club de São Paulo no período de março de 1999 a setembro de 2005. Foram analisados 4036 laudos endoscópicos. Os exames endoscópicos foram realizados trinta minutos após corrida e por um único examinador. Dos eqüinos que participaram do estudo, 2229 foram submetidos à medicação prévia com furosemida e 1737 não foram medicados (solicitações). Os resultados obtidos com relação à incidência de HPIE no grupo dos animais medicados e não medicados foram 52,40% e 60,00% respectivamente, não havendo variação estatisticamente significativa na incidência de HPIE quanto à distribuição etária e sexo. No entanto, a incidência de grau 4 da HPIE nas fêmeas foi duas vezes maior quando comparado com os machos. De modo geral, não se observou correlação positiva entre a HPIE e alterações das vias aéreas anteriores e traquéia, a não ser nos eqüinos com deslocamento dorsal do palato mole (estatisticamente significativa) ou com neuropatia laringeana recorrente esquerda, apesar de não apresentar significado estatístico. Os eqüinos acometidos por doença inflamatória das vias aéreas não apresentaram relação com HPIE. Dentre as alterações das vias aéreas anteriores estudadas, a neuropatia laringeana recorrente esquerda e deslocamento dorsal do palato mole apresentaram correlação positiva com hemorragia pulmonar induzida por exercício, sendo que apenas para a segunda foi estatisticamente significativa. / Exercise-induced pulmonary hemorrhage (EIPH) is characterize by blood found in upper and lower respiratory tract. It is considered by many authors to have a negative effect on the athletic performance of racing horses, causing significantive economic losses. Some authors suggest that obstructive and inflammatory process breaks out HPIE, but this question hasn´t been settled so far. The aim of this study is to identify the relations between exercise-induced pulmonary hemorrhage and alterations of upper airways and trachea on Thoroughbreds racehorses that raced at the tracks of the São Paulo Jockey Club from March, 1999 to September, 2005. The endoscopic examination was made 30 minutes after the race by a single examiner, and 4036 results have been analyzed. Among these horses, 2229 took previous furosemide medication and 1737 didn´t. The results regarding the presence of EIPH were 52.40% for the first group and 60% for the second, with no significant difference related to age and sex. However, the prevalence of grade 4 EIPH among females was two times bigger than among males. No positive relation between EIPH and alterations of upper airways and trachea was observed, although in dorsal displacement of the soft palate that was statistically significantive or with recurrent laryngeal neuropathy left although no statistically significative. The horses that presented disease of upper airways didn´t any relation with EIPH. Among alterations of upper airways analyzed, the recurrent laryngeal neuropathy left and dorsal displacement of the soft palate showed positive relation with EIPH, and only the second one was statistically significative.

Rare diseases, when considered as a whole, affect up to 7% of the population, which would represent 3.5 million individuals in the United Kingdom alone. However, while 'personalised medicine' is now yielding remarkable results using recent sequencing technologies in terms of diagnosing genetic conditions, we have made much less headway in translating this patient information into therapies and effective treatments. Even with recent calls for greater research into personalised treatments for those affected by a rare disease, progress in this area is still severely lacking, in part due to the astronomical cost and time involved in bringing treatments to the clinic. Gene correction using the recently-described genome editing technology CRISPR/Cas9, which allows precise editing of DNA, offers an exciting new avenue of treatment, if not cure, for rare diseases; up to 80% of which have a genetic component. This system allows the researcher to target any locus in the genome for cleavage with a short guide-RNA, as long as it precedes a highly ubiquitous NGG sequence motif. If a repair sequence is then also provided, such as a wild-type copy of the mutated gene, it can be incorporated by homology-directed repair (HDR), leading to gene correction. As both guide-RNA and repair template are easily generated, whilst the machinery for editing and delivery remain the same, this system could usher in the era of 'personalised medicine' and offer hope to those with rare genetic diseases. However, currently it is difficult to test the efficacy of CRISPR/Cas9 for gene correction, especially in vivo. Therefore, in my PhD I have developed a novel fluorescent reporter system which provides a rapid, visual read-out of both non-homologous end joining (NHEJ) and homology-directed repair (HDR) driven by CRISPR/Cas9. This system is built upon a cassette which is stably and heterozygously integrated into a ubiquitously expressed locus in the mouse genome. This cassette contains a strong hybrid promoter driving expression of membrane-tagged tdTomato, followed by a strong stop sequence, and then membrane-tagged EGFP. Unedited, this system drives strong expression of membrane-tdTomato in all cell types in the embryo and adult mouse. However, following the addition of CRISPR/Cas9 components, and upon cleavage, the tdTomato is rapidly excised, resulting via NHEJ either in cells without fluorescence (due to imperfect deletions) or with membrane-EGFP. If a repair template containing nuclear tagged-EGFP is also supplied, the editing machinery may then use the precise HDR pathway, which results in a rapid transition from membrane-tdTomato to nuclear- EGFP. Thereby this system allows the kinetics of editing to be visualised in real time and allows simple scoring of the proportion of cells which have been edited by NHEJ or corrected by HDR. It therefore provides a simple, fast and scalable manner to optimise reagents and protocols for gene correction by CRISPR/Cas9, especially compared to sequencing approaches, and will prove broadly useful to many researchers in the field. Further to this, I have shown that methods which lead to gene correction in our reporter system are also able to partially repair mutations found in the disease-causing gene, Zmynd10; which is implicated in the respiratory disorder primary ciliary dyskinesia (PCD), for which there is no effective treatment. PCD is an autosomal-recessive rare disorder affecting motile cilia (MIM:244400), which results in impaired mucociliary clearance leading to neonatal respiratory distress and recurrent airway infections, often progressing to lung failure. Clinically, PCD is a chronic airway disease, similar to CF, with progressive deterioration of lung function and lower airway bacterial colonization. However, unlike CF which is monogenic, over 40 genes are known to cause PCD. The high genetic heterogeneity of this rare disease makes it well suited to such a genome editing strategy, which can be tailored for the correction of any mutated locus.

Le chat est la seule espèce animale qui développe spontanément une entité clinique similaire à bien des égards à lasthme allergique humain. Communément appelée « asthme félin » par homologie à la maladie humaine, cette entité pathologique est le résultat dune inflammation persistante des voies respiratoires, associée à des phases aiguës de bronchospasme, une hyperréactivité bronchique à des stimuli divers et dans les stades avancés à des remaniements tissulaires de la paroi bronchique (e.g., érosions épithéliales, hypertrophie de la musculature lisse, hyperplasie glandulaire). Des modèles dasthme félin, obtenus par sensibilisation expérimentale à un allergène, reproduisent la majorité des caractéristiques cliniques, fonctionnelles et lésionnelles de la maladie naturelle et sont au premier plan de la découverte de nouvelles stratégies thérapeutiques (i.e., cyclosporine A, corticostéroïdes oraux et inhalés, immunothérapie spécifique). De la pathogénie de lasthme, ressort toute limportance de dominer lobstruction récurrente des voies respiratoires. Même si les bronchodilatateurs inhalés sont recommandés dans la prise en charge des crises dasthme chez le chat, leur efficacité clinique reste incertaine et peu étayée. Ainsi, les principes actifs, les posologies et les protocoles thérapeutiques actuellement préconisés sont dans une large mesure empiriques et/ou extrapolés de la médecine humaine, et nécessitent dêtre validés dans des conditions expérimentales contrôlées. Nos travaux sinscrivent donc dans cette optique et visent à définir une approche thérapeutique tant préventive que symptomatique des crises de bronchospasme chez le chat, ainsi quune utilisation rationnelle des bronchodilatateurs à longue durée daction pour un contrôle optimal de linflammation asthmatique. Lors dune première étude, nous avons investigué lactivité in vitro, vis-à-vis du muscle lisse bronchique félin, de différentes agents bronchodilatateurs parmi lesquels des agonistes β2-adrénergiques (isoprotérénol, salbutamol [SAL], fénotérol, formotérol, salmétérol [SLM]), un anticholinergique (ipratropium bromide [IB]) et une méthylxanthine (théophylline). Tous ont produit une relaxation dose-dépendante de la musculature lisse bronchique, avec des spécificités propres en termes de puissance, defficacité ou dactivité intrinsèque. Sur une base comparative, le formotérol est le ß2-mimétique le plus puissant, et lisoprotérénol le plus efficace avec le fénotérol. Le fénotérol et le formotérol sont des agonistes complets des récepteurs ß2-adrénergiques, le SAL et le SLM des agonistes partiels. Tenant compte des résultats des essais in vitro et de la disponibilité de formulations administrables par aérosols dans lespèce féline, les effets bronchoprotecteurs (intensité, durée daction) de six médications inhalées ont été caractérisés chez le chat sain, en préambule à leur utilisation dans des conditions pathologiques. Un modèle de bronchoconstriction induite par le carbachol a été retenu dans le cadre de cette deuxième étude. Il ressort de cette étude que le SLM en aérosol-doseur (25µg) présente un effet bronchoprotecteur soutenu persistant 24 heures mais est aussi la médication la moins efficace. Le SAL et lIB (nébulisation ou aérosol-doseur) sont des bronchodilatateurs à courte durée daction (48 heures) dont lutilisation combinée en aérosol-doseur (SAL IB : 100µg/20µg) met en exergue une synergie daction. Les conditions naturelles étant souvent incompatibles avec une approche anticipative de la crise dasthme, les traitements instaurés sont davantage à visée curative que prophylactique. Dans une troisième étude, nous avons exploré les effets bronchorelaxants du SAL (100µg) et de lIB (20µg), administrés seuls ou en traitement combiné, sur une bronchoconstriction induite par un aéroallergène (Ascaris suum) chez des chats rendus expérimentalement asthmatiques. La technique dinhalation par aérosol-doseur a été privilégiée vu les effets synergiques de la combinaison « SAL IB » et lintérêt de cette voie dadministration dans la gestion à domicile des crises dasthme. Aux doses testées, les bronchodilatateurs inhalés nont exercé aucun effet notable, naffectant en rien la résolution du bronchospasme induit. Chez lhomme, les crises et les épisodes dexacerbation de lasthme sont fréquents dans le cours évolutif de la maladie. Aucune étude chez le chat asthmatique en crise aiguë (induite ou spontanée) natteste de lefficacité des corticostéroïdes inhalés ni ne mentionne dans ce contexte lintérêt scientifique dune association aux ß2-mimétiques à longue durée daction. Nous avons donc comparé les effets de la prednisolone orale (1mg/kg q12h) à ceux dune dose élevée de fluticasone inhalée, seule (500µg q12h aérosol-doseur) ou en traitement combiné avec du SLM (500µg/50µg q12h aérosol-doseur), sur la fonction et linflammation pulmonaires dans un modèle félin dasthme aigu. Cette quatrième étude a montré quune courte cure orale de prednisolone diminue significativement linflammation bronchique à éosinophiles. De fortes doses de fluticasone inhalée se sont avérées bénéfiques dans le contrôle de lhyperréactivité bronchique non spécifique, sans toutefois exercer des effets marqués sur linflammation bronchique sous-jacente. Combiner cette corticothérapie inhalée au SLM a permis dobtenir des effets anti-éosinophiliques accrus et comparables à ceux de la prednisolone orale. Aucune des médications testées na modifié significativement la réponse clinique et fonctionnelle consécutive à linhalation de lallergène. Létude précédente permet de supposer que le SLM potentialise lactivité anti-inflammatoire des corticostéroïdes inhalés et/ou est doté de propriétés anti-inflammatoires intrinsèques. Dans une cinquième étude, nous avons donc investigué les effets du SLM en monothérapie (50µg q12h aérosol-doseur) sur la fonction et linflammation pulmonaires. Il ressort de cette étude, conduite sur un modèle félin dasthme aigu, que le SLM en monothérapie nexerce pas deffet protecteur sur la survenue dun bronchospasme allergique et est dépourvu de tout effet anti-inflammatoire propre. Les résultats obtenus, dans les conditions expérimentales de nos essais, conduisent aux conclusions suivantes : 1) les bronchodilatateurs inhalés (SAL, IB, SLM) sont dune efficacité thérapeutique limitée dans la prévention et le traitement symptomatique du bronchospasme allergique chez le chat sensibilisé à Ascaris suum 2) en revanche, recourir au SLM comme thérapie adjuvante aux corticostéroïdes inhalés ouvre de nouvelles perspectives thérapeutiques dans le contrôle de linflammation et de lhyperréactivité bronchiques chez le chat asthmatique./The cat is the only animal species that spontaneously develops a clinical entity closely similar to human allergic asthma and commonly referred to as feline asthma. Feline asthma is a chronic inflammatory disease of the lower airways characterised by intermittent respiratory distress due to bronchoconstriction, non-specific bronchial hyperresponsiveness and airway remodeling at latter stages (e.g., epithelial erosions, smooth muscle hypertrophy, glandular hyperplasia). Based on experimental sensitisation to allergens, models of feline asthma mimic many clinical, functional and lesional features of the naturally developing condition. Moreover, development and implementation of feline asthma models have greatly facilitated the search for novel therapies (i.e., cyclosporin A, oral and inhaled corticosteroids, specific immunotherapy). In considering the pathogenesis of asthma, it is of major importance to control recurrent airway obstruction. Although inhaled bronchodilators are recommended for the management of acute asthmatic exacerbations in cats, their clinical efficacy remains uncertain and poorly documented. Most currently recommended drugs, dosages and therapeutic schemes are largely empirical and extrapolated from human medicine, and need to be further validated under controlled experimental conditions. Hence, our work was aimed at determining the potential of inhaled bronchodilators for preventive and curative treatment of acute bronchospasms in asthmatic cats as well as at exploring the benefit of using long-acting bronchodilators to optimally control the airway inflammation. In the first study, we investigated in vitro effects on isolated feline bronchi of different bronchodilating agents including β2-adrenergic agonists (isoproterenol, salbutamol [SAL], fenoterol, formoterol, salmeterol [SLM]), an anticholinergic (ipratropium bromide [IB]) and a methylxanthin derivative (theophylline). All compounds caused a dose-related relaxation of bronchial smooth muscle, each exhibiting specificities in terms of potency, efficacy and intrinsic activity. On a comparative basis, isoproterenol and fenoterol are the most efficacious β2-mimetics while formoterol is the most potent one. Fenoterol and formoterol act as full agonists of β2-adrenoceptors, SAL and SLM as partial agonists. Taking into account results from in vitro testing procedures and availability of aerosol formulations suitable for lung delivery in cats, we compared the antispasmodic effects (magnitude, duration of action) of six inhaled medications against carbachol-induced bronchoconstriction in healthy cats. This second study showed that SLM by metered-dose inhaler (25µg) has a sustained activity for as long as 24 hours but is also the least efficacious medication. SAL and IB (nebulisation or metered-dose inhaler) are short-acting bronchodilators (4-8 hours) whose combination delivered with a metered-dose inhaler (SAL IB: 100µg/20µg) exhibits a synergistic antispasmodic effect. In the natural disease, asthmatic crisis are difficult to predict in terms of occurrence. Therefore, therapeutic interventions are more curative than preventive. In a third study, we explored the bronchodilating effects of SAL (100µg) and IB (20µg), delivered either alone or as a combined therapy, on allergen-induced bronchospasms in Ascaris suum-sensitised cats. The inhalation technique using a metered-dose inhaler was retained given the synergistic effects of the combination SAL IB with this method and its therapeutic interest for at-home management of asthmatic crisis. At the tested doses, these bronchodilators failed to reverse allergen-induced bronchospasms in cats with experimental asthma. In human beings, crisis and exacerbations of asthma are frequent events in the natural course of the disease. Efficacy of inhaled corticosteroids in cats with acute asthmatic exacerbations (induced or spontaneous) has not yet been determined, nor the potential benefit of adding long-acting β2-agonists in this context. Thus, the fourth study was aimed at comparing the effects of oral prednisolone (1mg/kg q12h) with those of inhaled fluticasone at high doses, alone (500µg q12h metered-dose inhaler) or combined with salmeterol (500µg/50µg q12h metered-dose inhaler), on lung function and airway inflammation in a feline model of acute asthma. This study showed that a short course of oral prednisolone significantly reduced allergen-induced bronchial eosinophilic inflammation. High doses of inhaled fluticasone proved to be efficient for decreasing non specific airway hyperresponsiveness but failed to markedly reduce the underlying airway inflammation. Adding salmeterol to inhaled fluticasone led to anti-eosinophilic effects of the same magnitude as those found for oral prednisolone. None of these treatments improved clinical and functional responses to allergen exposure. According to the previous study, it may be that SLM has an anti-inflammatory effect on its own and/or functions as a steroid-potentiating agent. In a fifth study, we investigated the effects of salmeterol as monotherapy (50 µg q12h metered-dose inhaler) on lung function and airway inflammation in our feline model of acute asthma. This inhaled medication did not prevent occurrence of allergic bronchospasm in Ascaris suum-sensitised and challenged cats, nor did it possess intrinsic anti-inflammatory activity. Under our experimental conditions, the main results achieved led to the following conclusions: 1) the inhaled bronchodilators (SAL, IB, SLM) are of limited efficacy for the prevention and symptomatic treatment of allergic bronchospasm in cats sensitised to Ascaris suum; 2) in contrast, using salmeterol as adjuvant therapy to inhaled corticosteroids opens up new perspectives for the treatment of bronchial inflammation and hyperresponsiveness in asthmatic cats.