Добірка наукової літератури з теми "Allergie respiratoire – Physiopathologie"

Coronavirus disease 2019 (COVID-19) is currently a worldwide emergency caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). In observational clinical studies, statins have been identified as beneficial to hospitalized patients with COVID-19. However, experimental evidence of underlying statins protection against SARS-CoV-2 remains elusive. Here we reported for the first-time experimental evidence of the protective effects of simvastatin treatment both in vitro and in vivo. We found that treatment with simvastatin significantly reduced the viral replication and lung damage in vivo, delaying SARS-CoV-2-associated physiopathology and mortality in the K18-hACE2-transgenic mice model. Moreover, simvastatin also downregulated the inflammation triggered by SARS-CoV-2 infection in pulmonary tissue and in human neutrophils, peripheral blood monocytes, and lung epithelial Calu-3 cells in vitro, showing its potential to modulate the inflammatory response both at the site of infection and systemically. Additionally, we also observed that simvastatin affected the course of SARS-CoV-2 infection through displacing ACE2 on cell membrane lipid rafts. In conclusion, our results show that simvastatin exhibits early protective effects on SARS-CoV-2 infection by inhibiting virus cell entry and inflammatory cytokine production, through mechanisms at least in part dependent on lipid rafts disruption.

Abstract Invasive pulmonary aspergillosis (IPA) is increasingly recognized as a life-threatening superinfection of severe respiratory viral infections, such as influenza. The pandemic of Coronavirus Disease 2019 (COVID-19) due to emerging SARS-CoV-2 rose concern about the eventuality of IPA complicating COVID-19 in intensive care unit mechanically-ventilated patients. While the association between severe influenza and IPA has been demonstrated, it remains unclear whether SARS-CoV-2 infection represents a specific risk factor for IPA. A variable incidence of such complication has been previously reported, which can be partly attributed to differences in diagnostic strategy and IPA definitions, and possibly local environmental/epidemiological factors. In this article, we discuss the similarities and differences between influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA). Compared to IAPA, the majority of CAPA cases have been classified as putative rather than proven/probable IPA, in the absence of positive serum galactomannan or histopathologic evidence of angio-invasion. Discrimination between Aspergillus airways colonization and CAPA is difficult. Distinct physiopathology and cytokine profiles of influenza and COVID-19 may explain these discrepancies. Whether CAPA represents a distinct entity is still debatable and many questions remain unanswered, such as its actual incidence, the predisposing role of corticosteroids or immunomodulatory drugs, and the indications for antifungal therapy.

L’asthme est une maladie inflammatoire chronique des voies aériennesresponsable d’une morbi-mortalité significative et définie par une association entre dessymptômes cliniques et une obstruction bronchique variable. Les caractéristiques cardinalesde l’asthme sont une hyper-réactivité des voies aériennes, une inflammation bronchiqueassociée à une modification de la structure des bronches dont une hyperproduction demucus.L’ensemble de ces caractéristiques aboutit à de nombreuses présentations cliniques,appelées des phénotypes asthmatiques, qui sont la conséquence de multiples mécanismesphysiopathologiques distincts. Le phénotype asthmatique le plus fréquent est l’asthmeallergique dont les acariens représentent l’un des principaux pneumallergènes.L’hétérogénéité de cette pathologie requiert une approche globale incluant des travauxfondamentaux et une approche clinique translationnelle. Ces deux approches ont étédéveloppées dans cette thèse.Dans la première partie, l’implication d’un récepteur de l’immunité innée, lerécepteur Nod1, dans l’asthme allergique aux acariens a été investiguée. Ce récepteurreconnaît des fragments de peptidoglycanes bactériens et participe à la réponse immune. Ilest également impliqué dans la régulation du microbiote digestif. Chez les souris Nod1-/-, lesparamètres allergiques asthmatiques induits par les acariens sont réduits comparativementaux souris sauvages. Cette atténuation de la réponse allergique asthmatique n’est pas liée àune modification de la flore digestive des souris Nod1-/-. En revanche, les extraits d’acarienscontiennent une flore microbienne, principalement composée de bacille gram négatif,susceptible d’activer directement le récepteur Nod1 au niveau de l’épithélium des voiesrespiratoires. Cette activation participe à l’exacerbation de la réponse allergique asthmatiqueinduite aux acariens et offre une nouvelle perspective thérapeutique dans le traitement del’asthme allergique aux acariens.La deuxième partie de ce travail est consacrée à l’impact fonctionnel de bouchons demucus présents dans les voies aériennes de patients asthmatiques en fonction de leur statuttabagique en utilisant des outils précédemment développés. La présence de bouchons demucus est fréquente quel que soit le statut tabagique des asthmatiques. Une corrélationinverse a été retrouvée entre le nombre de segments pulmonaires présentant au moins unbouchon de mucus et l’obstruction des voies aériennes. Cette caractéristique clinique estcorrélée au pourcentage de polynucléaires éosinophiles dans les expectorations. Chez lespatients ayant un antécédent de tabagisme, la présence d’occlusions des voies aériennesest associée au pourcentage de neutrophiles. Les bouchons de mucus apparaissent commeun marqueur de sévérité de l’asthme et sont corrélés à différents types d’inflammationbronchique selon le statut tabagique.Cette thèse a contribué à faire avancer les connaissances fondamentales et clinicofonctionellesdans l’asthme. Ces résultats invitent à poursuivre les investigations dans cesdifférents domaines
Asthma is a chronic inflammatory airway disease responsible for significant morbidityand mortality defined by an association between clinical symptoms and variable airwayobstruction. The cardinal features of asthma are airway hyperresponsiveness, bronchialinflammation associated with changes in the structure of the bronchi including overproductionof mucus. Taken together, these characteristics result in numerous clinical presentations,called asthmatic phenotypes, which are the consequence of multiple distinctpathophysiological mechanisms. The most common asthma phenotype is allergic asthma, ofwhich house dust mites are one of the main pneumallergens. The heterogeneity of thispathology requires a comprehensive approach including fundamental work and translationalclinical approach. These two approaches have been developed in this thesis.In the first part, the involvement of an innate immunity receptor, the Nod1 receptor, inhouse dust mite allergic asthma was investigated. This receptor recognizes fragments ofbacterial peptidoglycans and participates in the immune response. It is also involved in theregulation of the digestive microbiota. In Nod1-/- mice, the mite-induced asthmatic allergicparameters are reduced compared to wild type mice. This attenuation of the allergicasthmatic response is not linked to a change in the digestive flora of Nod1-/- mice. In contrast,mite extracts contain microbial flora, mainly composed of gram-negative bacillus, capable ofdirectly activating the Nod1 receptor in the epithelium of the respiratory tract. This activationcontributes to the exacerbation of the allergic asthmatic response induced by house dustmites and offers a new therapeutic perspective in the treatment of allergic asthma to housedust mites.The second part of this work is devoted to the functional impact of mucus plugspresent in the airways of asthma patients according to their smoking status using previouslydeveloped tools. The presence of mucus plugs was common regardless of the smokingstatus of the asthmatics. An inverse correlation was found between the number of lungsegments with at least one mucus plug and airway obstruction. This clinical feature wascorrelated with the percentage of eosinophils in the sputum. In patients with a history ofsmoking, the presence of airway obstructions was correlated with the percentage ofneutrophils. Mucus plugs appear to be a marker of asthma severity and are correlated withdifferent types of bronchial inflammation depending on smoking status.This PhD has helped advance fundamental and clinical-functional knowledge inasthma. These results invite further investigations in these different fields

Decorin, is an extracellular matrix proteoglycan with important biological functions. Decorin deficiency affects collagen fibrillogenesis, airway mechanics, airway-parenchymal interdependence, and airway smooth muscle proliferation and apoptosis. We questioned whether decorin deficiency would alter allergen-induced asthma in a mouse model. Decorin-/- and decorin+/+ mice (C57Bl/6) were sensitized and challenged with ovalbumin. Control animals received saline. Responsiveness was assessed at baseline and after delivery of increasing concentrations of methacholine. Histological analyses were also performed. Decorin deficiency resulted in more modest hyperresponsiveness. Respiratory resistance and elastance along with tissue damping and tissue elastance, were increased in ovalbumin decorin +/+ and decorin-/-, but more so in decorin+/+ . Airway resistance was increased in ovalbumin decorin+/+ only. Inflammation and collagen staining within the airway wall, were increased in ovalbumin decorin+/+ mice only; whereas biglycan was significantly increased in ovalbumin decorin-/- mice only. These results reflect the role of decorin in the development of allergen-induced asthma.