48 research outputs found
Polypose naso-sinusienne : rÎle des facteurs inflammatoires dans les dysfonctions épithéliales et perspectives thérapeutiques
The sinonasal polyposis (SNP) is a chronic and common inflammatory disease of the nose and sinuses mucosa (4% of the population). SNP usually begins at around 40 years old. Association with asthma is particularly common (40% of cases). Sometimes SNP is associated with intolerance to aspirin and anti-inflammatory [1]. SNP manifestations are chronic nasal obstruction, smell disorders and invalidant chronic rhinorrhea, sneezing and facial pain. This inflammatory disease is characterized by a rich eosinophilic infiltrate, like asthma, and a remodeling of the nasal epithelium consists of a variable combination of squamous metaplasia, hyperplasia of mucous cells, basal and/or glandular, and thickening of the basement membrane. Changes to the connective tissue are constant: focal fibrosis, mucosal oedema and neovascularization [2]. Different studies showed the involvement of the epithelium in the pathophysiology of SNP, thus constituting a deregulated repair model. Normally after injury mechanisms, there is a repair of epithelium: migration of cells lining the injured area on naked extracellular matrix, cell proliferation, and after a few days, the establishment of junction between cells to obtain a sealed epithelium, and finally a process of differentiation [3]. This repair process is done through the secretion of growth factors by both the injured epithelial cells and the cells of the underlying connective tissue [3]. In the SNP, there is an inability to repair âad integrumâ the epithelium. Causes and mechanisms of these alterations of "tissue repair," are not yet characterized.The nasal epithelium is the first airway defense line with the mucociliary transport. The differentiated epithelium cells and especially the intercellular junctional complexes ensure the protection of epithelium from external agents [3]. This epithelium is submitted to different stresses: (i) inflammatory factors released in large quantities, (ii) mechanical shear stress generated by disturbances of the nasal air flow related the volume of polyps, but also (iii) microbiological and chemical stresses due to airborne contaminants or pathogens. All these attacks will have consequences who could participate to the local inflammation and the development of polyps (i) at the organ level (changing nasal resistances and/or nasal compliance) (ii) at the cellular level (properties of the cytoskeleton, cell interactions within the epithelium, migration and differentiation capabilities, mucociliary cleaning function) and (iii) at the molecular level (characteristics of mucus, ciliary alterations, proinflammatory signal activation). [4]La Polypose nasosinusienne (PNS) est une maladie inflammatoire chronique de la muqueuse du nez et des sinus, frĂ©quente, affectant jusqu'Ă 4% de la population. La PNS dĂ©bute gĂ©nĂ©ralement vers lâĂąge de 40 ans et lâassociation Ă un asthme est particuliĂšrement frĂ©quente (40% des cas environ) parfois complĂ©tĂ©e par lâassociation Ă une intolĂ©rance Ă lâaspirine et aux AINS [1]. La PNS se manifeste par une obstruction nasale chronique, des troubles de lâodorat et une rhinorrhĂ©e chronique invalidante, des Ă©ternuements et une pesanteur faciale. Cette maladie inflammatoire avec infiltrat riche en Ă©osinophiles est, Ă lâinstar de lâasthme, caractĂ©risĂ©e par un remodelage de lâĂ©pithĂ©lium nasal constituĂ© de lâassociation variable dâune mĂ©taplasie malpighienne, dâune hyperplasie des cellules Ă mucus, basales et/ou glandulaire, et dâun Ă©paississement de la membrane basale. Les modifications du tissu conjonctif sont constantes associant fibrose focale, ĆdĂšme muqueux et nĂ©ovascularisation [2]. Les diffĂ©rents travaux montrent lâimplication importante de lâĂ©pithĂ©lium dans la physiopathologie de la PNS qui constituerait un modĂšle de rĂ©paration dysrĂ©gulĂ©e. Normalement aprĂšs un processus lĂ©sionnel, il existe un mĂ©canisme de rĂ©paration de lâĂ©pithĂ©lium: la migration, sur la matrice extracellulaire dĂ©nudĂ©e, des cellules bordant la zone lĂ©sĂ©e, puis la prolifĂ©ration cellulaire, et au bout de quelques jours , lâĂ©tablissement de la jonctionnalitĂ© et de lâĂ©tanchĂ©itĂ© Ă©pithĂ©liale, et enfin un processus de « re »-diffĂ©renciation [3]. Ce processus de rĂ©paration se fait grĂące Ă la sĂ©crĂ©tion de facteurs de croissance par les cellules Ă©pithĂ©liales lĂ©sĂ©es et aussi par les cellules du tissu conjonctif sous jacent [3]. Dans la PNS, il existe une incapacitĂ© Ă rĂ©parer, lâĂ©pithĂ©lium ad integrum. Les causes et mĂ©canismes prĂ©cis de ces altĂ©rations de la "rĂ©paration tissulaire" ne sont pas encore caractĂ©risĂ©es.LâĂ©pithĂ©lium nasal constitue la premiĂšre ligne de dĂ©fense des voies aĂ©riennes grĂące au transport muco-ciliaire qui suppose un Ă©pithĂ©lium diffĂ©renciĂ© cohĂ©sif, notamment au niveau des complexes jonctionnels intercellulaires qui assurent lâimpermĂ©abilitĂ© de lâĂ©pithĂ©lium vis Ă vis des agents extĂ©rieurs [3]. Cet Ă©pithĂ©lium est soumis Ă des stress de diffĂ©rentes natures Ă savoir: (i) inflammatoire Ă cause des facteurs libĂ©rĂ©s en grande quantitĂ© dans la PNS, (ii) mĂ©canique Ă cause des contraintes de cisaillement gĂ©nĂ©rĂ©es par les perturbations de lâĂ©coulement aĂ©rien nasal liĂ©es au volume des polypes, mais aussi (iii) microbiologiques et chimiques Ă cause de agents aĂ©rocontaminants ou infectieux. Lâensemble de ces agressions vont avoir des consĂ©quences notamment biomĂ©caniques qui pourraient participer Ă lâautoentretien local de lâinflammation et au dĂ©veloppement des polypes : (i) Ă l'Ă©chelle de lâorgane (modification des rĂ©sistances et/ou de la compliance nasales) (ii) Ă lâĂ©chelle cellulaire et tissulaire (propriĂ©tĂ©s du cytosquelette, interactions cellulaires au sein de lâĂ©pithĂ©lium, capacitĂ©s de migration et de diffĂ©renciation, fonction dâĂ©puration muco-ciliaire) et (iii) sous-jacentes Ă lâĂ©chelle molĂ©culaire (caractĂ©ristiques du mucus, altĂ©rations des moteurs ciliaires, activations signalĂ©tiques pro-inflammatoires)[4]
Naso-sinus polyposis : role of factors inflammatory in epithelial dysfunctions and therapeutic perspectives
La Polypose nasosinusienne (PNS) est une maladie inflammatoire chronique de la muqueuse du nez et des sinus, frĂ©quente, affectant jusqu'Ă 4% de la population. La PNS dĂ©bute gĂ©nĂ©ralement vers lâĂąge de 40 ans et lâassociation Ă un asthme est particuliĂšrement frĂ©quente (40% des cas environ) parfois complĂ©tĂ©e par lâassociation Ă une intolĂ©rance Ă lâaspirine et aux AINS [1]. La PNS se manifeste par une obstruction nasale chronique, des troubles de lâodorat et une rhinorrhĂ©e chronique invalidante, des Ă©ternuements et une pesanteur faciale. Cette maladie inflammatoire avec infiltrat riche en Ă©osinophiles est, Ă lâinstar de lâasthme, caractĂ©risĂ©e par un remodelage de lâĂ©pithĂ©lium nasal constituĂ© de lâassociation variable dâune mĂ©taplasie malpighienne, dâune hyperplasie des cellules Ă mucus, basales et/ou glandulaire, et dâun Ă©paississement de la membrane basale. Les modifications du tissu conjonctif sont constantes associant fibrose focale, ĆdĂšme muqueux et nĂ©ovascularisation [2]. Les diffĂ©rents travaux montrent lâimplication importante de lâĂ©pithĂ©lium dans la physiopathologie de la PNS qui constituerait un modĂšle de rĂ©paration dysrĂ©gulĂ©e. Normalement aprĂšs un processus lĂ©sionnel, il existe un mĂ©canisme de rĂ©paration de lâĂ©pithĂ©lium: la migration, sur la matrice extracellulaire dĂ©nudĂ©e, des cellules bordant la zone lĂ©sĂ©e, puis la prolifĂ©ration cellulaire, et au bout de quelques jours , lâĂ©tablissement de la jonctionnalitĂ© et de lâĂ©tanchĂ©itĂ© Ă©pithĂ©liale, et enfin un processus de « re »-diffĂ©renciation [3]. Ce processus de rĂ©paration se fait grĂące Ă la sĂ©crĂ©tion de facteurs de croissance par les cellules Ă©pithĂ©liales lĂ©sĂ©es et aussi par les cellules du tissu conjonctif sous jacent [3]. Dans la PNS, il existe une incapacitĂ© Ă rĂ©parer, lâĂ©pithĂ©lium ad integrum. Les causes et mĂ©canismes prĂ©cis de ces altĂ©rations de la "rĂ©paration tissulaire" ne sont pas encore caractĂ©risĂ©es.LâĂ©pithĂ©lium nasal constitue la premiĂšre ligne de dĂ©fense des voies aĂ©riennes grĂące au transport muco-ciliaire qui suppose un Ă©pithĂ©lium diffĂ©renciĂ© cohĂ©sif, notamment au niveau des complexes jonctionnels intercellulaires qui assurent lâimpermĂ©abilitĂ© de lâĂ©pithĂ©lium vis Ă vis des agents extĂ©rieurs [3]. Cet Ă©pithĂ©lium est soumis Ă des stress de diffĂ©rentes natures Ă savoir: (i) inflammatoire Ă cause des facteurs libĂ©rĂ©s en grande quantitĂ© dans la PNS, (ii) mĂ©canique Ă cause des contraintes de cisaillement gĂ©nĂ©rĂ©es par les perturbations de lâĂ©coulement aĂ©rien nasal liĂ©es au volume des polypes, mais aussi (iii) microbiologiques et chimiques Ă cause de agents aĂ©rocontaminants ou infectieux. Lâensemble de ces agressions vont avoir des consĂ©quences notamment biomĂ©caniques qui pourraient participer Ă lâautoentretien local de lâinflammation et au dĂ©veloppement des polypes : (i) Ă l'Ă©chelle de lâorgane (modification des rĂ©sistances et/ou de la compliance nasales) (ii) Ă lâĂ©chelle cellulaire et tissulaire (propriĂ©tĂ©s du cytosquelette, interactions cellulaires au sein de lâĂ©pithĂ©lium, capacitĂ©s de migration et de diffĂ©renciation, fonction dâĂ©puration muco-ciliaire) et (iii) sous-jacentes Ă lâĂ©chelle molĂ©culaire (caractĂ©ristiques du mucus, altĂ©rations des moteurs ciliaires, activations signalĂ©tiques pro-inflammatoires)[4].The sinonasal polyposis (SNP) is a chronic and common inflammatory disease of the nose and sinuses mucosa (4% of the population). SNP usually begins at around 40 years old. Association with asthma is particularly common (40% of cases). Sometimes SNP is associated with intolerance to aspirin and anti-inflammatory [1]. SNP manifestations are chronic nasal obstruction, smell disorders and invalidant chronic rhinorrhea, sneezing and facial pain. This inflammatory disease is characterized by a rich eosinophilic infiltrate, like asthma, and a remodeling of the nasal epithelium consists of a variable combination of squamous metaplasia, hyperplasia of mucous cells, basal and/or glandular, and thickening of the basement membrane. Changes to the connective tissue are constant: focal fibrosis, mucosal oedema and neovascularization [2]. Different studies showed the involvement of the epithelium in the pathophysiology of SNP, thus constituting a deregulated repair model. Normally after injury mechanisms, there is a repair of epithelium: migration of cells lining the injured area on naked extracellular matrix, cell proliferation, and after a few days, the establishment of junction between cells to obtain a sealed epithelium, and finally a process of differentiation [3]. This repair process is done through the secretion of growth factors by both the injured epithelial cells and the cells of the underlying connective tissue [3]. In the SNP, there is an inability to repair âad integrumâ the epithelium. Causes and mechanisms of these alterations of "tissue repair," are not yet characterized.The nasal epithelium is the first airway defense line with the mucociliary transport. The differentiated epithelium cells and especially the intercellular junctional complexes ensure the protection of epithelium from external agents [3]. This epithelium is submitted to different stresses: (i) inflammatory factors released in large quantities, (ii) mechanical shear stress generated by disturbances of the nasal air flow related the volume of polyps, but also (iii) microbiological and chemical stresses due to airborne contaminants or pathogens. All these attacks will have consequences who could participate to the local inflammation and the development of polyps (i) at the organ level (changing nasal resistances and/or nasal compliance) (ii) at the cellular level (properties of the cytoskeleton, cell interactions within the epithelium, migration and differentiation capabilities, mucociliary cleaning function) and (iii) at the molecular level (characteristics of mucus, ciliary alterations, proinflammatory signal activation). [4
Efficacité à long terme du traitement des nodules de cordes vocales et évaluation du handicap vocal (étude de 90 cas consécutifs)
PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF
FcRn as a Transporter for Nasal Delivery of Biologics: A Systematic Review
International audienceFcRn plays a major role in regulating immune homeostasis, but it is also able to transport biologics across cellular barriers. The question of whether FcRn could be an efficient transporter of biologics across the nasal epithelial barrier is of particular interest, as it would allow a less invasive strategy for the administration of biologics in comparison to subcutaneous, intramuscular or intravenous administrations, which are often used in clinical practice. A focused systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. It was registered on the international prospective register of systematic reviews PROSPERO, which helped in identifying articles that met the inclusion criteria. Clinical and preclinical studies involving FcRn and the nasal delivery of biologics were screened, and the risk of bias was assessed across studies using the Oral Health Assessment Tool (OHAT). Among the 12 studies finally included in this systematic review (out of the 758 studies screened), 11 demonstrated efficient transcytosis of biologics through the nasal epithelium. Only three studies evaluated the potential toxicity of biologicsâ intranasal delivery, and they all showed that it was safe. This systematic review confirmed that FcRn is expressed in the nasal airway and the olfactory epithelium, and that FcRn may play a role in IgG and/or IgG-derived molecule-transcytosis across the airway epithelium. However, additional research is needed to better characterize the pharmacokinetic and pharmacodynamic properties of biologics after their intranasal delivery
Towards the in-vivo automated assessment of nasal cilia mobility
International audienceIntroduction. Cilia motility is an important diagnostic feature for various nasal diseases, both of acquired and genetic origin. So far this assessment has been performed ex-vivo in nasal samples. Sampling is invasive and may damage cilia, and ex-vivo measurements may not always reflect the in-vivo cilia function. In this work we investigated the possibility of assessing cilia motility in vivo in humans with a preliminary study using confocal micro-endoscopy.Materials and methods. We used the high-power laser confocal endoscope developed by Mauna Kea Technology (MKT). This device has a 1”m spatial resolution and a temporal resolution varying between 8 and 90 Hz. Ex-vivo pig trachea samples and human nasal biopsy samples were labelled with fluorescent marker Octadecyl Rhodamine B Chloride (R18). Beating cilia were easily identified allowing the acquisition of 40 videos ready for analysis. Using in-house software that estimates frequencies based on luminance variation in a small window and FFT analysis, we evaluated cilia and compared the beat frequency with ground truth.Results. We validated our estimations on all sequences acquired between 30 and 90Hz. Videos acquired at less than 30Hz did not offer sufficient temporal resolution We only observed occasional errors when the software identified a harmonic oscillation instead of the fundamental frequency
Nasal response to stress test in healthy subjects: an experimental pilot study Short tittle: Nasal response to stress
International audiencePurpose: Stress has been suspected to play a role in rhinitis. The role of stress on nasal patency has been not yet elucidated. The aim was to evaluate the potential effects of stress on nasal patency in healthy subjects.Methods: We conducted a prospective pilot study including 12 healthy subjects. Experimental protocol was divided in three periods (pre-task, task and recovery). In the task period, subjects were exposed to the "Trier Social Stress Test" (TSST), a standardized laboratory stressor. Different parameters including Spielberger State Anxiety Inventory (SSAI) score, visual analogic scale (VAS) of nasal patency feeling, heart rate, acoustic rhinometry measurements have been compared between the three different periods. The study population was divided into two groups according to the Spielberger Trait Anxiety Inventory (STAI) score: A "non anxious" group and a "weakly anxious" group.Results: Seven subjects were in the "non anxious" group and five in the "weakly anxious" group. TSST significantly increased heart rate in all volunteers. SSAI score was significantly increased (p = 0.04) after the task period (36.6 ± 11.3) when compared to the SSAI score in pre-task period (31.9 ± 12.6). VAS score of nasal patency feeling significantly decreased from pre-task to task and recovery periods. Mean minimal cross-sectional areas and mean volumes of the nasal cavities were not significantly different between the three periods, except in "weakly anxious" group, but the small number of subjects does not allow to draw a definite conclusion.Conclusion: We observed that stress influenced the feeling of nasal patency in healthy subjects. However, the objective effects of stress on nasal geometry were globally non-significant except in "weakly anxious" group. This latter result of our pilot study needs to be confirmed in a larger cohort
Oncostatin M Contributes to Airway Epithelial Cell Dysfunction in Chronic Rhinosinusitis with Nasal Polyps
International audienceChronic rhinosinusitis with nasal polyps (CRSwNP) is a typical type-2 inflammation involving several cytokines and is associated with epithelial cell dysfunction. Oncostatin M (OSM) (belonging to the interleukin(IL)-6 family) could be a key driver of epithelial barrier dysfunction. Therefore, we investigated the presence of OSM and IL-6 and the expression pattern of tight junctions (TJs) in the nasal tissue of CRSwNP patients and controls using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Then, their potential role in the epithelial barrier was evaluated in vitro in 27 different primary cultures of human nasal epithelial cells (HNECs) by measuring TJ expression and transepithelial electric resistance (TEER) with or without OSM or IL-6 (1, 10, and 100 ng/mL). The effect on ciliary beating efficiency was evaluated by high-speed videomicroscopy and on repair mechanisms with a wound healing model with or without OSM. OSM and IL-6 were both overexpressed, and TJ (ZO-1 and occludin) expression was decreased in the nasal polyps compared to the control mucosa. OSM (100 ng/mL) but not IL-6 induced a significant decrease in TJ expression, TEER, and ciliary beating efficiency in HNECs. After 24 h, the wound repair rate was significantly higher in OSM-stimulated HNECs at 100 ng/mL. These results suggest that OSM could become a new target for monoclonal antibodies
FcRn-Dependent Transcytosis of Monoclonal Antibody in Human Nasal Epithelial Cells In Vitro: A Prerequisite for a New Delivery Route for Therapy?
Monoclonal antibodies (mAbs) are promising therapies to treat airway chronic inflammatory disease (asthma or nasal polyps). To date, no study has specifically assessed, in vitro, the potential function of neonatal Fc receptor (FcRn) in IgG transcytosis through the human nasal airway epithelium. The objective of this study was to report the in vitro expression and function of FcRn in nasal human epithelium. FcRn expression was studied in an air–liquid interface (ALI) primary culture model of human nasal epithelial cells (HNEC) from polyps. FcRn expression was characterized by quantitative RT-PCR, western blot, and immunolabeling. The ability of HNECs to support mAb transcytosis via FcRn was assessed by transcytosis assay. This study demonstrates the expression of FcRn mRNA and protein in HNEC. We report a high expression of FcRn in the cytosol of ciliated, mucus, and basal cells by immunohistochemistry with a higher level of FcRn proteins in differentiated HNEC. We also proved in vitro transepithelial delivery of an IgG1 therapeutic mAb with a dose–response curve. This is the first time that FcRn expression and mAb transcytosis has been shown in a model of human nasal respiratory epithelium in vitro. This study is a prerequisite for FcRn-dependent nasal administration of mAbs
Pathogenesis of chronic rhinosinusitis with nasal polyps: role of IL-6 in airway epithelial cell dysfunction
International audienc
Dupilumab prevents nasal epithelial function alteration by ILâ4 in vitro: Evidence for its efficacy
International audienceBackground:Chronic rhinosinusitis with nasal polyp (CRSwNP) is a typical type 2 inflammation involving interleukin (IL)â4 and ILâ13. Dupilumab is a fully human monoclonal antibody targeting ILâ4 receptor α subunit, thereby blocking signaling by both cytokines. Our hypothesis was that ILâ4 and ILâ13, by inducing a severe epithelial dysregulation, are involved in CRSwNP pathogenesis. This study aimed to evaluate the in vitro direct effect of ILâ4, ILâ13, and dupilumab on nasal epithelial functions.Methods:Nasal polyps and control mucosa from 28 patients, as well as human nasal epithelial cells (HNEC) from 35 patients with CRSwNP were used. Three major epithelial functions were investigated: the epithelial barrier function (characterized by transepithelial electrical resistance measurements and tight junction protein expression), the ciliary motion (characterized by the ciliary beating efficiency index), and wound healing (characterized by the wound repair rate) under various stimulations (ILâ4, ILâ13, and dupilumab). The main outcome was a significant change in epithelial functions following exposure to ILâ4, ILâ13, and dupilumab for 48 h in the basal media.Results:ILâ4 (1, 10, and 100 ng/mL) but not ILâ13 induced a significant decrease in occludin and zonulaâoccludens protein expression, ciliary beating efficiency, and wound repair rate in HNEC. Dupilumab (0.04 mg/mL) had no effect on HNEC and specifically restored all epithelial functions altered when cells were exposed to a 48âh ILâ4 stimulation.Conclusion:Dupilumab, in vitro, restored epithelial integrity by counteracting the effect of ILâ4 on the epithelial barrier (increased epithelial permeability, decreased ciliary beating efficiency, and decreased wound repair rate)