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Enhanced Ca2+ sensitivity in hyperresponsive cultured bronchi is mediated by TNFα and NF-ΚB

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Abstract:

The mechanical properties and Ca2+ sensitivity of an organ-culture model derived from guinea pig airways have been examined. The cultured explants develop airway hyperresponsiveness to pharmacological agonists after 3-day culture, when compared with fresh and ovalbumin-sensitized tissues. The reactivity of cultured explants is dependent on the presence of the epithelium. They are also sensitive to glucocorticosteroid pretreatments, which neutralize the TNFα antibody and ΝF-ΚB inhibitor. Hence, specific immunostaining of ΝF-ΚB subunits (p65 and p50) was increased in the nuclear extract of cultured explants. In -escin-permeabilized preparations, step-increases in pCa revealed enhanced Ca2+ sensitivity of the contractile apparatus in cultured explants, which was prevented by epithelium removal. Pretreatments of cultured explants with neutralizing TNFα antibody and ΝF-ΚB inhibitor consistently reduced their Ca2+ sensitivity. These findings suggest that AHR developed in this organ culture model may be triggered by an inflammatory process mediated by the TNFα and NF-ΚB transcription factor, which results in an increased sensitivity to [Ca2+]i.

On a examiné les propriétés mécaniques et la sensibilité au Ca2+ dans un modèle de culture d’organes provenant des voies respiratoires de cobayes. Les explants cultivés ont développé une hyperréactivité bronchique (HRB) aux agonistes pharmacologiques après une mise en culture de 3 jours comparativement aux tissus frais et aux tissus sensibilisés à l’ovalbumine. La réactivité des explants cultivés dépend de la présence de l’épithélium. Les explants sont aussi sensibles aux prétraitements par les glucocorticostéroïdes, à un anticorps neutralisant le TNFα et à un inhibiteur de NF-ΚB. Ainsi, l’immunomarquage spécifique des sous-unités (p65 et p50) de NF-ΚB a augmenté dans l’extrait nucléaire des explants cultivés. Dans les préparations perméabilisées par la -escine, les augmentations progressives de pCa ont révélé une augmentation de la sensibilité de l’appareil contractile dans les explants, laquelle a été prévenue par l’enlèvement de l’épithélium. Des prétraitements avec un anticorps neutralisant le TNFα et un inhibiteur de NF-ΚB ont diminué de façon uniforme la sensibilité des explants au Ca2+. Ces résultats donnent à penser que l’HRB développée dans ce modèle de culture d’organes pourrait être déclenchée par un processus inflammatoire, véhiculé par le TNFα et le facteur de transcription NF-ΚB, qui provoque une augmentation de la sensibilité à la [Ca2+]i.

Document Type: Research Article

Publication date: October 1, 2006

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