Blocking ATP-releasing channels prevents high extracellular ATP levels and airway hyperreactivity in an asthmatic mouse model

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dc.contributor.authorArzola Martinez, Llilian
dc.contributor.authorBenavente, Rebeca
dc.contributor.authorVega, Genesis
dc.contributor.authorRios, Mariana
dc.contributor.authorFonseca, Wendy
dc.contributor.authorRasky, Andrew J.
dc.contributor.authorMorris, Susan
dc.contributor.authorLukacs, Nicholas W.
dc.contributor.authorVillalon, Manuel J.
dc.date.accessioned2024-01-10T13:10:26Z
dc.date.available2024-01-10T13:10:26Z
dc.date.issued2021
dc.description.abstractAllergic asthma is a chronic airway inflammatory response to different triggers like inhaled allergens. Excessive ATP in fluids from patients with asthma is considered an inflammatory signal and an important autocrine/paracrine modulator of airway physiology. Here, we investigated the deleterious effect of increased extracellular ATP (eATP) concentration on the mucociliary clearance (MCC) effectiveness and determined the role of ATP releasing channels during airway inflammation in an ovalbumin (OVA)-sensitized mouse model. Our allergic mouse model exhibited high levels of eATP measured in the tracheal fluid with a luciferin-luciferase assay and reduced MCC velocity determined by microspheres tracking in the trachea ex vivo. Addition of ATP had a dual effect on MCC, where lower ATP concentration (mu M) increased microspheres velocity, whereas higher concentration (mM) transiently stopped microspheres movement. Also, an augmented ethidium bromide uptake by the allergic tracheal airway epithelium suggests an increase in ATP release channel functionality during inflammatory conditions. The use of carbenoxolone, a nonspecific inhibitor of connexin and pannexini channels reduced the eATP concentration in the allergic mouse tracheal fluid and dye uptake by the airway epithelium, providing evidence that these ATP release channels are facilitating the net flux of ATP to the lumen during airway inflammation. However, only the specific inhibition of pannexinl with (10)Panx peptide significantly reduced eATP in bronchoalveolar lavage and decreased airway hyperresponsiveness in OVA-allergic mouse model. These data provide evidence that blocking eATP may be a pharmacological alternative to be explored in rescue therapy during episodes of airflow restriction in patients with asthma.
dc.description.funderANID
dc.description.funderMillennium Institute of Immunology and Immunotherapy
dc.fechaingreso.objetodigital2024-05-02
dc.format.extent11 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1152/ajplung.00450.2020
dc.identifier.eissn1522-1504
dc.identifier.issn1040-0605
dc.identifier.pubmedidMEDLINE:34231389
dc.identifier.urihttps://doi.org/10.1152/ajplung.00450.2020
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/77851
dc.identifier.wosidWOS:000693148000014
dc.information.autorucFacultad de Ciencias Biológicas; Villalon Bravo, Manuel Jose; S/I; 99264
dc.issue.numero2
dc.language.isoen
dc.nota.accesoSin adjunto
dc.publisherAMER PHYSIOLOGICAL SOC
dc.revistaAMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
dc.rightsregistro bibliográfico
dc.subjectairway hyperreactivity
dc.subjectasthma
dc.subjectATP
dc.subjectmucociliary clearance
dc.subjectPanx1
dc.subjectSMOOTH-MUSCLE CONTRACTION
dc.subjectCILIARY BEAT FREQUENCY
dc.subjectEPITHELIAL-CELLS
dc.subjectMUCOCILIARY CLEARANCE
dc.subjectADENOSINE-TRIPHOSPHATE
dc.subjectPANNEXIN CHANNELS
dc.subjectDENDRITIC CELLS
dc.subjectINFLAMMATION
dc.subjectLUNG
dc.subjectINHIBITION
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleBlocking ATP-releasing channels prevents high extracellular ATP levels and airway hyperreactivity in an asthmatic mouse model
dc.typeartículo
dc.volumen321
sipa.codpersvinculados99264
sipa.indexWOS
sipa.trazabilidadCarga SIPA;09-01-2024
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