A2B adenosine receptors regulate the mucus clearance component of the lung's innate defense system
| Autor: | Scott H. Donaldson, Andrew J. Hirsh, Ray D. Coakley, Mark T. Clunes, Mellisa Burn, Michael I. Lethem, Brett M. Rollins, Robert Tarran, Lucy A. Chambers |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Pulmonary and Respiratory Medicine
Adenosine Adenosine Deaminase Clinical Biochemistry Cystic Fibrosis Transmembrane Conductance Regulator Bronchi Adenosine-5'-(N-ethylcarboxamide) Respiratory Mucosa Receptor Adenosine A2B Adenosine deaminase Chlorides medicine otorhinolaryngologic diseases Cyclic AMP Humans Receptor Molecular Biology Cells Cultured Lung biology Cell Biology Articles respiratory system Mucus Adenosine receptor Cystic fibrosis transmembrane conductance regulator Epithelium Immunity Innate Cell biology Adenosine A2 Receptor Antagonists medicine.anatomical_structure Immunology biology.protein Calcium medicine.drug |
| Zdroj: | American journal of respiratory cell and molecular biology. 39(2) |
| ISSN: | 1535-4989 |
| Popis: | Adenosine (ADO) signaling is altered in both asthma and chronic obstructive pulmonary disease, and the A(2B) adenosine receptor (A(2B)-R) may drive pulmonary inflammation. Accordingly, it has been proposed that specific inhibition of the A(2B)-R could treat inflammatory lung diseases. However, stimulation of the cystic fibrosis transmembrane conductance regulator (CFTR) by ADO may be crucial in permitting the superficial epithelium to maintain airway surface liquid (ASL) volume, which is required to ensure hydrated and clearable mucus. Our goal was to determine which ADO receptor (ADO-R) underlies ASL volume regulation in bronchial epithelia. We used PCR techniques to determine ADO-R expression in bronchial epithelia and used nasal potential difference measurements, Ussing chambers studies, and XZ-confocal microscopy to look at Cl- secretion and ASL volume regulation. The A(2B)-R was the most highly expressed ADO-R in donor specimens of human bronchial epithelia, and inhibition of ADO-R in vivo prevented activation of CFTR. A(2B)-R was the only ADO-R detected in cultured human bronchial epithelial cells and inhibition of this receptor with specific A(2B)-R antagonists resulted in ASL height collapse and a failure to effect ASL height homeostasis. Removal of ADO with ADO deaminase and replacement with 5'N-ethylcarboxamide adenosine resulted in dose-dependent changes in ASL height, and suggested that the cell surface (ADO) may be in excess of 1 microM, which is sufficient to activate A(2B)-R. A(2B)-R are required for ASL volume homeostasis in human airways, and therapies directed at inhibiting A(2B)-R may lead to a cystic fibrosis-like phenotype with depleted ASL volume and mucus stasis. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|