Allergen-induced airway hyperresponsiveness is absent in ecto-5'-nucleotidase (CD73)-deficient mice.
Adenosine is formed from extracellular purines by ecto-5'-nucleotidase (CD73) and is an essential player in allergic airway inflammation. The contribution of adenosine and other purines to electrolyte transport and mucociliary clearance was studied in airways of allergen challenged mice. No signs for allergen-induced inflammation were found in CD73-/- mice, and adenosine monophosphate (AMP) was unable to elicit airway Cl(-) secretion in these animals. Tracheas of ovalbumin (OVA)-treated BALB/c and CD73+/+ mice were hyperresponsive towards methacholine when assessed by Penh and direct optical measurement of contraction. In addition Cl(-) secretion activated by ATP and ADP was enhanced. These changes were not observed in CD73-/- mice. Expression of CFTR or CLCA was unchanged upon OVA treatment of CD73 mice, suggesting enhanced Cl(-) secretion due to upregulated purinergic pathways. Mucociliary clearance was determined by measuring particle transport in excised mouse tracheas and was strongly enhanced in OVA-challenged CD73+/+ mice, but remained unchanged in CD73-/- mice. While mucociliary clearance is activated by allergen exposure independent of functional ecto-5'-nucleotidase, airway inflammation is largely dependent on CD73. Thus, ecto-5'-nucleotidase may provide a novel target for therapeutic intervention, probably by local application of ecto-5'-nucleotidase inhibitors through inhalation.
Schreiber
Rainer
R
Institut für Physiologie, Universität Regensburg, Universitätsstrasse 31, 93053, Regensburg, Germany.
Castrop
Hayo
H
Kunzelmann
Karl
K
D015720:5'-Nucleotidase / Q000172:deficiency* / Q000235:genetics; D000227:Adenine Nucleotides / Q000378:metabolism; D000241:Adenosine / Q000378:metabolism; D000485:Allergens; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D001985:Bronchial Provocation Tests; D016084:Bronchoconstriction; D016085:Bronchoconstrictor Agents; D002712:Chlorides / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009079:Mucociliary Clearance; D010047:Ovalbumin; D014132:Trachea / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology
D000227:Adenine Nucleotides; D000485:Allergens; D016085:Bronchoconstrictor Agents; D002712:Chlorides; D016210:Methacholine Chloride; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D010047:Ovalbumin; D015720:5'-Nucleotidase; D000241:Adenosine