CD38-deficient mice have reduced airway hyperresponsiveness following IL-13 challenge.
The transmembrane glycoprotein CD38 in airway smooth muscle is the source of cyclic-ADP ribose, an intracellular calcium-releasing molecule, and is subject to regulatory effects of cytokines such as interleukin (IL)-13, a cytokine implicated in asthma. We investigated the role of CD38 in airway hyperresponsiveness using a mouse model of IL-13-induced airway disease. Wild-type (WT) and CD38-deficient (CD38KO) mice were intranasally challenged with 5 microg of IL-13 three times on alternate days under isoflurane anesthesia. Lung resistance (R(L)) in response to inhaled methacholine was measured 24 h after the last challenge in pentobarbital-anesthetized, tracheostomized, and mechanically ventilated mice. Bronchoalveolar cytokines, bronchoalveolar and parenchymal inflammation, and smooth muscle contractility and relaxation using tracheal segments were also evaluated. Changes in methacholine-induced R(L) were significantly greater in the WT than in the CD38KO mice following intranasal IL-13 challenges. Airway reactivity after IL-13 exposure, as measured by the slope of the methacholine dose-response curve, was significantly higher in the WT than in the CD38KO mice. The rate of isometric force generation in tracheal segments (e.g., smooth muscle reactivity) was greater in the WT than in the CD38KO mice following incubation with IL-13. IL-13 treatment reduced isoproterenol-induced relaxations to similar magnitudes in tracheal segments obtained from WT and CD38KO mice. Both WT and CD38KO mice developed significant bronchoalveolar and parenchymal inflammation after IL-13 challenges compared with naïve controls. The results indicate that CD38 contributes to airway hyperresponsiveness in lungs exposed to IL-13 at least partly by increasing airway smooth muscle reactivity to contractile agonists.
Guedes
Alonso G P
AG
Department of Veterinary Clinicial Sciences, University of Minnesota, St. Paul, MN 55108, USA.
Paulin
Jaime
J
Rivero-Nava
Laura
L
Kita
Hirohito
H
Lund
Frances E
FE
Kannan
Mathur S
MS
D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency* / Q000235:genetics*; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000503:physiopathology* / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D018793:Interleukin-13 / Q000494:pharmacology; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics*; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout
D018793:Interleukin-13; D008562:Membrane Glycoproteins; D016210:Methacholine Chloride; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1