CD38-deficient mice have reduced airway hyperresponsiveness following IL-13 challenge

Abstract

-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 g of IL-13 three times on alternate days under isoflurane anesthesia. Lung resistance (RL) 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. interleukin-13; inflammation; asthma; eosinophil; airway smooth muscle CD38 IS A MULTIFUNCTIONAL ECTOENZYME that catalyzes the conversion of ␤-nicotinamide adenine dinucleotide to cyclic ADP-ribose (cADPR) and ADP-ribose (16). Both CD38 and its product cADPR are present in airway smooth muscle (ASM) cells and other mammalian cell types (8,26,32,39). Together with inositol 1,4,5-trisphosphate, cADPR is an important mediator of intracellular calcium ([Ca 2ϩ ] i ) release in smooth muscle cells including that of the airways (7,20,31). The dynamics of [Ca 2ϩ ] i responses to stimuli are central in the regulation of ASM contraction, bronchomotor tone, and airway caliber (33). cADPR induces Ca 2ϩ release from the sarcoplasmic reticulum through activation of ryanodine receptor channels in ASM cells (31). The [Ca 2ϩ ] i responses of human ASM cells exposed to acetylcholine, thrombin, and bradykinin are reduced by the competitive cADPR antagonist 8-bromo-cADPR in a magnitude that correlates positively with the level of CD38 expression (6).CD38-deficient (CD38KO) mice have been used to elucidate the role of CD38 in the function of several organs. CD38-generated cADPR plays a critical role in Ca 2ϩ -induced insulin secretion (21), os...

Calcium Signaling in Airway Smooth Muscle

“…Isolated tracheal rings from CD38 knockout mice, when pretreated with IL-13, showed significant reduction in rate of force development to carbachol compared with that of the IL-13-treated tracheae from the wild-type mice (84). However, intranasal exposure to IL-13 elicited a comparable inflammatory response in the both groups of mice (84). The findings of the above study indicate that IL-13-induced airway hyperresponsiveness requires CD38 expression in the airways and airway inflammation per se is not sufficient in the development of airway hyperresponsiveness.…”

“…When CD38 knockout and wild-type mice were intranasally exposed to IL-13, CD38 knockout mice displayed significantly attenuated airway hyperresponsiveness to inhaled methacholine compared with the wild-type controls (84). Isolated tracheal rings from CD38 knockout mice, when pretreated with IL-13, showed significant reduction in rate of force development to carbachol compared with that of the IL-13-treated tracheae from the wild-type mice (84). However, intranasal exposure to IL-13 elicited a comparable inflammatory response in the both groups of mice (84).…”

“…In order to determine if the in vitro effect of IL-13 on airway myocytes is representative of the physiologic effects of this cytokine, in vivo experiments were carried out in mouse models. When CD38 knockout and wild-type mice were intranasally exposed to IL-13, CD38 knockout mice displayed significantly attenuated airway hyperresponsiveness to inhaled methacholine compared with the wild-type controls (84). Isolated tracheal rings from CD38 knockout mice, when pretreated with IL-13, showed significant reduction in rate of force development to carbachol compared with that of the IL-13-treated tracheae from the wild-type mice (84).…”

The Association of Cortactin with Profilin-1 Is Critical for Smooth Muscle Contraction

“…Peptide-Asthma is characterized by airway hyperresponsiveness, which is largely attributed to hyperreactivity of airway smooth muscle (41)(42)(43)(44). However, the molecular mechanisms that control airway hyperresponsiveness and smooth muscle hyperreactivity are not fully understood.…”

NAD+-Consuming Enzymes in the Regulation of Lung Immune Responses

“…Moreover Deshpande et al [88] have shown decreased lung responsiveness to different doses of metacholine in CD38-/-mice, as determined by changes in lung resistance and dynamic compliance. Airway hyperreactivity (AHR) was also shown to be diminished in CD38-/-mice in several mouse models of allergic inflammation [89][90][91]. CD38-/-mice develop significant airway and parenchymal inflammation after nasal IL-13 challenges and both WT and CD38-/-mice develop AHR.…”