Ca2+-signaling in airway smooth muscle cells is altered in T-bet knock-out mice

Bergner, Albrecht; Kellner, Julia; Silva, Anita Kemp da; Gamarra, Fernando; Huber, Rudolf M.

doi:10.1186/1465-9921-7-33

Cited by 20 publications

(25 citation statements)

References 40 publications

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“…On the basis of our previous results, we suggest that a heightened [Ca 2ϩ ] i mobilization through the CD38/cADPR pathway in ASM cells upon agonist stimulation contributes to the increased ASM contraction, leading to excessive airway narrowing and AHR in vivo. This suggestion is also supported by other studies showing that enhanced calcium signaling in ASM cells is associated with enhanced ASM contractility and AHR in vivo (3,36). This is anticipated since Ca 2ϩ is an important signaling molecule regulating ASM contraction and bronchomotor tone.…”

Section: Discussionsupporting

confidence: 74%

“…We have also shown that CD38KO airway myocytes have reduced [Ca 2ϩ ] i responses to contractile agonists and that methacholine-induced increases in airway resistance are lower in CD38KO mice compared with wild-type (WT) controls (8). These studies demonstrated that the CD38/cADPR signaling has an important role in [Ca 2ϩ ] i homeostasis in ASM cells with clear implications to normal airway function.Changes in [Ca 2ϩ ] i homeostasis have been proposed to be an important mechanism underlying airway hyperresponsiveness (AHR), a prominent feature of the asthmatic phenotype (3,15,36). Previous studies from our laboratory and from others using human ASM cells have implicated the CD38/cADPR signaling in [Ca 2ϩ ] i hyperresponsiveness to contractile agonists with possible relevance to inflammatory airway diseases (7,18,19,37).…”

mentioning

confidence: 99%

“…Changes in [Ca 2ϩ ] i homeostasis have been proposed to be an important mechanism underlying airway hyperresponsiveness (AHR), a prominent feature of the asthmatic phenotype (3,15,36). Previous studies from our laboratory and from others using human ASM cells have implicated the CD38/cADPR signaling in [Ca 2ϩ ] i hyperresponsiveness to contractile agonists with possible relevance to inflammatory airway diseases (7,18,19,37).…”

mentioning

confidence: 99%

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

Guedes¹,

Paulin²,

Rivero-Nava³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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-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...

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Section: Discussionsupporting

confidence: 74%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Guedes¹,

Paulin²,

Rivero-Nava³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Lung slices were prepared as described previously (Bergner and Sanderson, 2002;Bergner et al, 2006). In brief, C57BL/6J mice (15-18 weeks old) were euthanized by CO 2 followed by cervical dislocation.…”

Section: Methodsmentioning

confidence: 99%

Phosphoinositide 3-Kinase γ Regulates Airway Smooth Muscle Contraction by Modulating Calcium Oscillations

Jiang¹,

Abel²,

Toews³

et al. 2010

J Pharmacol Exp Ther

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Phosphoinositide 3-kinase ␥ (PI3K␥) has been implicated in the pathogenesis of asthma, but its mechanism has been considered indirect, through release of inflammatory cell mediators. Because airway smooth muscle (ASM) contractile hyper-responsiveness plays a critical role in asthma, the aim of the present study was to determine whether PI3K␥ can directly regulate contractility of ASM. Immunohistochemistry staining indicated expression of PI3K␥ protein in ASM cells of mouse trachea and lung, which was confirmed by Western blot analysis in isolated mouse tracheal ASM cells. PI3K␥ inhibitor II inhibited acetylcholine (ACh)-stimulated airway contraction of cultured precision-cut mouse lung slices in a dose-dependent manner with 75% inhibition at 10 M. In contrast, inhibitors of PI3K␣, PI3K␤, or PI3K␦, at concentrations 40-fold higher than their reported IC 50 values for their primary targets, had no effect. It is noteworthy that airways in lung slices pretreated with PI3K␥ inhibitor II still exhibited an ACh-induced initial contraction, but the sustained contraction was significantly reduced. Furthermore, the PI3K␥-selective inhibitor had a small inhibitory effect on the ACh-stimulated initial Ca 2ϩ transient in ASM cells of mouse lung slices or isolated mouse ASM cells but significantly attenuated the sustained Ca 2ϩ oscillations that are critical for sustained airway contraction. This report is the first to show that PI3K␥ directly controls contractility of airways through regulation of Ca 2ϩ oscillations in ASM cells. Thus, in addition to effects on airway inflammation, PI3K␥ inhibitors may also exert direct effects on the airway contraction that contribute to pathologic airway hyper-responsiveness.

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“…Other functions of CRT include calcium homeostasis and quality control of protein folding. In a mouse model, it was shown that increased contractility in lung slices correlated with increased calcium in the sarcoplasmic reticulum (SR) [18]. CRT in the SR serves as a calcium chelator and may prevent release of calcium from the SR into the cytoplasm and, therefore, contraction.…”

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confidence: 99%

Playing a dirty trick on airway smooth muscle: house dust mite does it again

Zuyderduyn¹,

Hiemstra²

2011

Eur Respir J

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Increased airway smooth muscle (ASM) mass is a hallmark of asthma and is thought to be the main contributor to the increased airway hyperresponsiveness seen in asthmatics [1]. This increase is related to disease severity (reviewed in [2]) and caused by hyperplasia alone or in combination with hypertrophy, depending on the generation of airways [3,4]. Why and how ASM mass is increased is incompletely understood, but in vitro studies have shown that ASM cells isolated from asthmatics proliferate faster in culture [5]. In addition, cultured patient cells produce more chemokines and an altered array of extracellular matrix proteins compared with those of healthy individuals [6,7]. In vitro studies have shown that upon isolation, ASM cells display contractile function, but they rapidly change phenotype (i.e. acquire proliferative and synthetic capacity) and become noncontractile during culture under serum-rich conditions [8]. When these synthetic-proliferative cells are serum-deprived for a prolonged period of time, a small population (so-called ''hypercontractile'' cells) starts re-expressing contractile protein genes, such as ACTA2 (encoding a-smooth muscle actin (a-SMA)) [9]. This dedifferentiation/modulation and differentiation/maturation of ASM cells is referred to as phenotype switching or phenotypic plasticity, and although this phenomenon clearly exists in vitro, we do not know whether this plays a role in thickening of the ASM layer.The increase in ASM proliferation in asthma is thought to be associated with decreased levels of CCAAT enhancer protein (c/EBP)a (encoded by the CEBPA gene), a crucial controller of cell cycle progression, differentiation and inflammation. The biological effects of this protein are exerted by the full-length (p42) isoform and counteracted by a shorter isoform (p30), which is formed after translation of the protein. Previously, it was shown that ASM from asthmatics has reduced expression of c/EBPa, leading to reduced effects of glucocorticoids on proliferation of ASM cells [10]. Subsequently, it was shown that both the p42 and p30 isoforms of c/EBPa are reduced in asthmatic ASM cells and that culture in medium containing 5% fetal calf serum reduced the expression even more. Reduced expression was found to be the result of impaired translation and it was associated with decreased expression of the translation regulator eIF4E (eukaryotic initiation factor 4E) [11]. In addition to increased proliferation, interleukin (IL)-6 release (induced by growth factors) is increased in ASM from asthmatics and lack of c/EBPa is thought to be important for this process. Whether the change in ASM in asthmatics is innate or acquired due to exposure to external stimuli is yet to be discovered.Bronchial provocation using house dust mite (HDM) allergens results in bronchoconstriction in allergic patients. In addition to immunological mechanisms involving immunoglobulin (Ig)E and T-helper type 2 cells, it was shown that HDM also exerts direct effects on various cell types, including proteasedependent c...

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Ca2+-signaling in airway smooth muscle cells is altered in T-bet knock-out mice

Cited by 20 publications

References 40 publications

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

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

Phosphoinositide 3-Kinase γ Regulates Airway Smooth Muscle Contraction by Modulating Calcium Oscillations

Playing a dirty trick on airway smooth muscle: house dust mite does it again

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