scholarly journals Antagonizing the metabolic hormone cholecystokinin (CCK) and its receptor CCKAR in the lung abolishes obesity-induced airway hyperresponsiveness

2021 ◽  
Author(s):  
Ronald Pangniban ◽  
Maoyun Sun ◽  
Chan Young Park ◽  
Alvin Koh ◽  
David Kasahara ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Airway Smooth Muscle Cells ◽  
Obese Mice ◽  
Novel Therapy ◽  
Co Morbidity ◽  
Pharmacological Blockade ◽  
Metabolic Hormone

Abstract Obesity is a significant co-morbidity that associates with increased prevalence and severity of asthma. The mechanism underlying the obesity-asthma association remains poorly understood, and for obese asthmatics there is no effective therapy for obese asthmatics. Here we show that cholecystokinin (CCK)—a metabolic hormone best known for its roles in satiety regulation and fat metabolism–is increased in the lungs of obese mice and that pharmacological blockade of CCK and its receptor (CCKAR) signaling in the lung abolishes obesity-associated airway hyperresponsiveness (AHR)—a hallmark of asthma. By mining existing RNA-seq transcriptomic data, we first discovered CCKAR as a highly expressed G-protein-coupled receptor in primary human airway smooth muscle (ASM) cells. Interestingly, CCK is also expressed in ASM cells and is induced by free fatty acids. Activation of CCKAR by CCK induces ASM stiffening and contraction, which is abolished by either CRISPR-mediated CCKAR inactivation or CCKAR antagonists. In vivo, CCK levels are elevated in the lung of both genetically obese (db/db) and diet-induced obese mice. Importantly, intranasal administration of highly potent CCKAR antagonists (proglumide and devazepide) abolishes AHR in both genetically obese and diet-induced obese mice. Together, our results reveal an unexpected role for the metabolic hormone CCK and its receptor CCKAR in airway smooth muscle cells and in obesity-associated asthma. Our study provides critical pre-clinical data that support the repurposing of CCKAR antagonists as a novel therapy for obese asthmatics.

scholarly journals Altered CD38/Cyclic ADP-Ribose Signaling Contributes to the Asthmatic Phenotype

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Joseph A. Jude ◽  
Mythili Dileepan ◽  
Reynold A. Panettieri ◽  
Timothy F. Walseth ◽  
Mathur S. Kannan
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Intracellular Calcium ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Map Kinases ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells ◽  
Cd38 Expression ◽  
Cyclic Adp Ribose

CD38 is a transmembrane glycoprotein expressed in airway smooth muscle cells. The enzymatic activity of CD38 generates cyclic ADP-ribose from β-NAD. Cyclic ADP-ribose mobilizes intracellular calcium during activation of airway smooth muscle cells by G-protein-coupled receptors through activation of ryanodine receptor channels in the sarcoplasmic reticulum. Inflammatory cytokines that are implicated in asthma upregulate CD38 expression and increase the calcium responses to contractile agonists in airway smooth muscle cells. The augmented intracellular calcium responses following cytokine exposure of airway smooth muscle cells are inhibited by an antagonist of cyclic ADP-ribose. Airway smooth muscle cells from CD38 knockout mice exhibit attenuated intracellular calcium responses to agonists, and these mice have reduced airway response to inhaled methacholine. CD38 also contributes to airway hyperresponsiveness as shown in mouse models of allergen or cytokine-induced inflammatory airway disease. In airway smooth muscle cells obtained from asthmatics, the cytokine-induced CD38 expression is significantly enhanced compared to expression in cells from nonasthmatics. This differential induction of CD38 expression in asthmatic airway smooth muscle cells stems from increased activation of MAP kinases and transcription through NF-κB, and altered post-transcriptional regulation through microRNAs. We propose that increased capacity for CD38 signaling in airway smooth muscle in asthma contributes to airway hyperresponsiveness.

Leukotriene D4 induces MMP-1, which functions as an IGFBP protease in human airway smooth muscle cells

1996 ◽  
Vol 271 (6) ◽  
pp. L1014-L1022 ◽  
Author(s):  
R. Rajah ◽  
S. E. Nunn ◽  
D. J. Herrick ◽  
M. M. Grunstein ◽  
P. Cohen
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Smooth Muscle Cells ◽  
Igf Binding Proteins ◽  
Leukotriene D4 ◽  
Igf Binding ◽  
Dose Dependent Increase ◽  
Dose Dependent ◽  
Insulin Like Growth Factors

We have previously demonstrated that the asthma-associated proinflammatory eicosanoid leukotriene D4 (LTD4) is comitogenic with insulin-like growth factors (IGF) in airway smooth muscle (ASM) cells. This synergistic effect of LTD4 and IGF on ASM cell growth involves proteolysis of ASM-produced inhibitory IGF-binding proteins (IGFBP). In this report, we analyzed the conditioned media (CM) from LTD4-treated human ASM cells (ASM-LTD4-CM) by Western ligand blotting and demonstrated a marked LTD4-induced reduction in the levels of the intact IGFBP (predominantly IGFBP-2) secreted by these cells. The IGFBP-2 in the ASM-LTD4-CM was identified as lower-molecular-weight fragments by Western immunoblotting. Incubation with 125I-labeled IGFBP demonstrated that an IGFBP protease was induced in the ASM cells in response to LTD4 treatment. Immunodepletion of ASM-LTD4-CM with anti-matrix metalloproteinase (MMP)-1 antibodies demonstrated a dose-dependent reduction of IGFBP proteolysis. Tissue inhibitor of MMP-1 and Batimastat (synthetic) inhibited proteolysis of IGFBP. Immunoblotting the ASM-LTD4-CM with anti-MMP-1 demonstrated a dose-dependent increase in MMP-1 protein. Similar results were also obtained by immunocytochemistry. Collectively, these observations demonstrate that MMP-1 is an IGFBP protease induced by leukotrienes that plays a significant role in modulating IGF action in ASM cells. A similar mechanism may be applicable in vivo in the airways of patients with asthma.

scholarly journals Curcumin inhibits the proliferation of airway smooth muscle cells in vitro and in vivo

2013 ◽  
Vol 32 (3) ◽  
pp. 629-636 ◽  
Author(s):  
XIN ZENG ◽  
YING CHENG ◽  
YUEJUN QU ◽  
JIDE XU ◽  
ZHIYUAN HAN ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells

scholarly journals The GABAA agonist muscimol attenuates induced airway constriction in guinea pigs in vivo

2009 ◽  
Vol 106 (4) ◽  
pp. 1257-1263 ◽  
Author(s):  
Neil R. Gleason ◽  
George Gallos ◽  
Yi Zhang ◽  
Charles W. Emala
Keyword(s):  
Smooth Muscle ◽  
Cell Membrane ◽  
Airway Smooth Muscle ◽  
Guinea Pigs ◽  
Neural Control ◽  
Chronic Obstructive ◽  
Airway Smooth Muscle Cells ◽  
Membrane Hyperpolarization ◽  
Airway Constriction

GABAA channels are ubiquitously expressed on neuronal cells and act via an inward chloride current to hyperpolarize the cell membrane of mature neurons. Expression and function of GABAA channels on airway smooth muscle cells has been demonstrated in vitro. Airway smooth muscle cell membrane hyperpolarization contributes to relaxation. We hypothesized that muscimol, a selective GABAA agonist, could act on endogenous GABAA channels expressed on airway smooth muscle to attenuate induced increases in airway pressures in anesthetized guinea pigs in vivo. In an effort to localize muscimol's effect to GABAA channels expressed on airway smooth muscle, we pretreated guinea pigs with a selective GABAA antagonist (gabazine) or eliminated lung neural control from central parasympathetic, sympathetic, and nonadrenergic, noncholinergic (NANC) nerves before muscimol treatment. Pretreatment with intravenous muscimol alone attenuated intravenous histamine-, intravenous acetylcholine-, or vagal nerve-stimulated increases in peak pulmonary inflation pressure. Pretreatment with the GABAA antagonist gabazine blocked muscimol's effect. After the elimination of neural input to airway tone by central parasympathetic nerves, peripheral sympathetic nerves, and NANC nerves, intravenous muscimol retained its ability to block intravenous acetylcholine-induced increases in peak pulmonary inflation pressures. These findings demonstrate that the GABAA agonist muscimol acting specifically via GABAA channel activation attenuates airway constriction independently of neural contributions. These findings suggest that therapeutics directed at the airway smooth muscle GABAA channel may be a novel therapy for airway constriction following airway irritation and possibly more broadly in diseases such as asthma and chronic obstructive pulmonary disease.

scholarly journals ROCK insufficiency attenuates ozone-induced airway hyperresponsiveness in mice

2015 ◽  
Vol 309 (7) ◽  
pp. L736-L746 ◽  
Author(s):  
David I. Kasahara ◽  
Joel A. Mathews ◽  
Chan Y. Park ◽  
Youngji Cho ◽  
Gabrielle Hunt ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Muscle Contraction ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Matrix Protein ◽  
Pulmonary Inflammation ◽  
Inflammatory Cells ◽  
Smooth Muscle Contraction ◽  
Airway Smooth Muscle Cells ◽  
Wild Type

Ozone causes airway hyperresponsiveness (AHR) and pulmonary inflammation. Rho kinase (ROCK) is a key regulator of smooth muscle cell contraction and inflammatory cell migration. To determine the contribution of the two ROCK isoforms ROCK1 and ROCK2 to ozone-induced AHR, we exposed wild-type, ROCK1+/−, and ROCK2+/− mice to air or ozone (2 ppm for 3 h) and evaluated mice 24 h later. ROCK1 or ROCK2 haploinsufficiency did not affect airway responsiveness in air-exposed mice but significantly reduced ozone-induced AHR, with a greater reduction in ROCK2+/− mice despite increased bronchoalveolar lavage (BAL) inflammatory cells in ROCK2+/− mice. Compared with wild-type mice, ozone-induced increases in BAL hyaluronan, a matrix protein implicated in ozone-induced AHR, were lower in ROCK1+/− but not ROCK2+/− mice. Ozone-induced increases in other inflammatory moieties reported to contribute to ozone-induced AHR (IL-17A, osteopontin, TNFα) were not different in wild-type vs. ROCK1+/− or ROCK2+/− mice. We also observed a dose-dependent reduction in ozone-induced AHR after treatment with the ROCK1/ROCK2 inhibitor fasudil, even though fasudil was administered after induction of inflammation. Ozone increased pulmonary expression of ROCK2 but not ROCK1 or RhoA. A ROCK2 inhibitor, SR3677, reduced contractile forces in primary human airway smooth muscle cells, confirming a role for ROCK2 in airway smooth muscle contraction. Our results demonstrate that ozone-induced AHR requires ROCK. Whereas ROCK1-dependent changes in hyaluronan may contribute to ROCK1's role in O3-induced AHR, the role of ROCK2 is downstream of inflammation, likely at the level of airway smooth muscle contraction.

Airway smooth muscle responsiveness from dogs with airway hyperresponsiveness after O3 inhalation

1988 ◽  
Vol 65 (1) ◽  
pp. 57-64 ◽  
Author(s):  
G. L. Jones ◽  
P. M. O'Byrne ◽  
M. Pashley ◽  
R. Serio ◽  
J. Jury ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Potassium Chloride ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Electrical Field Stimulation ◽  
Field Stimulation ◽  
Electrical Field ◽  
Trachealis Muscle

Airway hyperresponsiveness occurs after inhalation of O3 in dogs. The purpose of this study was to examine the responsiveness of trachealis smooth muscle in vitro to electrical field stimulation, exogenous acetylcholine, and potassium chloride from dogs with airway hyperresponsiveness after inhaled O3 in vivo and to compare this with the responsiveness of trachealis muscle from control dogs. In addition, excitatory junction potentials were measured with the use of single and double sucrose gap techniques in both groups of dogs to determine whether inhaled O3 affects the release of acetylcholine from parasympathetic nerves in trachealis muscle. Airway hyperresponsiveness developed in all dogs after inhaled O3 (3 ppm for 30 min). The acetylcholine provocative concentration decreased from 4.11 mg/ml before O3 inhalation to 0.66 mg/ml after O3 (P less than 0.0001). The acetylcholine provocative concentration increased slightly after control inhalation of dry room air. Airway smooth muscle showed increased responses to both electrical field stimulation and exogenous acetylcholine but not to potassium chloride in preparations from dogs with airway hyperresponsiveness in vivo. The increased response to electrical field stimulation was not associated with a change in excitatory junctional potentials. These results suggest that a postjunctional alteration in trachealis muscle function occurs after inhaled O3 in dogs, which may account for airway hyperresponsiveness after O3 in vivo.

Interleukin-13 inhibits proliferation and enhances contractility of human airway smooth muscle cells without change in contractile phenotype

2011 ◽  
Vol 300 (6) ◽  
pp. L958-L966 ◽  
Author(s):  
Paul-André Risse ◽  
Taisuke Jo ◽  
Fernando Suarez ◽  
Nobuaki Hirota ◽  
Barbara Tolloczko ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Calcium Signaling ◽  
Airway Smooth Muscle ◽  
Airway Smooth Muscle Cells ◽  
Activated T Cells ◽  
Inhibition Of Proliferation ◽  
Th2 Cytokine ◽  
Number Of Cells

IL-13 is an important mediator of allergen-induced airway hyperresponsiveness. This Th2 cytokine, produced by activated T cells, mast cells, and basophils, has been described to mediate a part of its effects independently of inflammation through a direct modulation of the airway smooth muscle (ASM). Previous studies demonstrated that IL-13 induces hyperresponsiveness in vivo and enhances calcium signaling in response to contractile agonists in vitro. We hypothesized that IL-13 drives human ASM cells (ASMC) to a procontractile phenotype. We evaluated ASM phenotype through the ability of the cell to proliferate, to contract, and to express contractile protein in response to IL-13. We found that IL-13 inhibits human ASMC proliferation (expression of Ki67 and bromodeoxyuridine incorporation) in response to serum, increasing the number of cells in G0/G1 phase and decreasing the number of cells in G2/M phases of the cell cycle. IL-13-induced inhibition of proliferation was not dependent on signal transducer and activator of transcription-6 but was IL-13Rα2 receptor dependent and associated with a decrease of Kruppel-like factor 5 expression. In parallel, IL-13 increased calcium signaling and the stiffening of human ASMC in response to 1 μM histamine, whereas the stiffening response to 30 mM KCl was unchanged. However, Western blot analysis showed unchanged levels of calponin, smooth muscle α-actin, vinculin, and myosin. We conclude that IL-13 inhibits proliferation via the IL-13Rα2 receptor and induces hypercontractility of human ASMC without change of the phenotypic markers of contractility.

Potential role for phenotypic modulation of bronchial smooth muscle ceils in chronic asthma

1994 ◽  
Vol 72 (11) ◽  
pp. 1448-1457 ◽  
Author(s):  
Andrew J. Halayko ◽  
Newman L. Stephens
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells ◽  
Potential Contribution ◽  
Chronic Asthma ◽  
Phenotypic Modulation ◽  
Bronchial Smooth Muscle

Asthma is considered to be a chronic inflammatory disease of the airways and is highlighted by excessive airway narrowing in response to various stimuli. Subepithelial fibrosis and increased airway smooth muscle mass are characteristic pathological features of the disease. Airway remodelling in asthma involves cellular hyperplasia and hypertrophy of bronchial myocytes. Smooth muscle cells from a variety of tissues have been shown to be multifunctional mesenchymal cells capable of expressing considerable phenotypic plasticity in vivo in response to injury and pathological stimuli. The growth response of vascular smooth muscle cells following arterial injury has been fairly well characterized, and it appears many of the chemical mediators responsible are common to the inflamed bronchi seen in asthmatics. Specific studies regarding the effects of phenotypic modulation of airway smooth muscle and the potential contribution of this phenomenon to the pathogenesis of chronic asthma have not been carried out. Limited evidence, some indirect, suggests that contractile properties of smooth muscle from inflamed tissues are altered; if this is the case in asthma, then considerations of the effects of airway smooth muscle hypertrophy should be broadened beyond that of only contributing to bronchial hyperresponsiveness via an increase in bronchial wall thickness. Recruitment and modulation of smooth muscle cells to functionally different phenotypes, which contribute to fibrosis by secreting extracellular matrix materials and promote cellular hyperplasia by producing growth factors, are known to occur in atherogenic blood vessels; and evidence suggests that airway smooth muscle cells might play a similar role in asthma. We report the identification of markers of differentiation for airway smooth muscle cells. These markers should be useful tools in the elucidation of phenotypic heterogeneity of smooth muscle in asthmatic airways and, thereby, allow for the definition of a clearer role for bronchial smooth muscle cells in the pathogenesis of chronic asthma.Key words: airway smooth muscle cells, asthma, phenotype, pathogenesis, proliferation.

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