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.

TGF-β enhances deposition of perlecan from COPD airway smooth muscle

2012 ◽  
Vol 302 (3) ◽  
pp. L325-L333 ◽  
Author(s):  
Yukikazu Ichimaru ◽  
David I. Krimmer ◽  
Janette K. Burgess ◽  
Judith L. Black ◽  
Brian G. G. Oliver
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Signaling Molecules ◽  
Collagen I ◽  
Chronic Obstructive ◽  
Airway Smooth Muscle Cells ◽  
Organ Systems

Chronic obstructive pulmonary disease (COPD) and asthma are characterized by irreversible remodeling of the airway walls, including thickening of the airway smooth muscle layer. Perlecan is a large, multidomain, proteoglycan that is expressed in the lungs, and in other organ systems, and has been described to have a role in cell adhesion, angiogenesis, and proliferation. This study aimed to investigate functional properties of the different perlecan domains in relation to airway smooth muscle cells (ASMC). Primary human ASMC obtained from donors with asthma ( n = 13), COPD ( n = 12), or other lung disease ( n = 20) were stimulated in vitro with 1 ng/ml transforming growth factor-β1 (TGF-β1) before perlecan deposition and cytokine release were analyzed. In some experiments, inhibitors of signaling molecules were added. Perlecan domains I–V were seeded on tissue culture plates at 10 μg/ml with 1 μg/ml collagen I as a control. ASM was incubated on top of the peptides before being analyzed for attachment, proliferation, and wound healing. TGF-β1 upregulated deposition of perlecan by ASMC from COPD subjects only. TGF-β1 upregulated release of IL-6 into the supernatant of ASMC from all subjects. Inhibitors of SMAD and JNK signaling molecules decreased TGF-β1-induced perlecan deposition by COPD ASMC. Attachment of COPD ASMC was upregulated by collagen I and perlecan domains IV and V, while perlecan domain II upregulated attachment only of asthmatic ASMC. Seeding on perlecan domains did not increase proliferation of any ASMC type. TGF-β1-induced perlecan deposition may enhance attachment of migrating ASMC in vivo and thus may be a mechanism for ASMC layer hypertrophy in COPD.

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

Thromboxane A2 induces airway constriction through an M3 muscarinic acetylcholine receptor-dependent mechanism

2006 ◽  
Vol 290 (3) ◽  
pp. L526-L533 ◽  
Author(s):  
Irving C. Allen ◽  
John M. Hartney ◽  
Thomas M. Coffman ◽  
Raymond B. Penn ◽  
Jürgen Wess ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Acetylcholine Receptor ◽  
Airway Smooth Muscle ◽  
Muscle Tension ◽  
Muscarinic Acetylcholine Receptor ◽  
Airway Smooth Muscle Cells ◽  
Muscarinic Acetylcholine ◽  
Airway Constriction ◽  
Organ Systems ◽  
Lung Resistance

Thromboxane A2 (TXA2) is a potent lipid mediator released by platelets and inflammatory cells and is capable of inducing vasoconstriction and bronchoconstriction. In the airways, it has been postulated that TXA2 causes airway constriction by direct activation of thromboxane prostanoid (TP) receptors on airway smooth muscle cells. Here we demonstrate that although TXA2 can mediate a dramatic increase in airway smooth muscle constriction and lung resistance, this response is largely dependent on vagal innervation of the airways and is highly sensitive to muscarinic acetylcholine receptor (mAChR) antagonists. Further analyses employing pharmacological and genetic strategies demonstrate that TP-dependent changes in lung resistance and airway smooth muscle tension require expression of the M3 mAChR subtype. These results raise the possibility that some of the beneficial actions of anticholinergic agents used in the treatment of asthma and chronic obstructive pulmonary disease result from limiting physiological changes mediated through the TP receptor. Furthermore, these findings demonstrate a unique pathway for TP regulation of homeostatic mechanisms in the airway and suggest a paradigm for the role of TXA2 in other organ systems.

scholarly journals TGF-β regulates Nox4, MnSOD and catalase expression, and IL-6 release in airway smooth muscle cells

2011 ◽  
Vol 300 (2) ◽  
pp. L295-L304 ◽  
Author(s):  
Charalambos Michaeloudes ◽  
Maria B. Sukkar ◽  
Nadia M. Khorasani ◽  
Pankaj K. Bhavsar ◽  
Kian Fan Chung
Keyword(s):  
Smooth Muscle ◽  
Antioxidant Enzymes ◽  
Airway Smooth Muscle ◽  
Manganese Superoxide Dismutase ◽  
Redox Regulation ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Chronic Obstructive ◽  
Airway Smooth Muscle Cells ◽  
Nadph Oxidase 4

Reactive oxygen species (ROS) are generated as a result of normal cellular metabolism, mainly through the mitochondria and peroxisomes, but their release is enhanced by the activation of oxidant enzymes such as NADPH oxidases or downregulation of endogenous antioxidant enzymes such as manganese-superoxide dismutase (MnSOD) and catalase. Transforming growth factor-β (TGF-β), found to be overexpressed in airway smooth muscle (ASM) from asthmatic and chronic obstructive pulmonary disease patients, may be a pivotal regulator of abnormal ASM cell (ASMC) function in these diseases. An important effect of TGF-β on ASMC inflammatory responses is the induction of IL-6 release. TGF-β also triggers intracellular ROS release in ASMCs by upregulation of NADPH oxidase 4 (Nox4). However, the effect of TGF-β on the expression of key antioxidant enzymes and subsequently on oxidant/antioxidant balance is unknown. Moreover, the role of redox-dependent pathways in the mediation of the proinflammatory effects of TGF-β in ASMCs is unclear. In this study, we show that TGF-β induced the expression of Nox4 while at the same time inhibiting the expression of MnSOD and catalase. This change in oxidant/antioxidant enzymes was accompanied by elevated ROS levels and IL-6 release. Further studies revealed a role for Smad3 and phosphatidyl-inositol kinase-mediated pathways in the induction of oxidant/antioxidant imbalance and IL-6 release. The changes in oxidant/antioxidant enzymes and IL-6 release were reversed by the antioxidants N-acetyl-cysteine (NAC) and ebselen through inhibition of Smad3 phosphorylation, indicating redox-dependent activation of Smad3 by TGF-β. Moreover, these findings suggest a potential role for NAC in preventing TGF-β-mediated pro-oxidant and proinflammatory responses in ASMCs. Knockdown of Nox4 using small interfering RNA partially prevented the inhibition of MnSOD but had no effect on catalase and IL-6 expression. These findings provide novel insights into redox regulation of ASM function by TGF-β.

Platelet-Derived Growth Factors (PDGFs) are Key Players in the Stimulation of Airway Smooth Muscle Cells (ASMCs) Alteration in Asthma and Chronic Obstructive Pulmonary Disease (COPD) with Multifarious Inhibitors at an Early Stage of Development

2020 ◽  
Vol 17 (4) ◽  
pp. 324-332
Author(s):  
Xiaodong Shi ◽  
Kwaku Appiah-Kubi
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Smooth Muscle ◽  
Growth Factors ◽  
Smooth Muscle Cells ◽  
Pulmonary Disease ◽  
Airway Smooth Muscle ◽  
Muscle Cells ◽  
Chronic Obstructive ◽  
Airway Smooth Muscle Cells ◽  
Obstructive Pulmonary Disease

Background: Alterations in airway smooth muscle cells cause an increase in their mass and result in a significant impact on airway remodeling diseases such as asthma and chronic obstructive pulmonary disease. Several studies have used platelet-derived growth factors to stimulate the alterations of airway smooth muscle cells. Objective: This review discusses the platelet-derived growth factor-stimulated alterations of airway smooth muscle cells, diversity of inhibitors and inhibitory actions against these alterations and their related mechanisms, and how this diversity presents an avenue for the development of multifarious therapeutic targets for airway remodeling diseases especially asthma and chronic obstructive pulmonary disease. Methods: A comprehensive search of PubMed and Medscape database for studies that investigated the stimulation of the alterations of airway smooth muscle cells in asthma and chronic obstructive pulmonary disease by platelet-derived growth factors and inhibitions of these alterations. Results: Marked platelet-derived growth factor-stimulated alterations of airway smooth muscle cells are proliferation, migration and proliferative phenotype with diverse inhibitors and inhibitory actions against these alterations. Inhibitory actions are the result of the activation of protein kinase, overexpression of Tripartite motif protein, human transporter sub-family ABCA1 protein and miRNAs, knockdown of an isoform of reticulon 4 and follistatin protein, exogenous applications of recombinant proteins, supplements and active metabolite of retinoic acid, flavonoid extracts and polysaccharides extract. Conclusion: The multifarious inhibitors and inhibitory actions with varied mechanisms in platelet-derived growth factors-stimulated alterations of airway smooth muscle cells present a potential for diverse therapeutic targets for the treatment of airway remodeling diseases.

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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