CAT-2 amplifies the agonist-evoked force of airway smooth muscle by enhancing spermine-mediated phosphatidylinositol-(4)-phosphate-5-kinase-γ activity

2007 ◽  
Vol 293 (4) ◽  
pp. L883-L891 ◽  
Author(s):  
Hang Chen ◽  
Carol MacLeod ◽  
Bijia Deng ◽  
Lawrence Mason ◽  
Marion Kasaian ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Lung Tissue ◽  
Tracheal Ring ◽  
Isometric Tension ◽  
Maximal Dose ◽  
Lung Resistance ◽  
Evoked Force ◽  
Phosphatidylinositol 4 ◽  
Dependent Pathway

We investigated the effect the loss of the CAT-2 gene (CAT-2−/−) has on lung resistance (RL) and tracheal isometric tension. The RL of CAT-2−/− mice at a maximal dose of acetylcholine (ACh) was decreased by 33.66% ( P = 0.05, n = 8) compared with that of C57BL/6 (B6) mice. The isometric tension of tracheal rings from CAT-2−/− mice showed a significant decrease in carbachol (CCh)-induced force generation (33.01%, P < 0.05, n = 8) compared with controls. The isoproterenol- or the sodium nitroprusside-induced relaxation was not affected in tracheal rings from CAT-2−/− mice. The activity of iNOS and arginase in lung tissue lysates of CAT-2−/− mice was indistinguishable from that of B6 mice. Furthermore, the expression of phospholipase-Cβ (PLC-β) and phosphatidylinositol-( 4 )-phosphate-5-kinase-γ (PIP-5K-γ) was examined in the lung tissue of CAT-2−/− and B6 mice. The expression of PIP-5K-γ but not PLC-β was significantly reduced in CAT-2−/− compared with B6 mice. The reduced airway smooth muscle (ASM) contractility to CCh seen in the CAT-2−/− tracheal rings was completely reversed by pretreating the rings with 100 μM spermine. This increase in the CAT-2−/− tracheal ring contraction upon spermine pretreatment correlated with a recovery of the expression of PIP-5K-γ. Our data indicates that CAT-2 exerts control over ASM force development through a spermine-dependent pathway that directly correlates with the expression level of PIP-5K-γ in the lung.

Expression of dihydropyridine resistance differs in porcine bronchial and tracheal smooth muscle

1994 ◽  
Vol 267 (2) ◽  
pp. L106-L112 ◽  
Author(s):  
T. L. Croxton ◽  
C. Fleming ◽  
C. A. Hirshman
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Isometric Tension ◽  
Tracheal Smooth Muscle ◽  
Airway Smooth Muscle Cells ◽  
Channel Blockers ◽  
Response Curves ◽  
Voltage Dependent ◽  
Relaxation Responses ◽  
Ca2 Channels

Voltage-dependent and receptor-operated Ca2+ entry mechanisms have been demonstrated in airway smooth muscle, but their relative importance for maintenance of contraction is unknown. Blockade of voltage-dependent Ca2+ channels (VDC) has produced inconsistent relaxation. We postulated regional variations in Ca2+ handling by airway smooth muscle cells and compared the efficacy of dihydropyridine VDC blockers in tracheas and bronchi. Porcine tracheal smooth muscle strips and bronchial rings were mounted in tissue baths filled with physiological solutions and isometric tension was measured. Tissues were precontracted with carbachol or KCl, and relaxation dose-response curves to nifedipine, Mn2+, or Cd2+ were obtained. Relaxation responses to nifedipine were significantly different in carbachol-contracted tracheas and bronchi. Whereas carbachol-contracted tracheal muscle completely relaxed with 10(-6) M nifedipine, bronchial smooth muscle relaxed < 50%. In contrast, KCl-contracted bronchial muscle was completely relaxed by nifedipine. The nonspecific Ca2+ channel blockers Mn2+ and Cd2+ produced similar relaxation responses in each tissue. Thus VDC are the predominant mechanism for Ca2+ entry in porcine tracheal smooth muscle, but a dihydropyridine-insensitive pathway is functionally important in carbachol-contracted porcine bronchi. Regional variation may account for apparent inconsistencies between previous studies.

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 Qufeng Xuanbi Formula ameliorates airway remodeling in asthmatic mice by suppressing airway smooth muscle cells proliferation through MEK/ERK signaling pathway

2021 ◽  
Author(s):  
Bohan Wang ◽  
Lingling Tang ◽  
Suofang Shi ◽  
Ying Yang ◽  
Xianhong Sun ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Lung Tissue ◽  
Airway Remodeling ◽  
Erk Signaling ◽  
Immunofluorescent Staining ◽  
Control Group ◽  
Airway Smooth Muscle Cells ◽  
Therapeutic Effects ◽  
Protein Expressions

Abstract BackgroundAsthma is a common chronic respiratory disease. Qufeng Xuanbi Formula (QFXBF), a Chinese herbal decoction, has shown efficiency for the management of asthma. The purpose of current study is to investigate the potential therapeutic effects of QFXBF for the treatment of asthma both in vitro and in vivo. MethodsPDGF-induced ASMCs proliferation model and MTT assay have been applied for exploring the effects of QFXBF on the proliferation of ASMCs. Moreover, 40 female BALB/c mice were randomly divided into five groups: control group, OVA group, High QFXBF group, Low QFXBF group, and dexamethasone (DEX) group (n = 8 per group). The mouse allergic asthma model has been established by intranasally administered ovalbumin (OVA) sensitization method. Morphological changes of the lung tissue have been examined by hematoxylin and eosin (H&E) staining and Masson’s staining. Finally, the protein expressions of α-SMA, PCNA, p-MEK1/2, MEK1/2, p-ERK1/2, and ERK1/2 in ASMCs and lung tissue were determined by western blotting and immunofluorescent staining assays. ResultsPDGF induced significant increase in viability of ASMCs. Compared with mice in control group, the airway walls and airway smooth muscle of mice in OVA group mice thickened, and the inflammatory cells around the bronchus increased significantly. Moreover, administration of QFXBF markedly inhibited the proliferation of ASMCs and alleviated the pathologic changes induced by OVA. Furthermore, the protein expressions of p-ERK1/2, p-MEK1/2, PCNA, and α-SMA were significantly increased in OVA-treated mice and PDGF-treated ASMCs. Finally, treatment of QFXBF also significantly decreased the protein expression of p-ERK1/2, p-MEK1/2, α-SMA and PCNA. ConclusionQFXBF can inhibit the proliferation of ASMCs via suppressing the MEK/ERK signaling in PDGF-induced ASMCs and OVA-induced mice.

scholarly journals Androgens are bronchoactive drugs that act by relaxing airway smooth muscle and preventing bronchospasm

2014 ◽  
Vol 222 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Luis M Montaño ◽  
Julia Espinoza ◽  
Edgar Flores-Soto ◽  
Jaime Chávez ◽  
Mercedes Perusquía
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Calcium Binding ◽  
No Synthase ◽  
Preventive Effect ◽  
Site Of Action ◽  
Isolated Trachea ◽  
Underlying Mechanisms ◽  
Synthase Inhibitor ◽  
Dependent Pathway

Changes in the androgen levels in asthmatic men may be associated with the severity of asthma. Androgens induce a nongenomic relaxation in airway smooth muscle, but the underlying mechanisms remain unclear. The aim of this study was to investigate the potential bronchorelaxing action of testosterone (TES) and its metabolites (5α- and 5β-dihydrotestosterone (DHT). A preventive effect on ovalbumin (OVA)-induced bronchospasm was observed in sensitized guinea pigs for each androgen. Androgens were studied in response to bronchoconstrictors: carbachol (CCh) and KCl in isolated trachea rings with and without epithelium from non-sensitized and sensitized animals as well as on OVA-induced contraction. Androgens concentration-dependently abolished the contraction in response to CCh, KCl, and OVA. There were significant differences in the sensitivity to the relaxation induced by each androgen. 5β-DHT was more potent for relaxing KCl-induced contraction, while TES and 5α-DHT were more potent for CCh- and OVA-induced contraction. No differences were found in preparations with and without epithelium or in the presence of a nitric oxide (NO) synthase inhibitor or an inhibitor of K+channels. These data indicate the absence of involvement of the epithelium-, NO- and K+channels-dependent pathway in androgen-induced relaxation. However, in dissociated tracheal myocytes loaded with the calcium-binding fluorescent dye Fura -2, physiological concentrations of androgens decreased the KCl-induced [Ca2+]iincrement. 5β-DHT was the most potent at decreasing KCl-induced [Ca2+]iincrement and preventing bronchospasm. We suggest that androgen-induced brochorelaxation was mediated via decreased Ca2+influx through L-type Ca2+channels but additional Ca2+entry blockade may be involved. Molecular changes in androgen structure may determine its preferential site of action.

scholarly journals A-kinase-anchoring proteins coordinate inflammatory responses to cigarette smoke in airway smooth muscle

2015 ◽  
Vol 308 (8) ◽  
pp. L766-L775 ◽  
Author(s):  
Wilfred J. Poppinga ◽  
Irene H. Heijink ◽  
Laura J. Holtzer ◽  
Philipp Skroblin ◽  
Enno Klussmann ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cigarette Smoke ◽  
Airway Smooth Muscle ◽  
Lung Tissue ◽  
Inflammatory Responses ◽  
Camp Signaling ◽  
Chronic Obstructive ◽  
Mrna Levels ◽  
Anchoring Proteins

β2-Agonist inhibitors can relieve chronic obstructive pulmonary disease (COPD) symptoms by stimulating cyclic AMP (cAMP) signaling. A-kinase-anchoring proteins (AKAPs) compartmentalize cAMP signaling by establishing protein complexes. We previously reported that the β2-agonist fenoterol, direct activation of protein kinase A (PKA), and exchange factor directly activated by cAMP decrease cigarette smoke extract (CSE)-induced release of neutrophil attractant interleukin-8 (IL-8) from human airway smooth muscle (ASM) cells. In the present study, we tested the role of AKAPs in CSE-induced IL-8 release from ASM cells and assessed the effect of CSE on the expression levels of different AKAPs. We also studied mRNA and protein expression of AKAPs in lung tissue from patients with COPD. Our data show that CSE exposure of ASM cells decreases AKAP5 and AKAP12, both capable of interacting with β2-adrenoceptors. In lung tissue of patients with COPD, mRNA levels of AKAP5 and AKAP12 were decreased compared with lung tissue from controls. Using immunohistochemistry, we detected less AKAP5 protein in ASM of patients with COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II compared with control subjects. St-Ht31, which disrupts AKAP-PKA interactions, augmented CSE-induced IL-8 release from ASM cells and diminished its suppression by fenoterol, an effect mediated by disturbed ERK signaling. The modulatory role of AKAP-PKA interactions in the anti-inflammatory effects of fenoterol in ASM cells and the decrease in expression of AKAP5 and AKAP12 in response to cigarette smoke and in lungs of patients with COPD suggest that cigarette smoke-induced changes in AKAP5 and AKAP12 in patients with COPD may affect efficacy of pharmacotherapy.

S-nitrosoglutathione breakdown prevents airway smooth muscle relaxation in the guinea pig

2000 ◽  
Vol 279 (4) ◽  
pp. L716-L721 ◽  
Author(s):  
Kezhong Fang ◽  
Roger Johns ◽  
Timothy Macdonald ◽  
Michael Kinter ◽  
Benjamin Gaston
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Airway Smooth Muscle ◽  
Muscle Tone ◽  
Muscle Relaxation ◽  
Tracheal Ring ◽  
Protein Fractions ◽  
Smooth Muscle Relaxation ◽  
Smooth Muscle Tone ◽  
Catabolic Activity

Airway levels of the endogenous bronchodilator S-nitrosoglutathione (GSNO) are low in children with near-fatal asthma. We hypothesized that GSNO could be broken down in the lung and that this catabolism could inhibit airway smooth muscle relaxation. In our experiments, GSNO was broken down by guinea pig lung homogenates, particularly after ovalbumin sensitization (OS). Two lung protein fractions had catabolic activity. One was NADPH dependent and was more active after OS. The other was NADPH independent and was partially inhibited by aurothioglucose. Guinea pig lung tissue protein fractions with GSNO catabolic activity inhibited GSNO-mediated guinea pig tracheal ring relaxation. The relaxant effect of GSNO was partially restored by aurothioglucose. These observations suggest that catabolism of GSNO in the guinea pig 1) is mediated by lung proteins, 2) is partially upregulated after OS, and 3) may contribute to increased airway smooth muscle tone. We speculate that enzymatic breakdown of GSNO in the lung could contribute to asthma pathophysiology by inhibiting the beneficial effects of GSNO, including its effect on airway smooth muscle tone.

Enhanced nitric oxide production associated with airway hyporesponsiveness in the absence of IL-10

2005 ◽  
Vol 288 (5) ◽  
pp. L868-L873 ◽  
Author(s):  
Bill T. Ameredes ◽  
Jigme M. Sethi ◽  
He-Liang Liu ◽  
Augustine M. K. Choi ◽  
William J. Calhoun
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Tracheal Ring ◽  
No Production ◽  
Muscle Contractility ◽  
Smooth Muscle Contractility ◽  
Nos Inhibitors

Interleukin (IL)-10 is an anti-inflammatory cytokine implicated in the regulation of airway inflammation in asthma. Among other activities, IL-10 suppresses production of nitric oxide (NO); consequently, its absence may permit increased NO production, which can affect airway smooth muscle contractility. Therefore, we investigated airway reactivity (AR) in response to methacholine (MCh) in IL-10 knockout (−/−) mice compared with wild-type C57BL/6 (C57) mice, in which airway NO production was measured as exhaled NO (ENO), and NO production was altered with administration of either NO synthase (NOS)-specific inhibitors or recombinant murine (rm)IL-10. AR, measured as enhanced pause in vivo, and tracheal ring tension in vitro were lower in IL-10−/− mice by 25–50%, which was associated with elevated ENO levels (13 vs. 7 ppb). Administration of NOS inhibitors NG-nitro-l-arginine methyl ester (8 mg/kg ip) or l- N6-(1-iminoethyl)-lysine (3 mg/kg ip) to IL-10−/− mice decreased ENO by an average of 50%, which was associated with increased AR, to levels similar to C57 mice. ENO in IL-10−/− mice decreased in a dose-dependent fashion in response to administered rmIL-10, to levels similar to C57 mice (7 ppb), which was associated with a 30% increment in AR. Thus increased NO production in the absence of IL-10, decreased AR, which was reversed with inhibition of NO, either by inhibition of NOS, or with reconstitution of IL-10. These findings suggest that airway NO production can modulate airway smooth muscle contractility, resulting in airway hyporesponsiveness when IL-10 is absent.

Myosin cross-bridge kinetics in airway smooth muscle: a comparative study of humans, rats, and rabbits

2002 ◽  
Vol 282 (1) ◽  
pp. L83-L90 ◽  
Author(s):  
Y. Lecarpentier ◽  
F.-X. Blanc ◽  
S. Salmeron ◽  
J.-C. Pourny ◽  
D. Chemla ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Comparative Study ◽  
Mechanical Behavior ◽  
Airway Smooth Muscle ◽  
Rate Constants ◽  
Species Differences ◽  
Isometric Tension ◽  
New Formalism ◽  
Cross Bridge ◽  
Cross Bridges

To analyze the kinetics and unitary force of cross bridges (CBs) in airway smooth muscle (ASM), we proposed a new formalism of Huxley's equations adapted to nonsarcomeric muscles (Huxley AF. Prog Biophys Biophys Chem7: 255–318, 1957). These equations were applied to ASM from rabbits, rats, and humans ( n = 12/group). We tested the hypothesis that species differences in whole ASM mechanics were related to differences in CB mechanics. We calculated the total CB number per square millimeter at peak isometric tension (Ψ ×109), CB unitary force (Π), and the rate constants for CB attachment ( f 1) and detachment ( g 1 and g 2). Total tension, Ψ, and Π were significantly higher in rabbits than in humans and rats. Values of Π were 8.6 ± 0.1 pN in rabbits, 7.6 ± 0.3 pN in humans, and 7.7 ± 0.2 pN in rats. Values of Ψ were 4.0 ± 0.5 in rabbits, 1.2 ± 0.1 in humans, and 1.9 ± 0.2 in rats; f 1 was lower in humans than in rabbits and rats; g 2 was higher in rabbits than in rats and in rats than in humans. In conclusion, ASM mechanical behavior of different species was characterized by specific CB kinetics and CB unitary force.

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