Ginger metabolites and metabolite-inspired synthetic products modulate intracellular calcium and relax airway smooth muscle

2021 ◽  
Author(s):  
Elvedin Lukovic ◽  
Jose F Perez-Zoghbi ◽  
Yi Zhang ◽  
Yingdong Zhu ◽  
Shengmin Sang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Intracellular Calcium ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Symptom Control ◽  
Parent Compound ◽  
Continuous Treatment ◽  
Bioactive Component ◽  
Physiologic Activity ◽  
Synthetic Derivatives

Asthma affects millions of people worldwide and its prevalence is increasing. It is characterized by chronic airway inflammation, airway remodeling, and pathologic bronchoconstriction, and it poses a continuous treatment challenge with very few new therapeutics available. Thus, many asthmatics turn to plant-based complementary products, including ginger, for better symptom control, indicating an unmet needed for novel therapies. Previously, we demonstrated that 6-shogaol (6S), the primary bioactive component of ginger, relaxes human airway smooth muscle (hASM) likely by inhibition of phosphodiesterases (PDEs) in the b-adrenergic (cyclic nucleotide PDEs) and muscarinic (phospholipase C, PLC) receptor pathways. However, oral 6S is extensively metabolized and it is unknown if the resulting metabolites remain bioactive. Here we screened all the known human metabolites of 6S and several metabolite-based synthetic derivatives to better understand their mechanism of action and structure-function relationships. We demonstrate that several metabolites and metabolite-based synthetic derivatives are able to prevent Gq-coupled stimulation of intracellular calcium [Ca2+]i and inositol triphosphate (IP3) synthesis by inhibiting PLC, similar to the parent compound 6S. We also show that these compounds prevent re-contraction of ASM after b-agonist relaxation likely by inhibiting PDEs. Furthermore, they potentiate isoproterenol-induced relaxation. Importantly, moving beyond cell-based assays, metabolites also retain the functional ability to relax Gq-coupled-contractions in upper (human) and lower (murine) airways. The current study indicates that, although oral ginger may be metabolized rapidly, it retains physiologic activity through its metabolites. Moreover, we are able to use naturally occurring metabolites as inspiration to develop novel therapeutics for brochoconstrictive diseases.

scholarly journals Estrogen receptors differentially regulate intracellular calcium handling in human nonasthmatic and asthmatic airway smooth muscle cells

2020 ◽  
Vol 318 (1) ◽  
pp. L112-L124 ◽  
Author(s):  
Sangeeta Bhallamudi ◽  
Jennifer Connell ◽  
Christina M Pabelick ◽  
Y. S. Prakash ◽  
Venkatachalem Sathish
Keyword(s):  
Smooth Muscle ◽  
Estrogen Receptors ◽  
Intracellular Calcium ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Clinical Findings ◽  
Calcium Handling ◽  
Airway Smooth Muscle Cells ◽  
Adult Women ◽  
Channel Inhibition

Asthma is defined as chronic inflammation of the airways and is characterized by airway remodeling, hyperresponsiveness, and acute bronchoconstriction of airway smooth muscle (ASM) cells. Clinical findings suggest a higher incidence and severity of asthma in adult women, indicating a concrete role of sex steroids in modulating the airway tone. Estrogen, a major female sex steroid mediates its role through estrogen receptors (ER) ERα and ERβ, which are shown to be expressed in human ASM, and their expression is upregulated in lung inflammation and asthma. Previous studies suggested rapid, nongenomic signaling of estrogen via ERs reduces intracellular calcium ([Ca2+]i), thereby promoting relaxation of ASM. However, long-term ER activation on [Ca2+]i regulation in human ASM during inflammation or in asthma is still not known. In Fura-2-loaded nonasthmatic and asthmatic human ASM cells, we found that prolonged (24 h) exposure to ERα agonist (PPT) increased [Ca2+]i response to histamine, whereas ERβ activation (WAY) led to decreased [Ca2+] compared with vehicle. This was further confirmed by ER overexpression and knockdown studies using various bronchoconstrictor agents. Interestingly, ERβ activation was more effective than 17β-estradiol in reducing [Ca2+]i responses in the presence of TNF-α or IL-13, while no observable changes were noticed with PPT in the presence of either cytokine. The [Ca2+]i-reducing effects of ERβ were mediated partially via L-type calcium channel inhibition and increased Ca2+ sequestration by sarcoplasmic reticulum. Overall, these data highlight the differential signaling of ERα and ERβ in ASM during inflammation. Specific ERβ activation reduces [Ca2+]i in the inflamed ASM cells and is likely to play a crucial role in regulating ASM contractility, thereby relaxing airways.

scholarly journals Persistent Airflow Obstruction: A Marker of a Severe Asthma Cohort – Inflammatory, Functional and Pathological Features

2021 ◽  
Author(s):  
Regina Maria Carvalho-Pinto ◽  
Rodrigo Abensur Athanazio ◽  
Diogenes Seraphin Ferreira ◽  
Thais Mauad ◽  
Marisa Dolhnikoff ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Severe Asthma ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Symptom Control ◽  
Airflow Obstruction ◽  
Small Airways ◽  
High Resolution Computed Tomography ◽  
Muscle Area ◽  
Asthma Control Questionnaire

Abstract In our previous severe asthma cohort, 82% had fixed obstruction. Although they had greater airway smooth muscle area with decreased periostin, inflammation and remodeling weren’t associated with symptom control. High-resolution computed tomography (HRCT) and measures of small airways could be important tools for exploring asthma severity. Our aim was to describe characteristics associated to airflow obstruction in our non-controlled severe asthmatics according to obstruction profile. Persistent obstruction subgroups were also evaluated comparing disease severity. Methods: Patients were evaluated using asthma control questionnaire, induced sputum, spirometry, plethysmography, and Single Breath N2 washout test, at baseline, after oral corticosteroid (OC) and at the end of the treatment. They also underwent thorax HRCT and bronchoscopy with endobronchial biopsy.Results: Sixty-two were included and 77.4% classified as having persistent obstruction; 75% and 25% with moderate and severe obstruction, respectively. Pulmonary function values (FEV1) improved in both subgroups, except in severe. Patients with bronchial thickening, according to RB1 WA% and pi10, had significantly higher airway smooth muscle area.Conclusion: Patients with severe obstruction had greater lung function impairment, no response to OC or bronchodilator. This could be explained by airway remodeling characterized by higher airway smooth muscle area and bronchial thickness assessed by thorax HRCT.

Urokinase potentiates PDGF-induced chemotaxis of human airway smooth muscle cells

2003 ◽  
Vol 284 (6) ◽  
pp. L1020-L1026 ◽  
Author(s):  
Stephen M. Carlin ◽  
Michael Roth ◽  
Judith L. Black
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Kinase Inhibitor ◽  
Airway Remodeling ◽  
Muscle Cells ◽  
Mek Inhibitor ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway

We investigated the chemotactic action of PDGF and urokinase on human airway smooth muscle (HASM) cells in culture. Cells were put in collagen-coated transwells with 8-μm perforations, incubated for 4 h with test compounds, then fixed, stained, and counted as migrated nuclei by microscopy. Cells from all culture conditions showed some basal migration (migration in the absence of stimuli during the assay), but cells preincubated for 24 h in 10% FBS or 20 ng/ml PDGF showed higher basal migration than cells quiesced in 1% FBS. PDGFBB, PDGFAA, and PDGFABwere all chemotactic when added during the assay. PDGF chemotaxis was blocked by the phosphatidyl 3′-kinase inhibitor LY-294002, the MEK inhibitor U-0126, PGE2, formoterol, pertussis toxin, and the Rho kinase inhibitor Y-27632. Urokinase alone had no stimulatory effect on migration of quiescent cells but caused a dose-dependent potentiation of chemotaxis toward PDGF. Urokinase also potentiated the elevated basal migration of cells pretreated in 10% FBS or PDGF. This potentiating effect of urokinase appears to be novel. We conclude that PDGF and similar cytokines may be important factors in airway remodeling by redistribution of smooth muscle cells during inflammation and that urokinase may be important in potentiating the response.

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.

Isotonic relaxation of control and sensitized airway smooth muscle

2005 ◽  
Vol 83 (10) ◽  
pp. 941-951 ◽  
Author(s):  
N L Stephens ◽  
A Fust ◽  
H Jiang ◽  
W Li ◽  
X Ma
Keyword(s):  
Smooth Muscle ◽  
Intracellular Calcium ◽  
Airway Smooth Muscle ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Phase Iii ◽  
Contractile Element ◽  
Second Phase ◽  
Half Time ◽  
Phase Phase

Smooth muscle relaxation has most often been studied in isometric mode. However, this only tells us about the stiffness properties of the bronchial wall and thus only about wall capacitative properties. It tells us little about airflow. To study the latter, which of course is the meaningful parameter in regulation of ventilation and in asthma, we studied isotonic shortening of bronchial smooth muscle (BSM) strips. Failure of BSM to relax could be another important factor in maintaining high airway resistance. To analyze relaxation curves, we developed an index of isotonic relaxation, t1/2(P, lCE), which is the half-time for relaxation that is independent of muscle load (P) and of initial contractile element length (lCE). This index was measured in curves of relaxation initiated at 2 s (normally cycling crossbridges) and at 10 s (latch-bridges). At 10 s no difference was seen for adjusted t1/2(P, lCE) between curves obtained from control and sensitized BSM, (8.38 ± 0.92 s vs. 7.78 ± 0.93 s, respectively). At 2 s the half-time was almost doubled in the sensitized BSM (6.98 ± 0.01 s (control) vs. 12.74 ± 2.5 s (sensitized)). Thus, changes in isotonic relaxation are only seen during early contraction. Using zero load clamps, we monitored the time course of velocity during relaxation and noted that it varied according to 3 phases. The first phase (phase i) immediately followed cessation of electrical field stimulation (EFS) at 10 s and showed almost the same velocity as during the latter 1/3 of shortening; the second phase (phase ii) was linear in shape and is associated with zero load velocity, we speculate it could stem from elastic recoil of the cells' internal resistor; and the third phase (phase iii) was convex downwards. The zero load velocities in phase iii showed a surprising spontaneous increase suggesting reactivation of the muscle. Measurements of intracellular calcium (Fura-2 study) and of phosphorylation of the 20 kDa myosin light chain showed simultaneous increments, indicating phase iii represented an active process. Studies are under way to determine what changes occur in these 3 phases in a sensitized muscle. And of course, in the context of this conference, just what role the plastic properties of the muscle play in relaxation requires serious consideration.Key words: airway smooth muscle, sensitized smooth muscle, isotonic relaxation, intracellular calcium transients, myosin light chain (20 kDa) phosphorylation.

Overexpression of human Hsp27 inhibits serum-induced proliferation in airway smooth muscle myocytes and confers resistance to hydrogen peroxide cytotoxicity

2007 ◽  
Vol 293 (5) ◽  
pp. L1194-L1207 ◽  
Author(s):  
Sonemany Salinthone ◽  
Mariam Ba ◽  
Lisa Hanson ◽  
Jody L. Martin ◽  
Andrew J. Halayko ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Cell Death ◽  
Smooth Muscle ◽  
Cell Survival ◽  
Airway Smooth Muscle ◽  
Apoptotic Cell ◽  
Airway Remodeling ◽  
Small Heat Shock Protein ◽  
Nonmuscle Cells ◽  
Myocyte Proliferation

Airway smooth muscle (ASM) hypertrophy and hyperplasia are characteristics of asthma that lead to thickening of the airway wall and obstruction of airflow. Very little is known about mechanisms underlying ASM remodeling, but in vascular smooth muscle, it is known that progression of atherosclerosis depends on the balance of myocyte proliferation and cell death. Small heat shock protein 27 (Hsp27) is antiapoptotic in nonmuscle cells, but its role in ASM cell survival is unknown. Our hypothesis was that phosphorylation of Hsp27 may regulate airway remodeling by modifying proliferation, cell survival, or both. To test this hypothesis, adenoviral vectors were used to overexpress human Hsp27 in ASM cells. Cells were infected with empty vector (Ad5) or wild-type Hsp27 (AdHsp27 WT), and proliferation and death were assessed. Overexpressing Hsp27 WT caused a 50% reduction in serum-induced proliferation and increased cell survival after exposure to 100 μM hydrogen peroxide (H2O2) compared with mock-infected controls. Overexpression studies utilizing an S15A, S78A, and S82A non-phosphorylation mutant (AdHsp27 3A) and an S15D, S78D, and S82D pseudo-phosphorylation mutant (AdHsp27 3D) showed phosphorylation of Hsp27 was necessary for regulation of ASM proliferation, but not survival. Hsp27 provided protection against H2O2-induced cytotoxicity by upregulating cellular glutathione levels and preventing necrotic cell death, but not apoptotic cell death. The results support the notion that ASM cells can be stimulated to undergo proliferation and death and that Hsp27 may regulate these processes, thereby contributing to airway remodeling in asthmatics.

scholarly journals Scopoletin inhibits PDGF-BB-induced proliferation and migration of airway smooth muscle cells by regulating NF-κκB signaling pathway

2022 ◽  
Vol 50 (1) ◽  
pp. 92-98
Author(s):  
Zhongxiang Fan ◽  
Dan Tang ◽  
Qiang Wu ◽  
Qun Huang ◽  
Jie Song ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Signaling Pathway ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Muscle Cells ◽  
Chronic Inflammatory Disease ◽  
Migration And Invasion ◽  
Airway Smooth Muscle Cells ◽  
And Migration

Background: Asthma is a common chronic inflammatory disease of the airway, and airway remodeling and the proliferation mechanism of airway smooth muscle cells (ASMCs) is of great significance to combat this disease.Objective: To assess possible effects of scopoletin on asthma and the potential signaling pathway.Materials and methods: ASMCs were treated PDGF-BB and scopoletin and subjected to cell viability detection by CCK-8 assay. Cell migration of ASMCs was determined by a wound closure assay and transwell assay. The protein level of MMP2, MMP9, calponin and α-SMA were measured using western blot. The levels of NF-κB signaling pathway were detected by Western blotting.Results: Scopoletin inhibited proliferation of PDGF-BB - induced ASMCs. Also it suppressed the migration and invasion of PDGF-BB - induced ASMCs. We further showed that Scopoletin regulated phenotypic transition of ASMCs. Mechanically, Scopoletin inhibited proliferation and invasion of ASMCs by regulating NF-κB signaling pathway.Conclusions: We therefore thought Scopoletin could serve as a promising drug for the treatment of asthma.

Airway smooth muscle: A modulator of airway remodeling in asthma

2005 ◽  
Vol 116 (3) ◽  
pp. 488-495 ◽  
Author(s):  
Aili L. Lazaar ◽  
Reynold A. Panettieri Jr.
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Remodeling
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