scholarly journals Rapamycin decreases airway remodeling and hyperreactivity in a transgenic model of noninflammatory lung disease

2011 ◽  
Vol 111 (6) ◽  
pp. 1760-1767 ◽  
Author(s):  
Elizabeth L. Kramer ◽  
William D. Hardie ◽  
Elizabeth M. Mushaben ◽  
Thomas H. Acciani ◽  
Patricia A. Pastura ◽  
...  
Keyword(s):  
Body Weight ◽  
Smooth Muscle ◽  
Transgenic Mice ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Airway Hyperreactivity ◽  
Lung Mechanics ◽  
Small Airways ◽  
Mrna Levels ◽  
Rapamycin Treatment

Airway hyperreactivity (AHR) and remodeling are cardinal features of asthma and chronic obstructive pulmonary disease. New therapeutic targets are needed as some patients are refractory to current therapies and develop progressive airway remodeling and worsening AHR. The mammalian target of rapamycin (mTOR) is a key regulator of cellular proliferation and survival. Treatment with the mTOR inhibitor rapamycin inhibits inflammation and AHR in allergic asthma models, but it is unclear if rapamycin can directly inhibit airway remodeling and AHR, or whether its therapeutic effects are entirely mediated through immunosuppression. To address this question, we utilized transforming growth factor-α (TGF-α) transgenic mice null for the transcription factor early growth response-1 (Egr-1) (TGF-α Tg/Egr-1ko/ko mice). These mice develop airway smooth muscle thickening and AHR in the absence of altered lung inflammation, as previously reported. In this study, TGF-α Tg/Egr-1ko/ko mice lost body weight and developed severe AHR after 3 wk of lung-specific TGF-α induction. Rapamycin treatment prevented body weight loss, airway wall thickening, abnormal lung mechanics, and increases in airway resistance to methacholine after 3 wk of TGF-α induction. Increases in tissue damping and airway elastance were also attenuated in transgenic mice treated with rapamycin. TGF-α/Egr-1ko/ko mice on doxycycline for 8 wk developed severe airway remodeling. Immunostaining for α-smooth muscle actin and morphometric analysis showed that rapamycin treatment prevented airway smooth muscle thickening around small airways. Pentachrome staining, assessments of lung collagen and fibronectin mRNA levels, indicated that rapamycin also attenuated fibrotic pathways induced by TGF-α expression for 8 wk. Thus rapamycin reduced airway remodeling and AHR, demonstrating an important role for mTOR signaling in TGF-α-induced/EGF receptor-mediated reactive airway disease.

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.

scholarly journals Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Li ◽  
Li Zhang ◽  
Francesca Polverino ◽  
Feng Guo ◽  
Yuan Hao ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Mass ◽  
Airway Smooth Muscle ◽  
Aerobic Glycolysis ◽  
Airway Remodeling ◽  
Muscle Cells ◽  
Metabolic Reprogramming ◽  
Airway Smooth Muscle Cells ◽  
Mrna Levels

AbstractAlthough HHIP locus has been consistently associated with the susceptibility to COPD including airway remodeling and emphysema in genome-wide association studies, the molecular mechanism underlying this genetic association remains incompletely understood. By utilizing Hhip+/- mice and primary human airway smooth muscle cells (ASMCs), here we aim to determine whether HHIP haploinsufficiency increases airway smooth muscle mass by reprogramming glucose metabolism, thus contributing to airway remodeling in COPD pathogenesis. The mRNA levels of HHIP were compared in normal and COPD-derived ASMCs. Mitochondrial oxygen consumption rate and lactate levels in the medium were measured in COPD-derived ASMCs with or without HHIP overexpression as readouts of glucose oxidative phosphorylation and aerobic glycolysis rates. The proliferation rate was measured in healthy and COPD-derived ASMCs treated with or without 2-DG. Smooth muscle mass around airways was measured by immunofluorescence staining for α-smooth muscle actin (α-SMA) in lung sections from Hhip+/- mice and their wild type littermates, Hhip+/+ mice. Airway remodeling was assessed in Hhip+/- and Hhip+/- mice exposed to 6 months of cigarette smoke. Our results show HHIP inhibited aerobic glycolysis and represses cell proliferation in COPD-derived ASMCs. Notably, knockdown of HHIP in normal ASMCs increased PKM2 activity. Importantly, Hhip+/- mice demonstrated increased airway remodeling and increased intensity of α-SMA staining around airways compared to Hhip+/+ mice. In conclusion, our findings suggest that HHIP represses aerobic glycolysis and ASMCs hyperplasia, which may contribute to the increased airway remodeling in Hhip+/- mice.

scholarly journals FFAR1 activation attenuates histamine-induced myosin light chain phosphorylation and cortical tension development in human airway smooth muscle cells

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Shengjie Xu ◽  
Anthony Schwab ◽  
Nikhil Karmacharya ◽  
Gaoyuan Cao ◽  
Joanna Woo ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Airway Hyperreactivity ◽  
Human Airway Smooth Muscle ◽  
Tension Development ◽  
Cortical Tension ◽  
Human Airway ◽  
Mlc Phosphorylation

Abstract Background Activation of free fatty acid receptors (FFAR1 and FFAR4) which are G protein-coupled receptors (GPCRs) with established (patho)physiological roles in a variety of obesity-related disorders, induce human airway smooth muscle (HASM) cell proliferation and shortening. We reported amplified agonist-induced cell shortening in HASM cells obtained from obese lung donors. We hypothesized that FFAR1 modulate excitation–contraction (EC) coupling in HASM cells and play a role in obesity-associated airway hyperresponsiveness. Methods In HASM cells pre-treated (30 min) with FFAR1 agonists TAK875 and GW9508, we measured histamine-induced Ca2+ mobilization, myosin light chain (MLC) phosphorylation, and cortical tension development with magnetic twisting cytometry (MTC). Phosphorylation of MLC phosphatase and Akt also were determined in the presence of the FFAR1 agonists or vehicle. In addition, the effects of TAK875 on MLC phosphorylation were measured in HASM cells desensitized to β2AR agonists by overnight salmeterol treatment. The inhibitory effect of TAK875 on MLC phosphorylation was compared between HASM cells from age and sex-matched non-obese and obese human lung donors. The mean measurements were compared using One-Way ANOVA with Dunnett’s test for multiple group comparisons or Student’s t-test two-group comparison. For cortical tension measurements by magnetic twisted cytometry, mixed effect model using SAS V.9.2 was applied. Means were considered significant when p ≤ 0.05. Results Unexpectedly, we found that TAK875, a synthetic FFAR1 agonist, attenuated histamine-induced MLC phosphorylation and cortical tension development in HASM cells. These physiological outcomes were unassociated with changes in histamine-evoked Ca2+ flux, protein kinase B (AKT) activation, or MLC phosphatase inhibition. Of note, TAK875-mediated inhibition of MLC phosphorylation was maintained in β2AR-desensitized HASM cells and across obese and non-obese donor-derived HASM cells. Conclusions Taken together, our findings identified the FFAR1 agonist TAK875 as a novel bronchoprotective agent that warrants further investigation to treat difficult-to-control asthma and/or airway hyperreactivity in obesity.

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.

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.

Consequences of thyroid hormone deficiency induced by the specific ablation of thyroid follicle cells in adult transgenic mice

1994 ◽  
Vol 143 (1) ◽  
pp. 107-120 ◽  
Author(s):  
H Wallace ◽  
K McLaren ◽  
R Al-Shawi ◽  
J O Bishop
Keyword(s):  
Body Weight ◽  
Thyroid Hormone ◽  
Transgenic Mice ◽  
Follicle Cells ◽  
Hormone Deficiency ◽  
Mrna Levels ◽  
Thyroid Follicle ◽  
Receptor Mrna ◽  
The Many ◽  
Tsh Levels

Abstract The herpes simplex type 1 virus thymidine kinase (HSV1-TK) reporter gene was coupled to a bovine thyroglobulin promoter (TG-tk construct). Within the thyroid glands of transgenic mice expression was confined to thyroid follicle cells. Infusion of Ganciclovir (9-[(1,3-dihydroxy-2-propoxy)methyl]guanine) to 8 to 12 week transgenic females led to the complete loss of thyroid HSV1-TK activity (at 3 to 4 days) and thyroid follicles (between 7 and 14 days). During the first 5 days of treatment a single reciprocal oscillation in circulating thyroxine (T4) and TSH levels occurred. By 14 days the circulating triiodothyronine (T3) and T4 levels of all treated animals were below the detection limits of the assays, while TSH levels were elevated ten-fold and continued to increase thereafter. During 14 days of treatment the thyroids regressed, protein content fell by 80–90% and the C cells, normally dispersed within the central region of each gland, came together in aggregates. Pituitary GH levels in females rose and fell back to normal within 14 days and between 14 and 28 days fell to a level comparable with that of GH-deficient lit/lit mice. The levels of hepatic GH receptor mRNA and the predominant 6·6 kb T3 receptor mRNA were unaffected by thyrocyte ablation. Thyrocyte ablation had no effect on the level of prolactin (Prl) receptor mRNA in females, but increased Prl receptor mRNA levels in males and eliminated group 1 major urinary protein (MUP) mRNA in females. T4 replacement reversed the effects of thyrocyte ablation on MUP mRNA in females and on Prl receptor mRNA in males. Despite the many physiological changes induced by thyrocyte ablation, ablated mice have been maintained for up to 1 year without thyroid hormone supplementation. T4-deficient females were normally fertile and carried pups to term. Although transgenic males expressed HSV1-TK ectopically in spermatids and spermatozoa at levels similar to thyrocyte levels, a rate of Ganciclovir infusion which successfully ablated the thyrocytes did not affect the testis. As an alternative to infusion by minipump, thyrocyte ablation could be achieved by 6 twice-daily injections of Ganciclovir, at a level of 112 μg Ganciclovir/g body weight per day, and fetuses in utero could be thyrocyte ablated by administering 50 or 15 μg/g body weight per day to pregnant females between days 14 and 18 of gestation. These data demonstrate the potential value of transgenic thyrocyte ablation in the study of the effects of thyroid hormone deprivation. Journal of Endocrinology (1994) 143, 107–120

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

scholarly journals Characterization of cystic fibrosis airway smooth muscle cell proliferative and contractile activities

2019 ◽  
Vol 317 (5) ◽  
pp. L690-L701
Author(s):  
Joyce Hojin Jang ◽  
Alice Panariti ◽  
Michael J. O’Sullivan ◽  
Melissa Pyrch ◽  
Chris Wong ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Remodeling ◽  
Airway Smooth Muscle Cell ◽  
Cystic Fibrosis Airway ◽  
Contractile Activation ◽  
Pathological Behavior

Cystic fibrosis (CF) is a genetic disease that causes multiple airway abnormalities. Two major respiratory consequences of CF are airway hyperresponsiveness (AHR) and airway remodeling. Airway smooth muscle (ASM) is hypothesized to be responsible for the airway dysfunction, since their thickening is involved in remodeling, and excessive contraction by the ASM may cause AHR. It is unclear whether the ASM is intrinsically altered to favor increased contractility or proliferation or if microenvironmental influences induce pathological behavior in vivo. In this study, we examined the contractile and proliferative properties of ASM cells isolated from healthy donor and CF transplant lungs. Assays of proliferation showed that CF ASM proliferates at a higher rate than healthy cells. Through calcium analysis, no differences in contractile activation in response to histamine were found. However, CF ASM cells lagged in their reuptake of calcium in the sarcoplasmic reticulum. The combination CFTR corrector and potentiator, VX-809/770, used to restore CFTR function in CF ASM, resulted in a reduction in proliferation and in a normalization of calcium reuptake kinetics. These results show that impaired CFTR function in ASM cells causes intrinsic changes in their proliferative and contractile properties.

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