scholarly journals Dexamethasone rescues TGF-β1-mediated β2-adrenergic receptor dysfunction and attenuates phosphodiesterase 4D expression in human airway smooth muscle cells

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Elena Chung ◽  
Christie A. Ojiaku ◽  
Gaoyuan Cao ◽  
Vishal Parikh ◽  
Brian Deeney ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Adrenergic Receptor ◽  
Airway Smooth Muscle Cells ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Phosphodiesterase 4D ◽  
Camp Levels ◽  
Tgf Β1

Abstract Glucocorticoids (GCs) and β2-adrenergic receptor (β2AR) agonists improve asthma outcomes in most patients. GCs also modulate gene expression in human airway smooth muscle (HASM), thereby attenuating airway inflammation and airway hyperresponsiveness that define asthma. Our previous studies showed that the pro-fibrotic cytokine, transforming growth factor- β1 (TGF-β1) increases phosphodiesterase 4D (PDE4D) expression that attenuates agonist-induced levels of intracellular cAMP. Decreased cAMP levels then diminishes β2 agonist-induced airway relaxation. In the current study, we investigated whether glucocorticoids reverse TGF-β1-effects on β2-agonist-induced bronchodilation and modulate pde4d gene expression in HASM. Dexamethasone (DEX) reversed TGF-β1 effects on cAMP levels induced by isoproterenol (ISO). TGF-β1 also attenuated G protein-dependent responses to cholera toxin (CTX), a Gαs stimulator downstream from the β2AR receptor. Previously, we demonstrated that TGF-β1 treatment increased β2AR phosphorylation to induce hyporesponsiveness to a β2 agonist. Our current data shows that expression of grk2/3, kinases associated with attenuation of β2AR function, are not altered with TGF-β1 stimulation. Interestingly, DEX also attenuated TGF-β1-induced pde4d gene expression. These data suggest that steroids may be an effective therapy for treatment of asthma patients whose disease is primarily driven by elevated TGF-β1 levels.

Modulation of epidermal growth factor receptor binding to human airway smooth muscle cells by glucocorticoids and β2-adrenergic receptor agonists

2009 ◽  
Vol 296 (4) ◽  
pp. L693-L699 ◽  
Author(s):  
Karen M. Kassel ◽  
Nancy A. Schulte ◽  
Myron L. Toews
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Adrenergic Receptor ◽  
Lung Fibroblasts ◽  
Airway Smooth Muscle Cells ◽  
Protein Synthesis Inhibitor ◽  
Egf Receptors ◽  
Human Airway Smooth Muscle ◽  
Synthesis Inhibitor ◽  
Human Airway

EGF receptors (EGFRs) are increased in airway smooth muscle in asthma, which may contribute to both their hyperproliferation and hypercontractility. Lysophosphatidic acid (LPA) is a candidate pathological agent in asthma and other airway diseases, and LPA upregulates EGFRs in human airway smooth muscle (HASM) cells. We tested whether therapeutic glucocorticoids and/or β2-adrenergic receptor (β2AR) agonists also alter EGFR binding in HASM cells. Exposure to glucocorticoids for 24 h induced a twofold increase in EGFR binding similar to that with LPA; fluticasone was markedly more potent than dexamethasone. The increase in EGFR binding by glucocorticoids required 24-h exposure, consistent with transcription-mediated effects. Although the increase in EGFR binding was blocked by the protein synthesis inhibitor cycloheximide for LPA, fluticasone, and dexamethasone, only LPA induced a significant increase in EGFR protein expression detected by immunoblotting. In contrast to the increased binding induced by the glucocorticoids, the β2AR agonists isoproterenol, albuterol, and salmeterol all induced a decrease in EGFR binding. β2AR agonist effects were multiphasic, with an initial decline at 2–4 h that reversed by 6 h and a second, somewhat greater decrease by 18–24 h. In cells pretreated with glucocorticoids, the decreases in EGFR binding by subsequent β2AR treatment were not statistically significant; glucocorticoid upregulation of EGFRs also prevented further increases by LPA. Similar increases by glucocorticoids and decreases by β2AR agonists were found in HFL-1 human lung fibroblasts. These complex and opposing effects of clinically relevant glucocorticoids and β2AR agonists on airway mesenchymal cell EGFRs likely contribute to their overall therapeutic profile in the diseased airway.

Nox4 mediates TGF-β1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells

2007 ◽  
Vol 292 (6) ◽  
pp. L1543-L1555 ◽  
Author(s):  
Anne Sturrock ◽  
Thomas P. Huecksteadt ◽  
Kimberly Norman ◽  
Karl Sanders ◽  
Thomas M. Murphy ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Smooth Muscle ◽  
Protein Phosphorylation ◽  
Airway Smooth Muscle ◽  
Retinoblastoma Protein ◽  
Airway Smooth Muscle Cells ◽  
Oxygen Species ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Tgf Β1

Transforming growth factor-β1 (TGF-β1) plays a pivotal role in increasing airway smooth muscle mass in severe asthma by inducing proliferation and hypertrophy of human airway smooth muscle. The mechanism(s) for these effects of TGF-β1 have not been fully elucidated. In this study, we demonstrate that TGF-β1 is a potent inducer of expression of the nonphagocyte NAD(P)H oxidase catalytic homolog Nox4, diphenylene iodonium-inhibitable reactive oxygen species production, proliferation, and hypertrophy in cultured human airway smooth muscle cells. By confocal microscopy, TGF-β1-induced Nox4 was localized with the endoplasmic reticulum and the nucleus, implying a role for Nox4 in regulation of both the cell cycle and protein synthesis. Consistent with this hypothesis, TGF-β1 increased retinoblastoma protein phosphorylation at both Ser807/811 and Ser780. Silencing Nox4 prevented TGF-β1-mediated retinoblastoma protein phosphorylation, proliferation, and cell hypertrophy. TGF-β1 also increased phosphorylation of eukaryotic translation initiation factor 4E binding protein-1 at Thr37/46, and this was likewise blocked by silencing Nox4. This is the first report to suggest a functional role for Nox4 in cell cycle transition and to demonstrate that Nox4 influences the pathobiochemistry of asthma by generating reactive oxygen species that promote TGF-β1-induced proliferation and hypertrophy of human airway smooth muscle.

TGF-β1 stimulates IL-8 release, COX-2 expression, and PGE2release in human airway smooth muscle cells

2000 ◽  
Vol 279 (1) ◽  
pp. L201-L207 ◽  
Author(s):  
Choong Yi Fong ◽  
Linhua Pang ◽  
Elaine Holland ◽  
Alan J. Knox
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Transforming Growth Factor ◽  
Airway Smooth Muscle Cells ◽  
Dependent Manner ◽  
Human Airway Smooth Muscle ◽  
Human Airway ◽  
Cox Inhibitor ◽  
Cox 2 ◽  
Tgf Β1

We have recently shown that endogenous prostanoids are critical in bradykinin-stimulated interleukin (IL)-8 release from human airway smooth muscle (ASM) cells. In this study, we tested the ability of transforming growth factor (TGF)-β1 to stimulate IL-8 release, cyclooxygenase (COX)-2 expression and PGE2 generation in cultured human ASM cells and explored the role of COX products and COX-2 induction on IL-8 release. TGF-β1 stimulated IL-8 release, COX-2 induction, and PGE2 generation in a concentration- and time-dependent manner. Maximal IL-8 release was achieved with 10 ng/ml of TGF-β1 after 16 h of incubation, which was inhibited by the transcription inhibitor actinomycin D and the corticosteroid dexamethasone but was not affected by the nonselective COX inhibitor indomethacin and the selective COX-2 inhibitor NS-398 despite their inhibition on TGF-β1-induced PGE2 release. These results show for the first time that TGF-β1 stimulates IL-8 release, COX-2 induction, and PGE2 generation in human ASM cells and that PGE2 generation is not critical for TGF-β1-induced IL-8 release. These findings suggest that TGF-β1 may play an important role in the pathophysiology of asthma.

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