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

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.

Serum TGF‐β as a predictive biomarker for severe disease and fatality of COVID‐19

“…Of note, this refers to TGF‐β levels in hospitalized patients before the onset of dexamethasone treatment. TGF‐β‐mediated pathology (e.g., airway remodeling and organ fibrosis) is known to be reduced by this treatment [14, 15]. Notably, serum levels of other cytokines elevated during the first 2 weeks of COVID‐19, that is, IFN‐α, IFN‐y, IL‐6, IL15, and IL‐18, did not forecast severe disease, further underscoring the predictive value of TGF‐β (Supporting Information Table S2 and Fig.…”

Genetic deletion of phosphodiesterase 4D in the liver improves kidney damage in high-fat fed mice: liver-kidney crosstalk

“…Furthermore, PDE4D deficiency in HFD mouse livers significantly reduced renal injury by decreasing TGF-β1 signal amplification in the kidney. Other studies have shown that the profibrotic cytokine TGF-β1 increases PDE4D expression [ 48 ]. Thus, PDE4D and TGF-β1 may positively regulate each other as renal fibrosis progresses and mediate liver-kidney crosstalk.…”

Could a Nebulized or Dry Powder Inhalation of a Dopamine D1R Agonist Be a Treatment of Idiopathic Pulmonary Fibrosis?

“…However, the apparent increase in D1DR fails to change D1DR signaling from full and partial agonists. Previous studies demonstrated that TGF-b1-mediated epithelial-mesenchymal transition of alveolar type II cells leads to an increase in the cAMP-specific phosphodiesterase 4 (PDE4) (Kolosionek et al, 2009); similarly, in tracheal smooth muscle, TGF-b1 reduces Ga s -mediated signaling (Chung et al, 2020). As PDE4 was not examined, it is unclear if the increase in receptor signaling is buffeted by an increase in PDE4.…”