Asthma and lower airway diseaseMechanism of glucocorticoid protection of airway smooth muscle from proasthmatic effects of long-acting β2-adrenoceptor agonist exposure
Section snippets
Materials
Human ASM cells were obtained from Bio Whittaker, Inc (Walkersville, Md), and all chemicals were purchased from Sigma-Aldrich (St Louis, Mo) unless otherwise indicated.
Animals
Sixteen adult New Zealand White rabbits were used in this study, which was approved by the Biosafety and Animal Research Committee of the Research Institute at Children's Hospital of Philadelphia.
Culture and treatment of cells
Human ASM cells were cultured in growth medium supplemented with 10% FBS (Bio Whittaker, Inc, Walkersville, Md) and maintained in an
Glucocorticoid prevention of homologous ß2AR desensitization in HASM cells
To evaluate the role of glucocorticoids in modulating ASM function in the ß2AR-desensitized state, we initially examined the effect of pretreatment with dexamethasone on isoproterenol-induced cAMP accumulation in HASM cells after their prolonged homologous ß2AR desensitization. Accordingly, acute changes in intracellular cAMP accumulation, detected at 5 minutes after administration of a near half-maximal effective concentration of isoproterenol (1.0 μmol/L),13, 14 were compared in HASM cells
Discussion
Chronic use of LABAs to treat asthma has been associated with impaired bronchodilation, heightened bronchoconstriction, and an increase in asthma morbidity,1, 2, 3 presumably reflecting the adverse effects of prolonged homologous β2AR desensitization of the airways.4 Although mechanisms implicated in mediating acute homologous desensitization of the β2AR in ASM are well described, including uncoupling of the β2AR from the stimulatory G protein, Gs, as a result of its phosphorylation by G
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Cited by (27)
Important lessons learned from studies on the pharmacology of glucocorticoids in human airway smooth muscle cells: Too much of a good thing may be a problem
2020, Pharmacology and TherapeuticsCitation Excerpt :Moreover, features of ASM remodeling are also synergistically repressed by GCs/β2-agonists combination (Dekkers et al., 2012; Roth et al., 2002). Combination therapy has also been reported to prevent some of the deleterious effects of β2-agonist monotherapy such as the increased expression of M3 muscarinic receptor/signaling (Liu, Wu, Wang, Huang, & Liu, 2015) or receptor desensitization (Nino, Hu, Grunstein, & Grunstein, 2010). The mechanisms underlying the superior therapeutic effect of GCs/β2-agonists combination treatment in ASM cells has been attributed to epigenetic changes at target gene promoters (Nie, Knox, & Pang, 2005), to the increased and/or restoration of the expression of GC-inducible genes (Kaur et al., 2008; Rider, King, Holden, Giembycz, & Newton, 2011) including MKP-1 (Manetsch et al., 2013) or A20 (Altonsy, Mostafa, Gerber, & Newton, 2017), or to the decreased cellular uptake of β2-agonists via GC-induced inhibition of the organic cation transporter (OCT3) (Horvath et al., 2007).
MKP-1: A negative feedback effector that represses MAPK-mediated pro-inflammatory signaling pathways and cytokine secretion in human airway smooth muscle cells
2012, Cellular SignallingCitation Excerpt :The essential negative feedback role played by MKP-1 in the control of innate immunity and inflammation has been supported by studies in knock-out mice [8–10]. We and others have recently demonstrated the important role played by MKP-1 in repressing pro-remodeling functions of ASM cells [4,6,11–13]. Our earlier studies have revealed that apart from activating MAPKs in a temporally distinct manner, TNFα also appears to transiently upregulate the protein levels of the endogenous MAPK deactivator — MKP-1 [4,6,14].
β-agonist-associated reduction in RGS5 expression promotes airway smooth muscle hyper-responsiveness
2011, Journal of Biological ChemistryCitation Excerpt :These differences might be explained simply by the different agonists used. In another series of reports, Grunstein and co-workers showed that chronic exposure of ASM to salmeterol induced transcriptional up-regulation of phosphodiesterase 4D5, which promotes cAMP degradation, through a Gαi-Erk-MKP1 dependent mechanism (20, 41–42). Although procontractile signaling elements such as IP3 and Ca2+ flux in ASM cells exposed to salmeterol were not examined in these studies, rabbit tracheas treated with salmeterol contracted more to acetylcholine, which was reversed by either glucocorticoid or phosphodiesterase inhibitor pretreatment.
The matrix: Redefined role in the pathogenesis of asthma
2011, Pediatrics and NeonatologyHomeostatic glucocorticoid signaling in airway smooth muscle: A roadmap to asthma pathogenesis
2023, Frontiers in Endocrinology
Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.