Emerging targets for novel therapy of asthma
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Section snippets
Introduction — rationale for new asthma therapies
Asthma is a complex syndrome characterized by reversible airways obstruction resulting from allergen exposure and other triggers releasing multiple bronchoconstricting mediators that stimulate airway muscle to contract, thereby further narrowing airways that are already partially occluded by mucous and edema. Symptoms of dyspnea, coughing, exaggerated airway narrowing and wheezing typically accompany the characteristic chronic airway wall inflammation of asthma. Acute bronchoconstriction
Novel G-protein-coupled receptor pathways: bitter taste and EP4 receptors
Recent work on GPCRs in airway smooth muscle shows that several previously uncharacterized signaling pathways can elicit bronchodilation (Figure 1). Bitter taste receptor (e.g. TAS2R) agonists cause hyperpolarization of ASM and reduce calcium levels near the plasma membrane thus eliciting bronchodilation [7•]. Bitter taste agonists may act through activation of BK channels, but the necessity of BK activation has been challenged [8]. Interestingly activation of bitter taste receptors elicits
Phosphorylation of HSP20 as a novel cAMP-dependent bronchodilation mechanism
One of the emerging mechanisms of cAMP-dependent airway smooth muscle relaxation is phosphorylation of the small heat shock protein, HSP20 (HSPB1) (reviewed by [15]). Figure 2 is a model summarizing two proposed molecular mechanisms of bronchodilation — depolymerization of F-actin and inhibition of actin and myosin crossbridge formation. Both mechanisms are thought to be regulated by phosphorylation of Ser16 of HSP20 by PKA during smooth muscle relaxation induced by vasodilators and
Rho/Rho kinase pathway
Activation of the Rho/Rho kinase pathway has multiple effects on airway smooth muscle contraction, proliferation and cell migration. Contraction in response to neurotransmitters and other bronchoconstrictors is enhanced by activation of Rho kinases which inhibit myosin light chain phosphatase resulting in ‘calcium sensitization’ [24, 25]. A Rho kinase inhibitor produces relaxation by ‘calcium desensitization’ [24]. Figure 2 shows that myosin light chain phosphatase is a target of the Rho/ROCK
Statins
Rho proteins that couple GPCR activation to Rho kinases and downstream targets are prenylated to enhance their localization to the plasma membrane and allow signaling complexes to form. The prenylation reactions of Rho-family proteins, including farnesylation and geranyl-geranylation, depend on mevalonate produced by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity. This suggests that Rho-dependent processes in inflammation and airway smooth muscle contraction might be
Epigenetic reprogramming by histone modifications and microRNAs
Pathways controlling transcription have been studied extensively in lung cells to elucidate mechanisms of asthma pathogenesis. In contrast, epigenetic mechanisms controlling protein abundance (Figure 3a) and microRNA-mediated control of translation (Figure 3b) are not as well defined, particularly in airway smooth muscle cells.
Conclusions and future directions
Important advances in anti-inflammatory therapies and G protein coupled receptors mediating bronchodilation should provide new tools to treat problematic asthma patients. However there are still no effective interventions that will reduce airway smooth muscle tone chronically or the smooth muscle mass in extensively remodeled airways of severe asthmatics. To address these problems new drugs targeting previously unrecognized or poorly characterized molecules and processes must be developed. One
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Support for studies of HSP20 and for production of this review was provided by a grant to WTG from the National Institutes of Health, HL077726. Preparation of the manuscript was supported by grants from the National Institutes of Health to JS (HL097805, HL107171, TR000430) and BCM (HL092588).
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The Rho kinase (ROCK) inhibitor Y-27632 reduces the β<inf>2</inf>-adrenoceptor density but enhance cAMP formation in primary equine bronchial epithelial cells
2021, European Journal of PharmacologyCitation Excerpt :Major risk factors contributing to the development of asthma appeared to be environmental allergens such as dust mites, hey dust, pollutants including mold, organic dust, and endotoxin (Sachdeva et al., 2019; Couetil et al., 2020 and the references therein). The characteristic features of the disease are reversible bronchoconstriction, airway inflammation and hyperresponsiveness, mucus secretion and airway remodeling (Gerthoffer et al., 2013; Couëtil et al., 2016). Besides all known and described cytokines and inflammatory mediators which have an impact on asthma pathogenesis, there is now substantial evidence that the Rho/ROCK-kinase is also involved in many of the pathways that contribute to the pathologies associated with these respiratory diseases, including induction of airway smooth muscle contraction, inflammation and remodeling, implying its relevance as promising and novel therapeutic target (Zhang et al., 2020).
Immune-Mediated Pulmonary Disease and Epigenetics
2018, The Epigenetics of AutoimmunityInterleukin-17A directly acts on bronchial smooth muscle cells and augments the contractility
2017, Pharmacological ReportsCitation Excerpt :The in vivo pretreatment with GGTI-2133 and lovastatin, direct and indirect inhibitors of RhoA geranylgeranylation respectively, also ameliorated the BSM hypercontractility and AHR [30–32]. The signaling of RhoA/Rho-kinases has been proposed as a new target for asthma therapy [28,33]. Several reports including the current study (Fig. 1) demonstrated that, in animal models of allergic asthma, RhoA protein expression is up-regulated in smooth muscles of the airways [6,15,17,21,29].
The expression of bitter taste receptors in mesenteric, cerebral and omental arteries
2017, Life SciencesCitation Excerpt :Recent reports have shown that TAS2R is also expressed in extra-oral organs. Strikingly, TAS2R in airway smooth muscle causes bronchodilation induced by bitter tastants [7,12], making TAS2R an emerging target for novel asthma therapy [22,23]. For this reason, studies with TAS2R are mostly focused on the respiratory system, such as the bronchus and the pulmonary artery.
Airway smooth muscle in contractility and remodeling of asthma: potential drug target mechanisms
2023, Expert Opinion on Therapeutic Targets