Emerging targets for novel therapy of asthma

https://doi.org/10.1016/j.coph.2013.04.002Get rights and content

Highlights

Significant advances in understanding the cell and molecular biology of inflammation and airway smooth muscle (ASM) contractility have identified several potential novel targets for therapies of asthma. New agents targeting G-protein coupled receptors (GPCRs) including bitter taste receptors (TAS2R) agonists and prostaglandin EP4 receptor agonists elicit ASM relaxation. The cAMP/PKA pathway continues to be a promising drug target with the emergence of new PDE inhibitors and a novel PKA target protein, HSP20, which mediates smooth muscle relaxation via actin depolymerization. Smooth muscle relaxation can also be elicited by inhibitors of the RhoA/Rho kinase pathway via inhibition of myosin light chain phosphorylation and actin depolymerization. Targeting epigenetic processes that control chromatin remodeling and RNA-induced gene silencing in airway cells also holds great potential for novel asthma therapy. Further investigation may identify agents that inhibit smooth muscle contraction and/or restrain or reverse obstructive remodeling of the airways.

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).

References (47)

  • C. Donovan et al.

    PPARgamma ligands regulate noncontractile and contractile functions of airway smooth muscle: implications for asthma therapy

    PPAR Res

    (2012)
  • F. Novelli et al.

    Efficacy of anticholinergic drugs in asthma

    Expert Rev Respir Med

    (2012)
  • V.V. Dimov et al.

    Immunomodulators in asthma therapy

    Curr Allergy Asthma Rep

    (2009)
  • G.M. Walsh

    Novel cytokine-directed therapies for asthma

    Discov Med

    (2011)
  • D.A. Deshpande et al.

    Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction

    Nat Med

    (2010)
  • C.H. Zhang et al.

    Activation of BK channels may not be required for bitter tastant-induced bronchodilation

    Nat Med

    (2012)
  • S.S. An et al.

    TAS2R activation promotes airway smooth muscle relaxation despite beta(2)-adrenergic receptor tachyphylaxis

    Am J Physiol Lung Cell Mol Physiol

    (2012)
  • K.S. Robinett et al.

    Agonist-promoted homologous desensitization of human airway smooth muscle bitter taste receptors

    Am J Respir Cell Mol Biol

    (2011)
  • W. Wasiak et al.

    A six week double blind, placebo controlled, crossover study of the effect of misoprostol in the treatment of aspirin sensitive asthma

    Thorax

    (1999)
  • C. Benyahia et al.

    PGE(2) receptor (EP(4)) agonists: potent dilators of human bronchi and future asthma therapy?

    Pulm Pharmacol Ther

    (2012)
  • J. Buckley et al.

    EP4 receptor as a new target for bronchodilator therapy

    Thorax

    (2011)
  • C.K. Billington et al.

    cAMP regulation of airway smooth muscle function

    Pulm Pharmacol Ther

    (2013)
  • A.C. Beall et al.

    Cyclic nucleotide-dependent vasorelaxation is associated with the phosphorylation of a small heat shock-related protein

    J Biol Chem

    (1997)
  • Cited by (44)

    • 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 Pharmacology
      Citation 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 Autoimmunity
    • Interleukin-17A directly acts on bronchial smooth muscle cells and augments the contractility

      2017, Pharmacological Reports
      Citation 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 Sciences
      Citation 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.

    View all citing articles on Scopus
    View full text