Review
New asthma targets: recent clinical and preclinical advances

https://doi.org/10.1016/S1367-5931(02)00349-6Get rights and content

Abstract

Current asthma therapy is directed at the relief of chronic inflammation or improving lung function through bronchodilation. These approaches treat the overt symptoms of asthma but do not approach underlying causes of the disease. Such therapies have limited efficacy and for a number of patients the disease remains poorly controlled. The short-term future of asthma therapy will probably focus on the treatment of multiple symptoms to provide improved lung function. Long-term approaches to asthma will have to focus on modulation of the mechanisms that are the underlying causes of the various asthmatic pathophysiologies. These targets include a number of TH2-type T-cell-generated cytokines and chemokines, G-protein-coupled receptors, TH2-related transcription factors, neurotrophins and adhesion molecules. Additional new targets and understanding of asthma may also arise from genetic analysis.

Introduction

Asthma is a complex disease characterized by chronic inflammation of the airways, hyper-responsiveness of airway smooth muscle to various spasmogens and periodic airway obstruction resulting in decreased lung function (as measured by the forced expiratory volume in one second [FEV1]) [1]. The underlying causal agents of each of these characteristics has been the subject of research efforts for many years. Research of biochemical and animal model-systems have resulted in a large number of potential targets with diverse functions and potential roles in the pathophysiology of asthma. More recently, genetic analysis of asthma susceptibility in humans has begun to elucidate potential new targets.

The chronic inflammatory component of asthma is largely made up of eosinophils with a smaller contribution from neutrophils and phagocytic cells. Studies have indicated that agents released from activated eosinophils, such as major basic protein, eosinophil cationic protein and various enzymes, have the ability to cause tissue damage [2]. It is held by some that the tissue damage resulting from the chronic inflammatory state is the genesis of the other pathophysiological changes that take place in the asthmatic airway. However, studies indicate that increased airway hyper-responsiveness can be obtained in the absence of inflammation 3., 4., 5.. As a result, it has been very difficult to determine whether asthma is indeed a disease that progresses in a serial manner, with one pathophysiology being the direct effect of a prior one, or whether asthma is a series of more or less parallel changes in the airways that ultimately coalesce into what physicians define as asthma.

Current effective treatment of asthma has approached the disease from the objective of treating symptoms. The most prescribed agents to date are corticosteroids, which have been shown to inhibit infiltrating cells, cytokine production and the production of a number of other neurogenic and growth factors associated with asthma. These have limitations in that long-term administration of oral and high-dose inhaled steroids is still considered undesirable, particularly in the growing pediatric asthma population. Short-acting and long-acting beta agonists are drugs that target the decreased airway function aspect of the disease by acting as potent bronchodilators. Short-acting beta agonists are used to ameliorate acute exacerbations. These work with a quick onset of action but lose effectiveness if used on a chronic basis [6]. Long-acting beta agonists are used to prevent exacerbations and provide a partial bronchodilation compared with those of the short-acting forms. Leukotriene synthesis inhibitors and receptor antagonists provide a reduction in inflammation as well as lessening the frequency of exacerbations. Leukotriene antagonists are not as effective anti-inflammatory agents as corticosteroids, but the combined effect of these agents makes them attractive therapies. New therapies either directed at existing targets or at new targets will have to offer benefits over existing therapies such as decreased side-effect liability, multi-symptom treatment or treatment of underlying causal pathology. This review summarizes recent clinical and preclinical research over the past year and attempts to shed light on new targets that are likely to emerge as new asthma therapies.

Section snippets

Recent clinical advances

Current clinical data regarding asthma treatments have examined only a few new therapies while the majority of clinical investigation has been focused on the efficacy of combining existing therapies. The combination of long-acting beta-agonists and corticosteroids has been the most extensively tested to date. Several reports demonstrate the efficacy of this treatment in reducing inflammation and reversing poor airway function 6., 7., 8.. This combination is approved for use in asthma and is

Glucocorticoids

Recent preclinical studies into the detailed molecular mechanisms by which glucocorticoids effect gene transcription are revealing previously unknown activities and potential new targets for asthma treatment. In addition to effects on various transcription factors, such as NFκB and AP-1, it now appears that glucocorticoids may modulate the histone acetylation state of target genes. Two recent studies indicate that corticosteroids inhibit the histone acetylase activity inherent to certain

Conclusions

Short-term advances in asthma therapy will come with the combination of existing therapies that together enhance the efficacy of treating acute symptoms. Beyond this, major targets for new therapies will seek to be disease-modifying. Several preclinical and early clinical therapies are focused in this direction. The remodeling of airways in asthma is still a poorly understood pathophysiology. It still is not clear whether this remodeling is a direct effect of chronic airway inflammation or if

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

References (81)

  • M.R. Blackburn et al.

    Adenosine-deaminase deficient mice generated using a two-stage genetic engineering strategy exhibit a combined immunodeficiency

    J Biol Chem

    (1998)
  • H. Renz

    The role of neurotrophins in bronchial asthma

    Eur J Pharmacol

    (2001)
  • F. Pons et al.

    Nerve growth factor secretion by human lung epithelial A549 cells in pro- and anti-inflammatory conditions

    Eur J Pharmacol

    (2001)
  • R.A. Worthylake et al.

    Leukocyte transendothelial migration: orchestrating the underlying molecular machinery

    Curr Opin Cell Biol

    (2001)
  • L.C. Fiscus et al.

    L-selectin is required for the development of airway hyperresponsiveness but not airway inflammation in a murine model of asthma

    J Allergy Clin Immunol

    (2001)
  • M.L.K. Tang et al.

    Important roles for L-selectin and ICAM-1 in the development of allergic airway inflammation in asthma

    Pulm Pharmacol Ther

    (2001)
  • R.E. Mullings et al.

    Signal transducer and activator of transcription 6 (STAT-6) expression and function in asthmatic bronchial epithelium

    J Allergy Clin Immunol

    (2001)
  • P. Christodoulopoulos et al.

    TH2 cytokine-associated transcription factors in atopic and nonatopic asthma: evidence for differential signal transducer and activator of transcription 6 expression

    J Allergy Clin Immunol

    (2001)
  • R.K. Kumar

    Understanding airway wall remodeling in asthma: a basis for improvements in therapy?

    Pharmacol Ther

    (2001)
  • M. Corbel et al.

    Modulation of airway remodeling-associated mediators by the antifibrotic compound, pirfenidone, and the matrix metalloproteinase inhibitor, batimastat, during acute lung injury in mice

    Eur J Pharmacol

    (2001)
  • T.D. Howard et al.

    Gene-gene interaction in asthma: IL-4RA and IL-13 in a Dutch population with asthma

    Am J Hum Genet

    (2002)
  • C. Szalai et al.

    Polymorphism in the gene regulatory region of MCP-1 is associated with asthma susceptibility and severity

    J Allergy Clin Immunol

    (2001)
  • H. Nakamura et al.

    Variant eotaxin: Its effects on the asthma phenotype

    J Allergy Clin Immunol

    (2001)
  • R.G. Barr et al.

    β2-adrenoreceptor polymorphism and body mass index are associated with adult-onset asthma in sedentary but not active women

    Chest

    (2001)
  • E. Noguchi et al.

    Association between a new polymorphism in the activation-induced cytidine deaminase gene and atopic asthma and the regulation of total serum IgE

    J Allergy Clin Immunol

    (2001)
  • P.J. Barnes

    Pathophysiology of asthma

    Br J Clin Pharmacol

    (1996)
  • S. Greenfeder et al.

    Th2 cytokines and asthma: the role of interleukin-5 in allergic eosinophilic disease

    Respir Res

    (2001)
  • K. Ishida et al.

    Inhibition of antigen-induced airway hyperresponsiveness but not acute hypoxia nor airway eosinophilia by an antagonist of platelet-activating factor

    J Immunol

    (1990)
  • P.J. Mauser et al.

    Inhibitory effect of the TRFK-5 anti-IL-5 antibody in a guinea pig model of asthma

    Am Rev Respir Dis

    (1993)
  • P.A. Hutson et al.

    Early and late-phase bronchoconstriction after allergen challenge of nonanesthetized guinea pig. I. The association of disordered airway physiology to leukocyte infiltration

    Am Rev Respir Dis

    (1988)
  • R. Naedele-Risha et al.

    Dual components of optimal asthma therapy: scientific and clinical rationale for the use of long-acting β-agonists with inhaled coricosteroids

    J Am Osteopath Assoc

    (2001)
  • I.D. Bijl-Hofland et al.

    Inhaled corticosteroids, combined with long-acting beta(2)-agonists, improve the perception of bronchoconstriction in asthma

    Am J Respir Crit Care Med

    (2001)
  • C.S. Robinson et al.

    Addition of leukotriene antagonists to therapy in chronic persistent asthma: a randomised double-blind placebo-controlled trial

    Lancet

    (2001)
  • H.S. Nelson et al.

    Comparison of inhaled salmeterol and oral zafirlukast in asthmatic patients using concomitant inhaled coricosteroids

    Med Gen Med

    (2001)
  • M. Soler et al.

    The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics

    Eur Respir J

    (2001)
  • P.A. Procopiou et al.

    Novel glucocorticoid antedrugs possessing a 17β-(γ-lactone) ring

    J Med Chem

    (2001)
  • P.J. Barnes

    TH2 cytokines and asthma: an introduction

    Respir Res

    (2001)
  • A. Tomkinson et al.

    A murine IL-4 receptor antagonist that inhibits IL-4- and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness

    J Immunol

    (2001)
  • T.T. Kung et al.

    Effect of anti-mIL-9 antibody on the development of pulmonary inflammation and airway hyperresponsiveness in allergic mice

    Am J Respir Cell Mol Biol

    (2001)
  • Y.-L. Lee et al.

    Construction of single-chain interleukin-12 DNA plasmid to treat airway hyperresponsiveness in an animal model of asthma

    Hum Gene Ther

    (2001)
  • Cited by (9)

    • 10H-Phenothiazines: A new class of enzyme inhibitors for inflammatory diseases

      2009, European Journal of Medicinal Chemistry
      Citation Excerpt :

      The pathophysiological functions of acute and chronic inflammatory diseases such as asthma, arthritis, autoimmuno disorders are due to production of a variety of chemical mediators such as leukotrienes, cytokines and prostaglandins released from biosynthetic cascade of arachidonic acid catalyzed via phospholipase A2 (PLA2), lipoxygenase and cycloxygenase enzymes [1–3]. These regulatory enzymes are believed to play an important role in initiating and amplifying the inflammatory disorders in the body, contributing to diseases such as asthma (bronco contraction), autoimmune disorders, etc. [4–6]. Phenothiazines form an important class of heterocyclic compounds possessing wide spectrum diverse biological activities like antitumor, antimalarial, antipsychotic, anti-inflammatory, etc. [7–9].

    View all citing articles on Scopus
    View full text