Associate editor: J.S. Fedan
Novel signal transduction modulators for the treatment of airway diseases☆

https://doi.org/10.1016/j.pharmthera.2005.08.001Get rights and content

Abstract

Multiple signal transduction pathways are involved in the inflammatory process in the airways of patients with asthma and chronic obstructive pulmonary disease (COPD), hence modulators of these pathways may result in novel anti-inflammatory treatments. The advantage of this approach is that these pathways are activated in many inflammatory and structural cells of the airways, hence a broad spectrum of anti-inflammatory effects may be possible. However, this also makes it more likely that side effects may be limiting, but this may not be a problem if the signal transduction pathway is selectively activated in disease and the therapeutic index may be increased by inhaled delivery. Phosphodiesterase-4 (PDE4) inhibitors are the most advanced treatment in this category as anti-inflammatory treatment for asthma and COPD, although side effects are dose limiting. Other promising approaches are inhibitors of p38 mitogen-activated protein (MAP) kinase, inhibitor of nuclear factor-κB kinase-2 (IKK2), and Syk kinase, all of which are in clinical development. Several other kinases and transcription factors are also targets for novel drug development. It is likely that modulators of signal transduction pathways may lead to the development of several novel anti-inflammatory treatments for asthma and COPD in the future.

Introduction

There has been an explosion of information about the complex signal transduction pathways and transcription factors involved in chronic inflammation, suggesting that targeting these pathways may have beneficial effects in inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Several novel classes of drugs that modulate signal transduction pathways are now in development for the treatment of airway diseases, although so far none are available in clinical practice (Barnes, 2004b, Barnes & Hansel, 2004).

Targeting signal transduction pathways is an attractive approach to treating inflammatory diseases, as the same pathways are usually involved in several cell types and regulate several coordinated inflammatory processes, hence modulators have the prospect of a wide spectrum of beneficial effects. Multiple inflammatory signals activate a variety of cell surface receptors that activate a limited number of signal transduction pathways, most of which involve cascades of kinases. These kinases in turn may activate transcription factors that regulate multiple inflammatory genes. Signal transduction modulators are a logical approach to switching off inflammation as they target a limited number of common intracellular pathways and thus signal transduction pathways are critical points for intervention (Fig. 1). However, this same advantage is also a disadvantage as the widespread distribution of the same signal transduction pathways means that modulators have a high risk of adverse side effects due to lack of cell and effect specificity. One way to tip the balance in favor of beneficial effects is to target signal transduction pathways that are confined to specific cell types or that are only activated in the disease process. There are multiple mediators involved in both asthma and COPD (Barnes et al., 1998, Barnes, 2004a) and not surprisingly inhibition of specific mediators by receptor antagonists or mediator synthesis inhibitors has been found to have little or no beneficial effect in these diseases. The most effective mediator antagonists in asthma are cysteinyl–leukotriene receptor-1 antagonists, such as montelukast and zafirlukast, but they are much less effective than corticosteroids, which have a broad spectrum of anti-inflammatory actions (Barnes, 2003).

Section snippets

Corticosteroid effects on signal transduction pathways

Corticosteroids are highly effective as anti-inflammatory therapy in asthma and have the capacity to inhibit all of the activated inflammatory pathways. Although the molecular mechanisms of action are not completely understood, there is growing evidence that they switch off multiple inflammatory genes that have been activated by proinflammatory transcription factors, such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) and that they do this by recruitment of the nuclear regulator

Phosphodiesterase inhibitors

Phosphodiesterases (PDEs) break down cyclic nucleotides that inhibit cell activation (secretion and contraction) and at least 11 families of enzymes have now been discovered (Essayan, 2001). Theophylline, long used as a bronchodilator in asthma and COPD, is a relatively weak and non-selective PDE inhibitor. Relatively high doses of theophylline are needed for bronchodilatation leading to a high incidence of side effects that are largely mediated by PDE inhibition. The increase in cyclic

Transcription factor inhibitors

Many transcription factors are involved in the expression of inflammatory genes in the airways and are therefore possible targets for anti-inflammatory drugs.

Kinase inhibitors

Over 700 kinases are involved in signal transduction providing a new generation of therapies (Cohen, 2002). A major problem has been the development of specific inhibitors as the catalytic site that binds ATP is similar between kinases, leading to a search for allosteric inhibitors. Selective kinase inhibitors, such as imatinib and gefitinib, are already in clinical use and it is likely that many more selective kinase inhibitors will be developed in the future. Several kinases are involved in

Peroxisome proliferator-activated receptor activators

Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated nuclear hormone receptors belonging to the steroid receptor superfamily, and the 3 recognized subtypes, PPAR-α, -γ, and -δ, are widely expressed (Berger & Moller, 2002). There is evidence that activation of PPAR-γ agonists may have anti-inflammatory and immunomodulatory effects. For example, PPARγ agonists, such as troglitazone, inhibit the release of inflammatory cytokines from monocytes and induce apoptosis

Conclusions

Many signal transduction pathways are involved in inflammation in airway diseases so that inhibition of these pathways is a logical anti-inflammatory approach. The advantage of signal transduction modulators is their relatively broad spectrum of effects compared with drugs acting at surface receptors, but this may mean that adverse effects are more likely to occur. This problem could be overcome by inhaled administration, or by selecting pathways that are abnormally activated in airway disease

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    ☆

    Conflict of interest: The author receives research funding from the following pharmaceutical companies, all of whom have an interest in developing drugs for the treatment of airway disease: GlaxoSmithKline, AstraZeneca, Novartis, Pfizer, Boehringer Ingelheim, and Mitsubishi.

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