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Nitric oxide (NO) is produced by many cells within the respiratory tract and endogenous NO may play an important signalling role in the physiological control of airway function and in the pathophysiology of airway diseases [1–3]. All three isoforms of NO synthase (NOS) exist within the respiratory tract [4–6]. The endothelial constitutive isoform (eNOS) is localised to bronchial endothelial cells and to epithelial cells [7] and the neuronal isoform (nNOS) to parasympathetic nerves and to epithelial cells [8, 9]. Inducible NOS (iNOS) may be localised to several cell types, including epithelial cells and macrophages [10–12] and may be expressed even in the normal human respiratory tract (Fig. 1).
Multiple kinases play a critical role in orchestrating the chronic inflammation and structural changes in the respiratory tract of patients with asthma and chronic obstructive pulmonary disease (COPD). Kinases activate signaling pathways that lead to contraction of airway smooth muscle and release of inflammatory mediators (such as cytokines, chemokines, growth factors) as well as cell migration, activation, and proliferation. For this reason there has been great interest in the development of kinase inhibitors as anti-inflammatory therapies, particular where corticosteroids are less effective, as in severe asthma and COPD. However, it has proven difficult to develop selective kinase inhibitors that are both effective and safe after oral administration and this has led to a search for inhaled kinase inhibitors, which would reduce systemic exposure. Although many kinases have been implicated in inflammation and remodeling of airway disease, very few classes of drug have reached the stage of clinical studies in these diseases. The most promising drugs are p38 MAP kinases, isoenzyme-selective PI3-kinases, Janus-activated kinases, and Syk-kinases, and inhaled formulations of these drugs are now in development. There has also been interest in developing inhibitors that block more than one kinase, because these drugs may be more effective and with less risk of losing efficacy with time. No kinase inhibitors are yet on the market for the treatment of airway diseases, but as kinase inhibitors are improved from other therapeutic areas there is hope that these drugs may eventually prove useful in treating refractory asthma and COPD.
Summary Circulating catecholamines are not abnormally elevated in asthmatics. The normal circadian fall in circulating adrenaline at night may contribute to nocturnal wheezing by facilitating release of bronchoconstrictor mast cell mediators. Asthmatics who develop exercise‐induced wheezing show an impaired catecholamine response to exercise which may facilitate mediator release during exercise. Endogenous catecholamines in asthma may therefore play a modulatory role on the release of mast cell mediators.
Despite enormous unmet medical needs in respiratory medicine, very few new classes of safe and effective therapy have been introduced over the past 40 years. In spite of its enormous burden, respiratory medicine appears to have fewer new approved therapies than other common disease areas, such as cardiovascular, metabolic and neurological diseases, with fewer drug candidates and a higher failure rate. Furthermore, as in other areas of drug discovery, the time for drug development is getting longer and the risk of failure ever higher, leading to enormous and growing development costs. In order to identify some of the barriers to drug discovery in respiratory medicine, a European Respiratory Society Presidential Summit was held on July 2–3, 2014, in Rome, Italy. This meeting brought together respiratory scientists, clinicians, regulators, clinical pharmacologists and the pharmaceutical industry from across Europe to explore how these barriers might be overcome to facilitate the future development of new and effective therapies for respiratory diseases. This editorial highlights some of the opportunities for improving respiratory drug development that were discussed at the 2014 European Respiratory Society Presidential Summit. These include the development of more predictive preclinical disease models, the regulatory framework needed for better respiratory drug development, and how Germany is hoping to address the issues discussed above through a recently established national centre for lung research. The 2014 ERS Presidential Summit discusses how development of new respiratory drugs can be accelerated <http://ow.ly/IcOsZ>
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No abstract is provided for this article.
