Asthma affects 155 million people worldwide. In the United States alone there has been a recent two-fold increase in the number of cases of asthma driving pharmaceutical market values up to as high as $8 billion worldwide. Despite a large number of drugs available to clinicians, up to 15% of patients suffer from uncontrollable disease symptoms, while many patients responding to their medication demonstrate poor compliance. Both of these factors increase the demand for novel therapies that possess new modes of action. 

There is also a pressing need to develop new therapeutics for COPD, particularly those that control the underlying and largely untreatable inflammatory and destructive processes that cause its relentless progression. Worldwide, 600 million people suffer from COPD, with some three million dying from the disease each year representing a global market of US$2.8 billion.

As in all inflammatory diseases, there is increased oxidative stress in both allergic inflammation and COPD, as activated inflammatory cells produce reactive oxygen species. This suggests that antioxidants may be of use in the therapy of both COPD and asthma. However, existing antioxidants are weak and are not able to neutralize the high level of oxidative stress in the airways, and so more potent antioxidants are needed in the future. Alternatively therapeutic strategies could target the consequences of oxidative stress.

One such consequence is apoptosis and in an attempt to prevent this phenomenon mechanisms have evolved to stimulate compensatory angiogenesis. During anoxic conditions angiogenic factors including the prototypic VEGF are released. VEGF is able to stimulate the generation of new blood vessels and it is also able to prevent the death of existing endothelial cells. Asthma is associated with increased VEGF and angiogenesis. In contrast, field-leaders from the University of Colorado Health Sciences Center have reported that VEGF levels are reduced in the airways of patients with emphysema. This mirrors the death of endothelial and epithelial cells which together make up the alveolar septum a structure that separates adjacent alveoli and is responsible for gas exchange. On the other hand VEGF blockers promote alveolar cell apoptosis–dependent emphysema in rats. These studies underline the differences between asthma and COPD and support the concept that a failure of VEGF-related compensatory mechanisms may underlie the etiology of COPD. Very recently VEGF levels have been shown to correlate with disease severity such that mild emphysema is associated with an increase in protein levels while severe disease is characterized with decreased expression.

Most recently, Rubin Tuder and colleagues have investigated further the role of reduced VEGF levels in lung alveolar septal cell apoptosis and emphysema. In particular the VEGF receptor blocker SU5416 was shown to increase alveolar enlargement, alveolar septal cell apoptosis, and expression of markers of oxidative stress. Each of these phenomena were prevented by the superoxide dismutase mimetic M40419. Furthermore, a broad-spectrum caspase inhibitor markedly reduced the expression of markers of oxidative stress induced by SU5416 treatment. These data suggest that VEGF limits oxidative stress and apoptosis, and that reduced levels of this growth factor during emphysema may therefore play an important role in tissue destruction associated with this disease. Hence strategies that prevent the reduction of VEGF or the endogenous administration of VEGF may represent novel treatments for patients with COPD. In the “Focus on Cardiovascular Disease” section of this edition of TherapeuticAdvances we report a clinical trial demonstrating the safety and efficacy of endogenous administration of VEGF to patients with angina. A similar study in a cohort of COPD patients is eagerly awaited.

Entry date Wednesday, April 23, 2003

Adapted from Tuder et al, Am J Respir Cell Mol Biol 2003 Jan 31; [epub ahead of print] - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk