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An important effect of steroids on angiogenesis in asthma
The vascular changes which occur in airways diseases such as asthma are starting to attract considerable attention from the respiratory research community. In addition to the vascular engorgement which occurs as part of the acute inflammatory process, several groups have demonstrated increased new vessel formation (angiogenesis) in chronic asthma.1–,3 Not only does this occur in adult asthma, but recent studies suggest it is a prominent feature of childhood asthma, suggesting that vascular remodelling may occur relatively early in the asthmatic process.4 The increased airway wall thickening produced by the expanded vasculature causes enhanced airway narrowing on stimulation with constrictor agents, thereby contributing to bronchial hyper-responsiveness. Furthermore, the increased blood flow may increase inflammatory cell trafficking and exudation and transudation of cytokines and mediators and contribute to airway hyper-responsiveness by supporting the increased airway smooth muscle mass which is a key feature of asthma histopathology.5
There are a number of candidate angiogenic factors for these changes, perhaps the most important of which are vascular endothelial growth factor (VEGF) and angiopoietin-1, distinct molecules which act together at different stages of angiogenic processes in several biological systems.6,7,8,9,10,11,12,13,14,15 Other molecules with angiogenic potential found in the airways include fibroblast growth factor,10 angiogenin10 and chemokines such as interleukin (IL)-816 and eotaxin.17 VEGF is subject to dynamic regulation while angiopoietin-1 is less so, and the latter may contribute in a more permissive way to the remodelling process. A number of stimuli can increase VEGF release from lung cells including cigarette smoke, hypoxia and Th1 and Th2 cytokines such as IL1β, IL4 and IL13, remodelling cytokines such as TGFβ and IL6, and vaso-active mediators such as bradykinin and PGE2.18–,27 Autocrine production of PGE2 may mediate the effect of some of these agents,18,27 and there is evidence from studies in mouse models to suggest that autocrine nitric oxide production may mediate some (but not all) of the effects of released VEGF in mouse asthma models.28 Endogenous angiostatic molecules such as endostatin and angiopoietin-2 exert a brake on this process, and the dynamic interplay between these and pro-angiogenic molecules helps shape repair and remodelling.29
Interestingly, recent studies in vitro with rhinovirus have shown that infection increases VEGF30,31—but not angiopoietin30—release, suggesting a mechanism whereby recurrent viral airway infections might contribute to airway remodelling in a cyclical manner. In mouse asthma models, airway VEGF is increased and VEGF receptor inhibitors inhibit cellular influx as well as inhibiting airway hyper-responsiveness and reducing microvascular leakage,32 consistent with VEGF having an important deleterious effect in asthma. In these and other studies,15 VEGF appears to regulate inflammatory processes as well as remodelling, which suggests that it is a complex multifunctional molecule with a wide repertoire of effects. There also appears to be a close relation between VEGF and matrix degradation which probably reflects the fact that establishment of new vessels requires matrix turnover and that, when the matrix is damaged, new vessels are required for tissue repair.
The study in this issue of Thorax by Feltis and colleagues33 (see page 314) addresses an important issue—namely, whether these angiogenic processes are modified by glucocorticoids. The authors undertook a placebo-controlled intervention study with inhaled fluticasone in 35 patients with mild asthma and performed immunohistochemistry and image analysis to obtain quantitative measures of vessels, angiogenic sprouts, VEGF, VEGF receptor 1, VEGF receptor 2 and angiopoietin-1 staining in airway biopsy specimens. They also measured VEGF concentrations in lavage fluid. The key findings were that vessel number, VEGF and sprout staining were decreased after 3 months of inhaled steroid treatment. However, no further reduction was seen at 12 months and relatively high doses of fluticasone were required. Their findings suggest that inhaled steroids downregulate angiogenic remodelling in the airways in asthma, associated with decreasing VEGF activity within the airway wall. Interestingly, VEGF levels in lavage fluid were not altered nor were receptor numbers or staining for angiopoietin-1. An interesting finding in this study was the fact that the vascular “sprouts”, which these authors have reported previously,34 were also reduced by fluticasone treatment. It would seem likely that these cystic structures in the vascular wall of airway vessels may be newly forming vessels.
Glucocorticoids have also been shown to reduce VEGF release in airway cell systems in culture, although their precise mechanism of action has not been established.35 VEGF regulation is complex and is controlled at both transcriptional and translational levels. Transcription factor binding sites in the VEGF promoter for specificity protein-1 (SP-1) seem to be particularly important, at least in airway smooth muscle,26 although this has not been studied in other airway cells. VEGF mRNA has regulatory elements in both its 3′ and 5′ UTR which control its degradation and are potential sites for post-transcriptional regulation.36 It is not clear whether the effect of glucocorticoids on VEGF production and angiogenesis is mediated by an effect on transcriptional or translational processes.
If glucocorticoids inhibit bronchial vascular changes, what is known about other asthma treatments? Interestingly, long-acting β-agonists have been shown to reduce the vascularity of asthmatic airways in vivo.1 Although there is some evidence that it might be due to a reduction in VEGF,35 an alternative explanation might be a reduction in the level of pro-angiogenic chemokines such as IL837 and eotaxin.38 The leucotriene antagonist pranlukast reduced sputum VEGF levels in a small study of untreated asthmatic subjects but had no additional effect when given concomitantly with inhaled steroids.39
Most studies on bronchial angiogenesis to date have used cell culture systems with relevant airway cells in vitro or biopsy studies such as those of Feltis et al.33 Recent reports of new three-dimensional cell culture systems for studying angiogenesis in vitro40 and reports using magnetic resonance imaging in animal models in vivo41 might provide additional tools, allowing a greater understanding of this important process over the next few years.
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Footnotes
Competing interests: None.