PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of thoraxThoraxVisit this articleSubmit a manuscriptReceive email alertsContact usBMJ
 
Thorax. 2007 April; 62(4): 283–285.
PMCID: PMC2092468

Blanching the airways: steroid effects in asthma

Short abstract

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.1,2,3 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 PGE2.18,19,20,21,22,23,24,25,26,27 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.

Footnotes

Competing interests: None.

References

1. Orsida B E, Ward C, Li X. et al Effect of a long‐acting beta2‐agonist over three months on airway wall vascular remodeling in asthma. Am J Respir Crit Care Med 2001. 164117–121.121 [PubMed]
2. Orsida B E, Li X, Hickey B. et al Vascularity in asthmatic airways: relation to inhaled steroid dose. Thorax 1999. 54289–295.295 [PMC free article] [PubMed]
3. Salvato G. Quantitative and morphological analysis of the vascular bed in bronchial biopsy specimens from asthmatic and non‐asthmatic subjects. Thorax 2001. 56902–906.906 [PMC free article] [PubMed]
4. Barbato A, Turato G, Baraldo S. et al Epithelial damage and angiogenesis in the airways of children with asthma. Am J Respir Crit Care Med 2006. 174975–981.981 [PubMed]
5. Knox A J, Stocks J, Sutcliffe A. Angiogenesis and vascular endothelial growth factor in COPD. Thorax 2005. 6088–89.89 [PMC free article] [PubMed]
6. Asai K, Kanazawa H, Kamoi H. et al Increased levels of vascular endothelial growth factor in induced sputum in asthmatic patients. Clin Exp Allergy 2003. 33595–599.599 [PubMed]
7. Kanazawa H, Hirata K, Yoshikawa J. Involvement of vascular endothelial growth factor in exercise induced bronchoconstriction in asthmatic patients. Thorax 2002. 57885–888.888 [PMC free article] [PubMed]
8. McDonald D M. Angiogenesis and remodeling of airway vasculature in chronic inflammation. Am J Respir Crit Care Med 2001. 164S39–S45.S45 [PubMed]
9. Hoshino M, Nakamura Y, Hamid Q A. Gene expression of vascular endothelial growth factor and its receptors and angiogenesis in bronchial asthma. J Allergy Clin Immunol 2001. 1071034–1038.1038 [PubMed]
10. Hoshino M, Takahashi M, Aoike N. Expression of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin immunoreactivity in asthmatic airways and its relationship to angiogenesis. J Allergy Clin Immunol 2001. 107295–301.301 [PubMed]
11. Yancopoulos G D, Davis S, Gale N W. et al Vascular‐specific growth factors and blood vessel formation. Nature 2000. 407242–248.248 [PubMed]
12. Ribatti D, Vacca A, Presta M. The discovery of angiogenic factors: a historical review. Gen Pharmacol 2000. 35227–231.231 [PubMed]
13. Baluk P, Lee C G, Link H. et al Regulated angiogenesis and vascular regression in mice overexpressing vascular endothelial growth factor in airways. Am J Pathol 2004. 1651071–1085.1085 [PubMed]
14. Rothenberg M E. VEGF obstructs the lungs. Nat Med 2004. 101041–1042.1042 [PubMed]
15. Lee C G, Link H, Baluk P. et al Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2‐mediated sensitization and inflammation in the lung. Nat Med 2004. 101095–1103.1103 [PubMed]
16. Tanner J E. Nucleosomes activate NF‐kappaB in endothelial cells for induction of the proangiogenic cytokine IL‐8. Int J Cancer 2004. 112155–160.160 [PubMed]
17. Salcedo R, Young H A, Ponce M L. et al Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. J Immunol 2001. 1667571–7578.7578 [PubMed]
18. Knox A J, Corbett L, Stocks J. et al Human airway smooth muscle cells secrete vascular endothelial growth factor: up‐regulation by bradykinin via a protein kinase C and prostanoid‐dependent mechanism. FASEB J 2001. 152480–2488.2488 [PubMed]
19. Wright J L, Tai H, Churg A. Cigarette smoke induces persisting increases of vasoactive mediators in pulmonary arteries. Am J Respir Cell Mol Biol 2004. 31501–509.509 [PubMed]
20. Nilsson I, Shibuya M, Wennstrom S. Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res 2004. 299476–485.485 [PubMed]
21. Wen F Q, Liu X, Manda W. et al TH2 Cytokine‐enhanced and TGF‐beta‐enhanced vascular endothelial growth factor production by cultured human airway smooth muscle cells is attenuated by IFN‐gamma and corticosteroids. J Allergy Clin Immunol 2003. 1111307–1318.1318 [PubMed]
22. Ammit A J, Moir L M, Oliver B. et al Effect of IL‐6 trans‐signaling on the pro‐remodeling phenotype of airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2007. 292L199–L206.L206 [PubMed]
23. Alagappan V K, McKay S, Widyastuti A. et al Proinflammatory cytokines upregulate mRNA expression and secretion of vascular endothelial growth factor in cultured human airway smooth muscle cells. Cell Biochem Biophys 2005. 43119–129.129 [PubMed]
24. Faffe D S, Flynt L, Bourgeois K. et al Interleukin‐13 and interleukin‐4 induce vascular endothelial growth factor release from airway smooth muscle cells: role of vascular endothelial growth factor genotype. Am J Respir Cell Mol Biol 2006. 34213–218.218 [PMC free article] [PubMed]
25. Faffe D S, Flynt L, Mellema M. et al Oncostatin M causes VEGF release from human airway smooth muscle: synergy with IL‐1beta. Am J Physiol Lung Cell Mol Physiol 2005. 288L1040–L1048.L1048 [PubMed]
26. Bradbury D, Clarke D, Seedhouse C. et al Vascular endothelial growth factor induction by prostaglandin E2 in human airway smooth muscle cells is mediated by E prostanoid EP2/EP4 receptors and SP‐1 transcription factor binding sites. J Biol Chem 2005. 28029993–30000.30000 [PubMed]
27. Stocks J, Bradbury D, Corbett L. et al Cytokines upregulate vascular endothelial growth factor secretion by human airway smooth muscle cells: role of endogenous prostanoids. FEBS Lett 2005. 5792551–2556.2556 [PubMed]
28. Bhandari V, Choo‐Wing R, Chapoval S P. et al Essential role of nitric oxide in VEGF‐induced, asthma‐like angiogenic, inflammatory, mucus, and physiologic responses in the lung. Proc Natl Acad Sci USA 2006. 10311021–11026.11026 [PubMed]
29. Suzaki Y, Hamada K, Sho M. et al A potent antiangiogenic factor, endostatin prevents the development of asthma in a murine model. J Allergy Clin Immunol 2005. 1161220–1227.1227 [PubMed]
30. Psarras S, Volonaki E, Skevaki C L. et al Vascular endothelial growth factor‐mediated induction of angiogenesis by human rhinoviruses. J Allergy Clin Immunol 2006. 117291–297.297 [PubMed]
31. De Silva D, Dagher H, Ghildyal R. et al Vascular endothelial growth factor induction by rhinovirus infection. J Med Virol 2006. 78666–672.672 [PubMed]
32. Lee Y C, Kwak Y G, Song C H. Contribution of vascular endothelial growth factor to airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate‐induced asthma. J Immunol 2002. 1683595–3600.3600 [PubMed]
33. Feltis B N, Wignarajah D, Reid D W. et al Effects of inhaled fluticasone on angiogenesis and vascular endothelial growth factor in asthma. Thorax 2007. 62314–319.319 [PMC free article] [PubMed]
34. Feltis B N, Wignarajah D, Zheng L. et al Increased vascular endothelial growth factor and receptors: relationship to angiogenesis in asthma. Am J Respir Crit Care Med 2006. 1731201–1207.1207 [PubMed]
35. Volonaki E, Psarras S, Xepapadaki P. et al Synergistic effects of fluticasone propionate and salmeterol on inhibiting rhinovirus‐induced epithelial production of remodelling‐associated growth factors. Clin Exp Allergy 2006. 361268–1273.1273 [PubMed]
36. Yoo P S, Mulkeen A L, Cha C H. Post‐transcriptional regulation of vascular endothelial growth factor:implications for tumor angiogenesis. World J Gastroenterol 2006. 124937–4942.4942 [PubMed]
37. Nie M, Knox A J, Pang L. β2‐Adrenoceptor agonists, like glucocorticoids, repress eotaxin gene transcription by selective inhibition of histone H4 acetylation. J Immunol 2005. 175478–486.486 [PubMed]
38. Pang L, Knox A J. Synergistic inhibition by beta(2)‐agonists and corticosteroids on tumor necrosis factor‐alpha‐induced interleukin‐8 release from cultured human airway smooth‐muscle cells. Am J Respir Cell Mol Biol 2000. 2379–85.85 [PubMed]
39. Kanazawa H, Yoshikawa T, Hirata K. et al Effects of pranlukast administration on vascular endothelial growth factor levels in asthmatic patients. Chest 2004. 1251700–1705.1705 [PubMed]
40. Thompson H G, Truong D T, Griffith C K. et al A three‐dimensional in vitro model of angiogenesis in the airway mucosa. Pulm Pharmacol Ther 2007. 20141–148.148 [PubMed]
41. Tigani B, Cannet C, Quintana H K. et al Lung inflammation and vascular remodeling after repeated allergen challenge detected noninvasively by MRI. Am J Physiol Lung Cell Mol Physiol. 2006 [Epub ahead of print]

Articles from Thorax are provided here courtesy of BMJ Publishing Group