Yonsei Med J.  2012 Mar;53(2):369-376. 10.3349/ymj.2012.53.2.369.

Serum Vascular Endothelial Growth Factor and Angiopoietin-2 Are Associated with the Severity of Systemic Inflammation Rather than the Presence of Hemoptysis in Patients with Inflammatory Lung Disease

• Park HY
• Hahm CR
• Jeon K
• Koh WJ
• Suh GY
• Chung MP
• Kim H
• Kwon OJ
• Um SW

• KMID: 1120205
• DOI: http://doi.org/10.3349/ymj.2012.53.2.369

Abstract

PURPOSE
Vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) are major mediators of angiogenesis and are induced by tissue inflammation and hypoxia. The purpose of this study was to investigate whether serum VEGF and Ang-2 are associated with the presence of hemoptysis and the extent of systemic inflammation in patients with inflammatory lung diseases.
MATERIALS AND METHODS
We prospectively enrolled 52 patients with inflammatory lung disease between June 2008 and October 2009.
RESULTS
The median values of VEGF and Ang-2 were 436 pg/mL and 2383 pg/mL, respectively. There was a significant positive correlation between serum Ang-2 and VEGF levels. VEGF levels were not significantly different according to the presence of hemoptysis. C-reactive protein (CRP) and Ang-2 level were significantly higher in patients without hemoptysis (n=26) than in those with hemoptysis (n=26; p<0.001 and p<0.001, respectively). CRP and arterial oxygen tension (PaO2) were significantly correlated with both serum VEGF (p=0.032 and p=0.016, respectively) and Ang-2 levels (p<0.001 and p=0.041, respectively), after adjusting for other factors. Age and the absence of hemoptysis were factors correlated with serum Ang-2 levels
CONCLUSION
Our study suggests that serum VEGF and Ang-2 levels are associated with PaO2 and the severity of inflammation rather than the presence of hemoptysis in patients with inflammatory lung diseases. Thus, hemoptysis may not be mediated by increased serum levels of VEGF and Ang-2 in patients with inflammatory lung diseases, and further studies are required to determine the mechanisms of hemoptysis.

Keyword

Angiogenesis; angiopoietin-2; hemoptysis; inflammation; vascular endothelial growth factor

MeSH Terms

Aged
Angiopoietin-2/*blood
Female
Hemoptysis/*blood
Humans
Inflammation/*blood
Lung Diseases/*blood
Male
Middle Aged
Prospective Studies
Vascular Endothelial Growth Factor A/*blood

Figure

• 

  Fig. 1 Correlation between serum VEGF and Ang-2 levels. VEGF, vascular endothelial growth factor; Ang-2, angiopoietin-2. p=0.028.

Reference

1. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995. 1:27–31.

2. Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J. 1997. 11:457–465.

3. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 1995. 146:1029–1039.

4. Matsuyama W, Hashiguchi T, Matsumuro K, Iwami F, Hirotsu Y, Kawabata M, et al. Increased serum level of vascular endothelial growth factor in pulmonary tuberculosis. Am J Respir Crit Care Med. 2000. 162:1120–1122.

5. Kanazawa H. Role of vascular endothelial growth factor in the pathogenesis of chronic obstructive pulmonary disease. Med Sci Monit. 2007. 13:RA189–RA195.

6. Inoue K, Matsuyama W, Hashiguchi T, Wakimoto J, Hirotsu Y, Kawabata M, et al. Expression of vascular endothelial growth factor in pulmonary aspergilloma. Intern Med. 2001. 40:1195–1199.

7. McColley SA, Stellmach V, Boas SR, Jain M, Crawford SE. Serum vascular endothelial growth factor is elevated in cystic fibrosis and decreases with treatment of acute pulmonary exacerbation. Am J Respir Crit Care Med. 2000. 161:1877–1880.

8. Donovan EA, Kummar S. Targeting VEGF in cancer therapy. Curr Probl Cancer. 2006. 30:7–32.

9. Mattern J, Koomägi R, Volm M. Association of vascular endothelial growth factor expression with intratumoral microvessel density and tumour cell proliferation in human epidermoid lung carcinoma. Br J Cancer. 1996. 73:931–934.

10. Nilsson I, Shibuya M, Wennström S. Differential activation of vascular genes by hypoxia in primary endothelial cells. Exp Cell Res. 2004. 299:476–485.

11. Tsigkos S, Koutsilieris M, Papapetropoulos A. Angiopoietins in angiogenesis and beyond. Expert Opin Investig Drugs. 2003. 12:933–941.

12. Hashizume H, Falcón BL, Kuroda T, Baluk P, Coxon A, Yu D, et al. Complementary actions of inhibitors of angiopoietin-2 and VEGF on tumor angiogenesis and growth. Cancer Res. 2010. 70:2213–2223.

13. Pouysségur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature. 2006. 441:437–443.

14. Boussat S, Eddahibi S, Coste A, Fataccioli V, Gouge M, Housset B, et al. Expression and regulation of vascular endothelial growth factor in human pulmonary epithelial cells. Am J Physiol Lung Cell Mol Physiol. 2000. 279:L371–L378.

15. Park JH, Park KJ, Kim YS, Sheen SS, Lee KS, Lee HN, et al. Serum angiopoietin-2 as a clinical marker for lung cancer. Chest. 2007. 132:200–206.

16. Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003. 9:685–693.

17. Hayes RJ, Bennett S. Simple sample size calculation for cluster-randomized trials. Int J Epidemiol. 1999. 28:319–326.

18. Kraft A, Weindel K, Ochs A, Marth C, Zmija J, Schumacher P, et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer. 1999. 85:178–187.

19. Alatas F, Alatas O, Metintas M, Ozarslan A, Erginel S, Yildirim H. Vascular endothelial growth factor levels in active pulmonary tuberculosis. Chest. 2004. 125:2156–2159.

20. Hyodo I, Doi T, Endo H, Hosokawa Y, Nishikawa Y, Tanimizu M, et al. Clinical significance of plasma vascular endothelial growth factor in gastrointestinal cancer. Eur J Cancer. 1998. 34:2041–2045.

21. Kikuchi K, Kubo M, Kadono T, Yazawa N, IHN H, Tamaki K. Serum concentrations of vascular endothelial growth factor in collagen diseases. Br J Dermatol. 1998. 139:1049–1051.

22. Futami R, Miyashita M, Nomura T, Makino H, Matsutani T, Sasajima K, et al. Increased serum vascular endothelial growth factor following major surgical injury. J Nihon Med Sch. 2007. 74:223–229.

23. Siner JM, Bhandari V, Engle KM, Elias JA, Siegel MD. Elevated serum angiopoietin 2 levels are associated with increased mortality in sepsis. Shock. 2009. 31:348–353.

24. van der Heijden M, Pickkers P, van Nieuw Amerongen GP, van Hinsbergh VW, Bouw MP, van der Hoeven JG, et al. Circulating angiopoietin-2 levels in the course of septic shock: relation with fluid balance, pulmonary dysfunction and mortality. Intensive Care Med. 2009. 35:1567–1574.

25. van der Heijden M, van Nieuw Amerongen GP, Koolwijk P, van Hinsbergh VW, Groeneveld AB. Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients. Thorax. 2008. 63:903–909.

26. Ricciuto DR, dos Santos CC, Hawkes M, Toltl LJ, Conroy AL, Rajwans N, et al. Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. Crit Care Med. 2011. 39:702–710.

27. Orfanos SE, Kotanidou A, Glynos C, Athanasiou C, Tsigkos S, Dimopoulou I, et al. Angiopoietin-2 is increased in severe sepsis: correlation with inflammatory mediators. Crit Care Med. 2007. 35:199–206.

28. Caine GJ, Blann AD, Stonelake PS, Ryan P, Lip GY. Plasma angiopoietin-1, angiopoietin-2 and Tie-2 in breast and prostate cancer: a comparison with VEGF and Flt-1. Eur J Clin Invest. 2003. 33:883–890.

29. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003. 9:677–684.

30. Mandriota SJ, Pyke C, Di Sanza C, Quinodoz P, Pittet B, Pepper MS. Hypoxia-inducible angiopoietin-2 expression is mimicked by iodonium compounds and occurs in the rat brain and skin in response to systemic hypoxia and tissue ischemia. Am J Pathol. 2000. 156:2077–2089.

31. Pichiule P, Chavez JC, LaManna JC. Hypoxic regulation of angiopoietin-2 expression in endothelial cells. J Biol Chem. 2004. 279:12171–12180.

32. Bruick RK, McKnight SL. Building better vasculature. Genes Dev. 2001. 15:2497–2502.

33. Semenza GL. Regulation of hypoxia-induced angiogenesis: a chaperone escorts VEGF to the dance. J Clin Invest. 2001. 108:39–40.

34. Lim HS, Lip GY, Blann AD. Angiopoietin-1 and angiopoietin-2 in diabetes mellitus: relationship to VEGF, glycaemic control, endothelial damage/dysfunction and atherosclerosis. Atherosclerosis. 2005. 180:113–118.

35. Kanazawa H, Nomura S, Asai K. Roles of angiopoietin-1 and angiopoietin-2 on airway microvascular permeability in asthmatic patients. Chest. 2007. 131:1035–1041.