Increased Levels of VEGF-A and HIF-1α in Turkish Children with Crimean-Congo Hemorrhagic Fever
AbstractBackground: Crimean-Congo Hemorrhagic Fever (CCHF) is a disease characterized by serious course, including acute viral fever, ecchymosis, thrombocytopenia, liver dysfunction and high rate of mortality. Hypoxia Inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor-A (VEGF-A) play an important role both in the inflammatory process and plasma leakage. The aim of this study was to define HIF-1α and VEGF-A serum levels obtained from CCHF patients and control group and to investigate whether these factors were correlated with the pathogenesis of this disease.Methods: Thirty cases younger than 17 yr confirmed by RT-PCR and/or ELISA for CCHF were included in this study. Thirty age and sex matched healthy peoples were enrolled as controls. Blood samples collected from the patient and control groups. Serum levels of HIF-1α and VEGF-A were measured with ELISA.Results: Levels of HIF-1α and VEGF-A were statistically significantly increased in CCHF patients compared to the control group (P< 0.05). A significant positive correlation was found between the levels of HIF-1α and VEGF-A in the patient group (P< 0.01). The levels of ALT, AST, CK, aPTT, WBC and Thrombocyte count were significantly higher in the patients than in the control group (P< 0.001). A positive correlation was found among the levels of AST and CK from biochemical parameters and VEGF and HIF-1α in the patient group (P< 0.05)Conclusion: HIF-1α and VEGF-A might play an important role in CCHF pathogenesis.
Bakir M, Ugurlu M, Dokuzoguz B, Bodur H, Tasyaran MA, Vahaboglu H (2005) Turkish CCHF Study Group. Crimean- Congo haemorrhagic fever outbreak in Middle Anatolia: a multicentre study of clinical features and outcome measures. J Med Microbiol. 54: 385–389.
Bakir M, Bakir S, Sari I, Celik VK, Gozel MG, Engin A (2013) Evaluation of the relationship between serum levels of VEGF and sVEGFR1 with mortality and prognosis in patients with Cri- mean-Congo hemorrhagic fever. J Med Virol. 85: 1794–1801.
Bodur H, Akinci E, Onguru P, Uyar Y, Basturk B, Gozel MG, Kayaslan BU (2010) Evidence of vascular endothe- lial damage in Crimean-Congo hemor- rhagic fever. Int J Infec Dis. 14: 704–707.
Burt FJ, Swanepoel R, Shieh WJ, Smith JF, Leman PA, Greer PW, Coffield LM, Rollin PE, Ksiazek TG, Peters CJ, Zaki SR (1997) Immunohistochemical and in situ localization of Crimean-Congo hemorrhagic fever (CCHF) virus in hu- man tissues and implications for CCHF pathogenesis. Arch Pathol Lab Med.121: 839–846.
Del Moral-Hernández O, Martínez-Hernán- dez NE, Mosso-Pani MA, Hernández- Sotelo D, Illades-Aguiar B, Flores-Al- faro E, Antonio-Vejar V, Leyva-Vázquez MA (2014) Association DENV1 and DENV2 infection with high serum lev- els of soluble thrombomodulin and VEGF in patients with dengue fever and dengue hemorrhagic fever. Int J Clin Exp Med. 7: 370–378.
Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability fac- tor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol. 146: 1029–1039.
Elson DA, Thurston G, Huang LE, Ginzinger DG, McDonald DM, Johnson RS, Ar- beit JM. (2001) Induction of hyper- vascularity without leakage or inflam- mation in transgenic mice overexpress- ing hypoxia-inducible factor-1α. Genes Dev. 15: 2520–2532.
Ergönül O, Celikbas A, Dokuzoguz B, Eren S, Baykam N, Esener H (2004) Char- acteristics of patients with Crimean- Congo Hemorrhagic Fever in a recent outbreak in Turkey and impact of oral ribavirin therapy. Clin Infect Dis. 39:284–287.
Ergonul O (2006) Crimean-Congo haemor- rhagic fever. Lancet Infect Dis. 6:203–214.
Ergonul O (2008) Treatment of Crimean- Congo hemorrhagic fever. Antiviral Res.78: 125–131.
Ferrara N, Gerber HP, Lecouter J (2003) The biology of VEGF and its receptors. Nat Med. 9: 669–676.
Furuta T, Murao LA, Lan NTP, Huy NT, Huong VTQ, Huy TT, Tham VD, Nga CTP, Ha TTN, Ohmoto Y, Kikuchi M, Morita K, Yasunami M, Hirayama K, Watanabe N (2012) Association of mast cell-derived VEGF and proteases in dengue shock syndrome. PLOS Negl Trop Dis. 6: e1505.
Geisbert TW, Jahrling PB (2004) Exotic emerging viral diseases: progress and challenges. Nat Med. 10: 110–121.
Hoeben A, Landuyt B, Highley MS, Wild- iers H, Van Oosterom AT, De Bruijn EA (2004) Vascular endothelial growth factor and angiogenesis. Pharmacol Rev.56: 549–580.
Hubalek Z, Rudolf I (2012) Tick-borne viru- ses in Europe. Parasitol Res. 111: 9–36.
Irwin DC, McCord JM, Nozik-Grayck E, Beckly G, Foreman B, Sullivan T, White M, Crossno Jr JT, Bailey D, Flores SC, Majka S, Klemm D, Martha C, TissotvanPatot MC (2009) A poten- tial role for reactive oxygen species and the HIF-1α–VEGF pathway in hy- poxia-induced pulmonary vascular leak. Free Radic Biol Med. 47: 55–61.
Jesmin S, Zaedi S, Islam AS, Sultana SN, Iwashima Y, Yamaguchi N, Hiroe M, Gando S (2012) Time-dependent alter- ations of VEGF and its signaling mol- ecules in acute lung injury in a rat model of sepsis. Inflammation. 35:484–500.
Karlsson S, Pettilä V, Tenhunen J, Lund V, Hovilehto S, Ruokonen E Finnsepsis Study Group (2008) Vascular endothe- lial growth factor in severe sepsis and septic shock. Anesth Analg. 106: 1820–1826.
Kilani MM, Mohammed KA, Nasreen N, Tepper RS, Antony VB (2004) RSV causes HIF-1 alpha stabilization via NO release in primary bronchial epithelial cells. Inflammation. 28: 245–251.
Ma Y, Liu B, Yuan B, Wang J, Yu H, Zhang Y, Xu Z, Zhang Y, Yi J, Zhang C, Zhou X, Yang A, Zhuang R, Jin B (2012) Sustained high level of serum VEGF at convalescent stage contrib- utes to the renal recovery after HTNV infection in patients with hemorrhagic
fever with renal syndrome. Clin Dev Immunol. 81: 23–86.
Maltezou HC, Andonova L, Andraghetti R, Bouloy M, Ergonul O, Jongejan F, Kalvatchev N, Nichol S, Niedrig M, Platonov A, Thomson G, Leitmeyer K, Zeller H (2010) Crimean-Congo hem- orrhagic fever in Europe: current situ- ation calls for preparedness. Euro Sur- veill. 11;15(10):19504.
Manalo DJ, Rowan A, Lavoie T, Natarajan L, Kelly BD, Ye SQ, Garcia JGN, Se- menza GL (2005) Transcriptional reg- ulation of vascular endothelial cell re- sponses to hypoxia by HIF-1. Blood.105: 659–669.
Morinet F, Casetti L, François JH, Capron C, Pillet S (2013) Oxygen tension level and human viral infections. Virology.444: 31–36
Ozturk B, Kuscu F, Tutuncu E, Sencan I, Gurbuz Y, Tuzun H (2010) Evaluation of the association of serum levels of hyaluronic acid, sICAM-1, sVCAM-1, and VEGF-A with mortality and prog- nosis in patients with Crimean-Congo hemorrhagic fever. J Clin Virol. 47:115–119
Pickkers P, Sprong T, van Eijk L, van der Hoeven H, Smits P, van Deuren M (2005) Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and cor- relates with vascular permeability. Shock. 24: 508–512.
Podar K, Anderson KC (2005) The pathophys- iologic role of VEGF in hematologic malignancies therapeutic implications. Review, Blood. 105: 1383–1395.
Schnittler HJ, Feldmann H (2003) Viral hemorrhagic fever a vascular disease? Thromb Haemost. 89: 967–972.
Schäfer ST, Frede S, Winning S, Bick A, Roshangar P, Fandrey J, Peters J, Adamzik M (2013) Hypoxia-inducible factor and target gene expression are decreased in patients with sepsis: pro- spective observational clinical and cel- lular studies. Anesthesiology 118: 1426–1436.
Srikiatkhachorn A, Ajariyakhajorn C, Endy TP, Kalayanarooj S, Libraty DH, Green S, Ennis FA, Rothman AL (2007) Vi- rus-induced decline in soluble vascular endothelial growth receptor 2 is asso- ciated with plasma leakage in dengue hemorrhagic Fever. J Virol. 81: 1592–1600.
Textoris J, Beaufils N, Quintana G, Lassoued AB, Zieleskiewicz L, Wiramus S, Blas- co V, Lesavre N, Martin C, Gabert J, Leone M (2012) Hypoxia-inducible factor (HIF1α) gene expression in hu- man shock states. Crit Care. 16(4): R120. doi: 10.1186/cc11414.
Tseng CS, Lo HW, Teng HC, Lo WC, Ker CG (2005) Elevated levels of plasma VEGF in patients with dengue hemor- rhagic fever. Fems Immunol Med Mic.43: 99–102.
Van der Flier M, van Leeuwen HJ, van Kes- sel KP, Kimpen JL, Hoepelman AI, Geelen SP (2005) Plasma vascular en- dothelial growth factor in severe sep- sis. Shock. 23: 35–38.
Whitehouse CA (2004) Crimean-Congo hemorrhagic fever. Antiviral Res 64:145–160.
Yano K, Liaw PC, Mullington JM, Shih SC, Okada H, Boydak N, Kang PM, Toltl L, Belikoff B, Buras J, Simms BT, Mizgerd JP, Carmeliet P, Karumanchi SA, Aird WC (2006) Vascular endo- thelial growth factor is an important determinant of sepsis morbidity and mortality. J Exp Med. 203: 1447–1458.
Zhang RY, Liu YY, Qu HP, Tang YQ (2013) The angiogenic factors and their soluble receptors in sepsis: friend, foe, or both? Crit Care. 17: 446.
Zinkernagel AS, Johnson RS, Nizet V (2007) Hypoxia inducible factor (HIF) function in innate immunity and infec- tion. J Mol Med. 85: 1339–1346.