Omics profiles in chronic venous ulcer wound fluid: Innovative applications for translational medicine

Expert Review of Molecular Diagnostics

Volumn 14, Issue 6, 2014, Pages 737-762

  Mannello, Ferdinando ^a   Ligi, Daniela ^a   Canale, Matteo ^a   Raffetto, Joseph D ^b,c  

^a UNIVERSITY OF URBINO   (Italy)

^b VA BOSTON HEALTHCARE SYSTEM   (United States)

^c BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

Biomarker; Chronic venous disease; Cytokine; Genomic; Inflammation; Metabolomic; Proteinase; Proteomic; Venous leg ulcer; Wound fluid

Indexed keywords

CYTOKINE; GROWTH FACTOR; TRANSCRIPTOME;

CHRONIC VEIN INSUFFICIENCY; DISEASE MARKER; ENDOTHELIAL DYSFUNCTION; GENOMICS; HEMODYNAMICS; HUMAN; INFLAMMATION; LEG ULCER; METABOLOMICS; MOLECULAR MECHANICS; PROTEIN DEGRADATION; PROTEOMICS; RECURRENCE RISK; REVIEW; RISK FACTOR; TRANSCRIPTOMICS; ULCER HEALING; WOUND CLOSURE; WOUND FLUID; ANIMAL; CHRONIC DISEASE; GENETICS; METABOLISM; PROCEDURES; TRANSLATIONAL RESEARCH; VARICOSE ULCER; VENOUS INSUFFICIENCY; WOUND HEALING;

ANIMALS; CHRONIC DISEASE; GENOMICS; HUMANS; METABOLOMICS; PROTEOMICS; TRANSCRIPTOME; TRANSLATIONAL MEDICAL RESEARCH; VARICOSE ULCER; VENOUS INSUFFICIENCY; WOUND HEALING;

EID: 84903140688     PISSN: 14737159     EISSN: 17448352     Source Type: Journal    
DOI: 10.1586/14737159.2014.927312     Document Type: Review

References (223)

1. Rabe E, Guex JJ, Puskas A, et al. Epidemiology of chronic venous disorders in geographically diverse populations: Results from the Vein Consult Program. Int Angiol 2012;31(2):105-15
2. Pannier F, Rabe E. The relevance of the natural history of varicose veins and refunded care. Phlebology 2012; 27(Suppl 1):23-6
3. Neglen P, Eklof B, Kulwicki A, et al. Prevention and treatment of venous ulcers in primary chronic venous insufficiency. J Vasc Surg 2010;52(5 Suppl):15S-20S
4. Moseley R, Stewart JE, Stephens P, et al. Extracellular matrix metabolites as potential biomarkers of disease activity in wound fluid: Lessons learned from other inflammatory diseases? Br J Dermatol 2004; 150(3):401-13
5. Pukstad BS, Ryan L, Flo TH, et al. Non-healing is associated with persistent stimulation of the innate immune response in chronic venous leg ulcers. J Dermatol Sci 2010;59(2):115-22
6. Moore K, Huddleston E, Stacey MC, Harding KG. Venous leg ulcers-The search for a prognostic indicator. Int Wound J 2007;4(2):163-72
7. Mannello F, Ligi D, Magnani M. Deciphering the single-cell omic: Innovative application for translational medicine. Expert Rev Proteomics 2012;9(6):635-48
8. Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins. Ann Epidemiol 2005;15(3):175-84 (Pubitemid 40269465)
9. Gloviczki P, Comerota AJ, Dalsing MC, et al. The care of patients with varicose veins and associated chronic venous diseases: Clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg 2011;53(5 Suppl): 2S-48S
10. Carroll C, Hummel S, Leaviss J, et al. Clinical effectiveness and cost-effectiveness of minimally invasive techniques to manage varicose veins: A systematic review and economic evaluation. Health Technol Assess 2013;17(48):i-141
11. Mannello F, Raffetto JD. Matrix metalloproteinase activity and glycosaminoglycans in chronic venous disease: The linkage among cell biology, pathology and translational research. Am J Transl Res 2011;3(2):149-58
12. Rabe E, Pannier F. Clinical, aetiological, anatomical and pathological classification (CEAP): Gold standard and limits. Phlebology 2012;27(Suppl 1):114-18
13. Bergan J. Molecular mechanisms in chronic venous insufficiency. Ann Vasc Surg 2007; 21(3):260-6 (Pubitemid 46678673)
14. Bergan JJ, Schmid-Schonbein GW, Coleridge Smith PD, et al. Chronic venous disease. Minerva Cardioangiol 2007;55(4): 459-76 (Pubitemid 350067958)
15. Kahn SR, Ginsberg JS. Relationship between deep venous thrombosis and the postthrombotic syndrome. Arch Intern Med 2004;164(1):17-26 (Pubitemid 38067385)
16. Labropoulos N, Mansour MA, Kang SS, et al. New insights into perforator vein incompetence. Eur J Vasc Endovasc Surg 1999;18(3):228-34 (Pubitemid 29431347)
17. Delis KT, Husmann M, Kalodiki E, et al. In situ hemodynamics of perforating veins in chronic venous insufficiency. J Vasc Surg 2001;33(4):773-82
18. Nicolaides AN, Allegra C, Bergan J, et al. Management of chronic venous disorders of the lower limbs: Guidelines according to scientific evidence. Int Angiol 2008;27(1): 1-59 (Pubitemid 351523668)
19. Bergan JJ, Schmid-Schonbein GW, Smith PD, et al. Chronic venous disease. N Engl J Med 2006;355(5):488-98 (Pubitemid 44162276)
20. Lim CS, Davies AH. Pathogenesis of primary varicose veins. Br J Surg 2009; 96(11):1231-42
21. Markovic JN, Shortell CK. Genomics of varicose veins and chronic venous insufficiency. Semin Vasc Surg 2013;26(1): 2-13
22. Raffetto JD and Mannello F. Pathophysiology of chronic venous disease. Int Angiol 2014;In press
23. Oklu R, Habito R, Mayr M, et al. Pathogenesis of varicose veins. J Vasc Interv Radiol 2012;23(1):33-9
24. Mannello F, Ligi D, Canale M, Raffetto JD. Sulodexide down-regulates the release of cytokines, chemokines, and leukocyte colony stimulating factors from human macrophages: Role of glycosaminoglycans in inflammatory pathways of chronic venous disease. Curr Vasc Pharmacol 2014;12(1): 173-85
25. Nicolaides AN. Chronic venous disease and the leukocyte-endothelium interaction: From symptoms to ulceration. Angiology 2005; 56(Suppl 1):S11-19
26. Saharay M, Shields DA, Porter JB, et al. Leukocyte activity in the microcirculation of the leg in patients with chronic venous disease. J Vasc Surg 1997;26(2):265-73 (Pubitemid 27362663)
27. Ono T, Bergan JJ, Schmid-Schonbein GW, Takase S. Monocyte infiltration into venous valves. J Vasc Surg 1998;27(1):158-66 (Pubitemid 28081172)
28. Takase S, Bergan JJ, Schmid-Schonbein G. Expression of adhesion molecules and cytokines on saphenous veins in chronic venous insufficiency. Ann Vasc Surg 2000; 14(5):427-35
29. Ackerman Z, Seidenbaum M, Loewenthal E, Rubinow A. Overload of iron in the skin of patients with varicose ulcers. Possible contributing role of iron accumulation in progression of the disease. Arch Dermatol 1988;124(9):1376-8
30. Zamboni P, Izzo M, Tognazzo S, et al. The overlapping of local iron overload and HFE mutation in venous leg ulcer pathogenesis. Free Radic Biol Med 2006;40(10):1869-73
31. Pappas PJ, Lal BK, Ohara N, et al. Regulation of matrix contraction in chronic venous disease. Eur J Vasc Endovasc Surg 2009;38(4):518-29
32. Yeoh-Ellerton S, Stacey MC. Iron and 8-isoprostane levels in acute and chronic wounds. J Invest Dermatol 2003;121(4): 918-25 (Pubitemid 37239139)
33. Caggiati A, Franceschini M, Heyn R, Rosi C. Skin erythrodiapedesis during chronic venous disorders. J Vasc Surg 2011; 53(6):1649-53
34. Zamboni P, Scapoli G, Lanzara V, et al. Serum iron and matrix metalloproteinase-9 variations in limbs affected by chronic venous disease and venous leg ulcers. Dermatol Surg 2005; 31(6):644-9 (Pubitemid 43093415)
35. Raffetto JD. Inflammation in chronic venous ulcers. Phlebology 2013;28(Suppl 1): 61-7
36. Raffetto JD, Marston WA. Venous ulcer: What is new? Plast Reconstr Surg 2011; 127(Suppl 1):279S-88S
37. Yasim A, Kilinc M, Aral M, et al. Serum concentration of procoagulant, endothelial and oxidative stress markers in early primary varicose veins. Phlebology 2008; 23(1):15-20
38. Shoab SS, Scurr JH, Coleridge-Smith PD. Increased plasma vascular endothelial growth factor among patients with chronic venous disease. J Vasc Surg 1998;28(3):535-40 (Pubitemid 28421727)
39. Kowalewski R, Malkowski A, Sobolewski K, Gacko M. Evaluation of transforming growth factor-beta signaling pathway in the wall of normal and varicose veins. Pathobiology 2010;77(1):1-6
40. Pascual G, Corrales C, Gomez-Gil V, et al. TGF-beta1 overexpression in the transversalis fascia of patients with direct inguinal hernia. Eur J Clin Invest 2007; 37(6):516-21 (Pubitemid 46817351)
41. Sola LR, Aceves M, Duenas AI, et al. Varicose veins show enhanced chemokine expression. Eur J Vasc Endovasc Surg 2009; 38(5):635-41
42. Kucukguven A, Khalil RA. Matrix metalloproteinases as potential targets in the venous dilation associated with varicose veins. Curr Drug Targets 2013;14(3): 287-324
43. Raffetto JD, Khalil RA. Matrix metalloproteinases in venous tissue remodeling and varicose vein formation. Curr Vasc Pharmacol 2008;6(3):158-72
44. Lim CS, Kiriakidis S, Sandison A, et al. Hypoxia-inducible factor pathway and diseases of the vascular wall. J Vasc Surg 2013;58(1):219-30
45. Sansilvestri-Morel P, Fioretti F, Rupin A, et al. Comparison of extracellular matrix in skin and saphenous veins from patients with varicose veins: Does the skin reflect venous matrix changes? Clin Sci (Lond) 2007; 112(4):229-39
46. Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous disease: Rationale, results and unanswered questions. Eur J Vasc Endovasc Surg 2011;41(1): 117-25
47. Jagielska J, Kapopara PR, Salguero G, et al. Interleukin-1 assembles a proangiogenic signaling module consisting of caveolin-1, tumor necrosis factor receptor-Associated factor 6, p38-mitogen-Activated protein kinase (MAPK), and MAPK-Activated protein kinase 2 in endothelial cells. Arterioscler Thromb Vasc Biol 2012;32(5): 1280-8
48. Kowalewski R, Sobolewski K, Malkowski A, et al. Glycosaminoglycan- degrading enzymes in the varicose vein wall. Int Angiol 2008; 27(6):529-35
49. Wolanska M, Sobolewski K, Glowinski S, et al. Glycosaminoglycans of normal veins and their alterations in varicose veins and varicose veins complicated by thrombophlebitis. Eur Surg Res 2001;33(1): 28-32 (Pubitemid 32429665)
50. Lundqvist K, Schmidtchen A. Immunohistochemical studies on proteoglycan expression in normal skin and chronic ulcers. Br J Dermatol 2001;144(2): 254-9 (Pubitemid 32178802)
51. Pappas PJ, DeFouw DO, Venezio LM, et al. Morphometric assessment of the dermal microcirculation in patients with chronic venous insufficiency. J Vasc Surg 1997;26(5):784-95 (Pubitemid 27505615)
52. Coccheri S, Mannello F. Development and use of sulodexide in vascular diseases: Implications for treatment. Drug Des Devel Ther 2013;8:49-65
53. Sprague AH, Khalil RA. Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 2009; 78(6):539-52
54. Raffetto JD, Khalil RA. Mechanisms of varicose vein formation: Valve dysfunction and wall dilation. Phlebology 2008;23(2): 85-98
55. Raffetto JD, Ross RL, Khalil RA. Matrix metalloproteinase 2-induced venous dilation via hyperpolarization and activation of K+ channels: Relevance to varicose vein formation. J Vasc Surg 2007;45(2):373-80 (Pubitemid 46149999)
56. Raffetto JD, Yu P, Reslan OM, et al. Endothelium-dependent nitric oxide and hyperpolarization-mediated venous relaxation pathways in rat inferior vena cava. J Vasc Surg 2012;55(6):1716-25
57. Agren MS, Eaglstein WH, Ferguson MW, et al. Causes and effects of the chronic inflammation in venous leg ulcers. Acta Derm Venereol Suppl (Stockh) 2000;210: 3-17
58. Widgerow AD. Chronic wound fluid-Thinking outside the box. Wound Repair Regen 2011;19(3):287-91
59. Chatterjee SS. Venous ulcers of the lower limb: Where do we stand? Indian J Plast Surg 2012;45(2):266-74
60. Peschen M, Lahaye T, Hennig B, et al. Expression of the adhesion molecules ICAM-1, VCAM-1, LFA-1 and VLA-4 in the skin is modulated in progressing stages of chronic venous insufficiency. Acta Derm Venereol 1999;79(1):27-32 (Pubitemid 29079324)
61. Weyl A, Vanscheidt W, Weiss JM, et al. Expression of the adhesion molecules ICAM-1, VCAM-1, and E-selectin and their ligands VLA-4 and LFA-1 in chronic venous leg ulcers. J Am Acad Dermatol 1996;34(3):418-23 (Pubitemid 26083817)
62. Simka M. Cellular and molecular mechanisms of venous leg ulcers development-The "puzzle" theory. Int Angiol 2010;29(1):1-19
63. Baker EA, Leaper DJ. Proteinases, their inhibitors, and cytokine profiles in acute wound fluid. Wound Repair Regen 2000; 8(5):392-8
64. Loots MA, Lamme EN, Zeegelaar J, et al. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J Invest Dermatol 1998;111(5):850-7 (Pubitemid 28509329)
65. Jones KR. Why do chronic venous leg ulcers not heal? J Nurs Care Qual 2009; 24(2):116-24
66. Barrientos S, Stojadinovic O, Golinko MS, et al. Growth factors and cytokines in wound healing. Wound Repair Regen 2008; 16(5):585-601
67. Cullen B, Watt PW, Lundqvist C, et al. The role of oxidised regenerated cellulose/ collagen in chronic wound repair and its potential mechanism of action. Int J Biochem Cell Biol 2002;34(12):1544-56
68. Cullen B, Smith R, McCulloch E, et al. Mechanism of action of PROMOGRAN, a protease modulating matrix, for the treatment of diabetic foot ulcers. Wound Repair Regen 2002;10(1):16-25 (Pubitemid 34496478)
69. Widgerow AD. Chronic wounds-is cellular 'reception' at fault? Examining integrins and intracellular signalling. Int Wound J 2013; 10(2):185-92
70. Bergan JJ, Pascarella L, Schmid-Schonbein GW. Pathogenesis of primary chronic venous disease: Insights from animal models of venous hypertension. J Vasc Surg 2008; 47(1):183-92
71. Robnett AH. Chronic ulcers of the leg of venous origin. Cleve Clin Q 1955;22(1):3-9
72. Lozano Sanchez FS, Marinello RJ, Carrasco CE, et al. Venous leg ulcer in the context of chronic venous disease. Phlebology 2014;29(4):220-6
73. Eming SA, Koch M, Krieger A, et al. Differential proteomic analysis distinguishes tissue repair biomarker signatures in wound exudates obtained from normal healing and chronic wounds. J Proteome Res 2010;9(9): 4758-66
74. Phillips TJ, al-Amoudi HO, Leverkus M, Park HY. Effect of chronic wound fluid on fibroblasts. J Wound Care 1998;7(10): 527-32
75. Seah CC, Phillips TJ, Howard CE, et al. Chronic wound fluid suppresses proliferation of dermal fibroblasts through a Ras-mediated signaling pathway. J Invest Dermatol 2005;124(2):466-74 (Pubitemid 40175897)
76. Fernandez ML, Broadbent JA, Shooter GK, et al. Development of an enhanced proteomic method to detect prognostic and diagnostic markers of healing in chronic wound fluid. Br J Dermatol 2008;158(2): 281-90
77. Escalante T, Rucavado A, Pinto AF, et al. Wound exudate as a proteomic window to reveal different mechanisms of tissue damage by snake venom toxins. J Proteome Res 2009;8(11):5120-31
78. Wyffels JT, Fries KM, Randall JS, et al. Analysis of pressure ulcer wound fluid using two-dimensional electrophoresis. Int Wound J 2010;7(4):236-48
79. Edsberg LE, Wyffels JT, Brogan MS, Fries KM. Analysis of the proteomic profile of chronic pressure ulcers. Wound Repair Regen 2012;20(3):378-401
80. Krysa J, Jones GT, van Rij AM. Evidence for a genetic role in varicose veins and chronic venous insufficiency. Phlebology 2012;27(7):329-35
81. Anwar MA, Georgiadis KA, Shalhoub J, et al. A review of familial, genetic, and congenital aspects of primary varicose vein disease. Circ Cardiovasc Genet 2012;5(4): 460-6
82. Cornu-Thenard A, Boivin P, Baud JM, De V. I, Carpentier PH. Importance of the familial factor in varicose disease. Clinical study of 134 families. J Dermatol Surg Oncol 1994;20(5):318-26
83. Serra R, Buffone G, de FA, et al. A genetic study of chronic venous insufficiency. Ann Vasc Surg 2012;26(5):636-42
84. Zamboni P, Tognazzo S, Izzo M, et al. Hemochromatosis C282Y gene mutation increases the risk of venous leg ulceration. J Vasc Surg 2005;42(2):309-14 (Pubitemid 41139239)
85. Tognazzo S, Gemmati D, Palazzo A, et al. Prognostic role of factor XIII gene variants in nonhealing venous leg ulcers. J Vasc Surg 2006;44(4):815-19 (Pubitemid 44441768)
86. Gemmati D, Tognazzo S, Serino ML, et al. Factor XIII V34L polymorphism modulates the risk of chronic venous leg ulcer progression and extension. Wound Repair Regen 2004;12(5):512-17 (Pubitemid 39314333)
87. Zamboni P, De MM, Ongaro A, et al. Factor XIII contrasts the effects of metalloproteinases in human dermal fibroblast cultured cells. Vasc Endovascular Surg 2004;38(5):431-8 (Pubitemid 39363367)
88. Gemmati D, Tognazzo S, Catozzi L, et al. Influence of gene polymorphisms in ulcer healing process after superficial venous surgery. J Vasc Surg 2006;44(3):554-62 (Pubitemid 44293187)
89. Xu HM, Zhao Y, Zhang XM, et al. Polymorphisms in MMP-9 and TIMP-2 in Chinese patients with varicose veins. J Surg Res 2011;168(1):e143-8
90. Yin H, Zhang X, Wang J, et al. Downregulation of desmuslin in primary vein incompetence. J Vasc Surg 2006;43(2): 372-8 (Pubitemid 43221936)
91. Lee S, Lee W, Choe Y, et al. Gene expression profiles in varicose veins using complementary DNA microarray. Dermatol Surg 2005;31(4):391-5 (Pubitemid 40489297)
92. Le FL, Mennen L, Aubry ML, et al. Thrombomodulin promoter mutations, venous thrombosis, and varicose veins. Arterioscler Thromb Vasc Biol 2001;21(3): 445-51
93. Cui C, Liu G, Huang Y, et al. MicroRNA profiling in great saphenous vein tissues of patients with chronic venous insufficiency. Tohoku J Exp Med 2012; 228(4):341-50
94. Escandon J, Vivas AC, Perez R, et al. A prospective pilot study of ultrasound therapy effectiveness in refractory venous leg ulcers. Int Wound J 2012;9(5):570-8
95. Grzela T, Bialoszewska A. Genetic risk factors of chronic venous leg ulceration: Can molecular screening aid in the prevention of chronic venous insufficiency complications? Mol Med Rep 2010;3(2): 205-11
96. Hamdan A. Management of varicose veins and venous insufficiency. JAMA 2012; 308(24):2612-21
97. Staiano-Coico L, Higgins PJ, Schwartz SB, et al. Wound fluids: A reflection of the state of healing. Ostomy Wound Manage 2000; 46(1A Suppl):85S-93S
98. Breslow R. Nutritional status and dietary intake of patients with pressure ulcers: Review of research literature 1943 to 1989. Decubitus 1991;4(1):16-21
99. Breslow RA, Bergstrom N. Nutritional prediction of pressure ulcers. J Am Diet Assoc 1994;94(11):1301-4 (Pubitemid 24366671)
100. Stotts NA, Wipke-Tevis D. Nutrition perfusion, and wound healing: An inseparable triad. Nutrition 1996;12(10): 733-4 (Pubitemid 26393837)
101. Wipke-Tevis DD, Stotts NA. Nutritional risk, status, and intake of individuals with venous ulcers: A pilot study. J Vasc Nurs 1996;14(2):27-33
102. James TJ, Hughes MA, Cherry GW, Taylor RP. Simple biochemical markers to assess chronic wounds. Wound Repair Regen 2000;8(4):264-9
103. Moseley R, Hilton JR, Waddington RJ, et al. Comparison of oxidative stress biomarker profiles between acute and chronic wound environments. Wound Repair Regen 2004;12(4):419-29 (Pubitemid 39007042)
104. bd-El-Aleem SA, Ferguson MW, Appleton I, et al. Expression of cyclooxygenase isoforms in normal human skin and chronic venous ulcers. J Pathol 2001;195(5):616-23
105. Ghaderian SM, Lindsey NJ, Graham AM, et al. Pathogenic mechanisms in varicose vein disease: The role of hypoxia and inflammation. Pathology 2010;42(5):446-53
106. bd-El-Aleem SA, Ferguson MW, Appleton I, et al. Expression of nitric oxide synthase isoforms and arginase in normal human skin and chronic venous leg ulcers. J Pathol 2000; 191(4):434-42
107. Luk PP, Sinha SN, Lord R. Upregulation of inducible nitric oxide synthase (iNOS) expression in faster-healing chronic leg ulcers. J Wound Care 2005;14(8):373-81
108. Wlaschek M, Scharffetter-Kochanek K. Oxidative stress in chronic venous leg ulcers. Wound Repair Regen 2005;13(5):452-61 (Pubitemid 41783163)
109. Zamboni P, Lanzara S, Mascoli F, et al. Inflammation in venous disease. Int Angiol 2008;27(5):361-9
110. Allhorn M, Lundqvist K, Schmidtchen A, Akerstrom B. Heme-scavenging role of alpha1-microglobulin in chronic ulcers. J Invest Dermatol 2003;121(3):640-6 (Pubitemid 37072280)
111. Myers HL. Topical chelation therapy for varicose pigmentation. Angiology 1966; 17(1):66-8
112. Wenk J, Foitzik A, Achterberg V, et al. Selective pick-up of increased iron by deferoxamine-coupled cellulose abrogates the iron-driven induction of matrix-degrading metalloproteinase 1 and lipid peroxidation in human dermal fibroblasts in vitro: A new dressing concept. J Invest Dermatol 2001; 116(6):833-9 (Pubitemid 32554365)
113. Ammons MC, Copie V. Mini-review: Lactoferrin: A bioinspired, anti-biofilm therapeutic. Biofouling 2013;29(4):443-55
114. Moor AN, Vachon DJ, Gould LJ. Proteolytic activity in wound fluids and tissues derived from chronic venous leg ulcers. Wound Repair Regen 2009;17(6): 832-9
115. Hasmann A, Wehrschuetz-Sigl E, Marold A, et al. Analysis of myeloperoxidase activity in wound fluids as a marker of infection. Ann Clin Biochem 2013;50(Pt 3):245-54
116. Lundqvist K, Herwald H, Sonesson A, Schmidtchen A. Heparin binding protein is increased in chronic leg ulcer fluid and released from granulocytes by secreted products of Pseudomonas aeruginosa. Thromb Haemost 2004;92(2):281-7 (Pubitemid 39172308)
117. Lundqvist K, Sorensen OE, Schmidtchen A. Increased levels of human neutrophil alpha-defensins in chronic venous leg ulcers. J Dermatol Sci 2008;51(2):131-4
118. Trostrup H, Lundquist R, Christensen LH, et al. S100A8/A9 deficiency in nonhealing venous leg ulcers uncovered by multiplexed antibody microarray profiling. Br J Dermatol 2011;165(2):292-301
119. Haukipuro K. Synthesis of collagen types I and III in reincised wounds in humans. Br J Surg 1991;78(6):708-12
120. Haukipuro K, Melkko J, Risteli L, et al. Synthesis of type I collagen in healing wounds in humans. Ann Surg 1991;213(1): 75-80
121. Rasmussen LH, Jensen LT, Avnstorp C, et al. Collagen types I and III propeptides as markers of healing in chronic leg ulcers. A noninvasive method for the determination of procollagen propeptides in wound fluid-influence of growth hormone. Ann Surg 1992;216(6):684-91
122. Meyer FJ, Burnand KG, Abisi S, et al. Effect of collagen turnover and matrix metalloproteinase activity on healing of venous leg ulcers. Br J Surg 2008;95(3): 319-25
123. Gallo R, Kim C, Kokenyesi R, et al. Syndecans-1 and-4 are induced during wound repair of neonatal but not fetal skin. J Invest Dermatol 1996;107(5):676-83 (Pubitemid 26371080)
124. Subramanian SV, Fitzgerald ML, Bernfield M. Regulated shedding of syndecan-1 and-4 ectodomains by thrombin and growth factor receptor activation. J Biol Chem 1997;272(23): 14713-20 (Pubitemid 27251736)
125. Kainulainen V, Wang H, Schick C, Bernfield M. Syndecans, heparan sulfate proteoglycans, maintain the proteolytic balance of acute wound fluids. J Biol Chem 1998;273(19):11563-9 (Pubitemid 28272053)
126. Grinnell F, Ho CH, Wysocki A. Degradation of fibronectin and vitronectin in chronic wound fluid: Analysis by cell blotting, immunoblotting, and cell adhesion assays. J Invest Dermatol 1992;98(4):410-16
127. Latijnhouwers MA, Bergers M, Veenhuis RT. Beekman B, nkersmit-Ter Horst MF, Schalkwijk J. Tenascin-C degradation in chronic wounds is dependent on serine proteinase activity. Arch Dermatol Res 1998;290(9):490-6
128. Trengove NJ, Bielefeldt-Ohmann H, Stacey MC. Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound Repair Regen 2000;8(1): 13-25 (Pubitemid 30140796)
129. Wiegand C, Schonfelder U, Abel M, et al. Protease and pro-inflammatory cytokine concentrations are elevated in chronic compared to acute wounds and can be modulated by collagen type I in vitro. Arch Dermatol Res 2010;302(6):419-28
130. Gartner MH, Shearer JD, Bereiter DF, et al. Wound fluid amino acid concentrations regulate the effect of epidermal growth factor on fibroblast replication. Surgery 1991;110(2):448-55
131. Stechmiller JK, Childress B, Cowan L. Arginine supplementation and wound healing. Nutr Clin Pract 2005;20(1):52-61 (Pubitemid 40261940)
132. Childress B, Stechmiller JK, Schultz GS. Arginine metabolites in wound fluids from pressure ulcers: A pilot study. Biol Res Nurs 2008;10(2):87-92
133. Trengove NJ, Langton SR, Stacey MC. Biochemical analysis of wound fluid from nonhealing and healing chronic leg ulcers. Wound Repair Regen 1996;4(2):234-9 (Pubitemid 126674092)
134. Fernandez ML, Upton Z, Edwards H, et al. Elevated uric acid correlates with wound severity. Int Wound J 2012;9(2):139-49
135. Fernandez ML, Upton Z, Shooter GK. Uric Acid and xanthine oxidoreductase in wound healing. Curr Rheumatol Rep 2014;16(2): 396
136. Dodd H. The chronic venous disorders of the lower limb (or varicose veins and ulceration of the leg). J R Inst Public Health 1958;21(2):39-47
137. Dormandy A. Pathophysiology of venous leg ulceration. Int J Microcirc Clin Exp 1997;17(Suppl 1):2-5 (Pubitemid 127793877)
138. James TJ, Hughes MA, Hofman D, et al. Antioxidant characteristics of chronic wound fluid. Br J Dermatol 2001;145(1):185-6
139. James TJ, Hughes MA, Cherry GW, Taylor RP. Evidence of oxidative stress in chronic venous ulcers. Wound Repair Regen 2003;11(3):172-6 (Pubitemid 36648874)
140. Anwar MA, Shalhoub J, Vorkas PA, et al. In-vitro identification of distinctive metabolic signatures of intact varicose vein tissue via magic angle spinning nuclear magnetic resonance spectroscopy. Eur J Vasc Endovasc Surg 2012;44(4):442-50
141. Lopez-Otin C, Overall CM. Protease degradomics: A new challenge for proteomics. Nat Rev Mol Cell Biol 2002; 3(7):509-19 (Pubitemid 34733432)
142. Strlic M, Thomas J, Trafela T, et al. Material degradomics: On the smell of old books. Anal Chem 2009;81(20):8617-22
143. Raffetto JD, Khalil RA. Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Biochem Pharmacol 2008;75(2):346-59 (Pubitemid 350298459)
144. Moali C, Hulmes DJ. Extracellular and cell surface proteases in wound healing: New players are still emerging. Eur J Dermatol 2009;19(6):552-64
145. Toriseva M, Kahari VM. Proteinases in cutaneous wound healing. Cell Mol Life Sci 2009;66(2):203-24
146. Hermes O, Schlage P, auf dem KU. Wound degradomics-current status and future perspectives. Biol Chem 2011; 392(11):949-54
147. Barrick B, Campbell EJ, Owen CA. Leukocyte proteinases in wound healing: Roles in physiologic and pathologic processes. Wound Repair Regen 1999;7(6): 410-22 (Pubitemid 30027563)
148. Herouy Y, Trefzer D, Hellstern MO, et al. Plasminogen activation in venous leg ulcers. Br J Dermatol 2000;143(5):930-6
149. Herouy Y, Trefzer D, Zimpfer U, et al. Matrix metalloproteinases and venous leg ulceration. Eur J Dermatol 2000;10(3): 173-80 (Pubitemid 30186553)
150. Campbell EJ, Cury JD, Shapiro SD, et al. Neutral proteinases of human mononuclear phagocytes. Cellular differentiation markedly alters cell phenotype for serine proteinases, metalloproteinases, and tissue inhibitor of metalloproteinases. J Immunol 1991;146(4): 1286-93
151. Claudy AL, Mirshahi M, Soria C, Soria J. Detection of undegraded fibrin and tumor necrosis factor-Alpha in venous leg ulcers. J Am Acad Dermatol 1991;25(4):623-7
152. Wysocki AB, Staiano-Coico L, Grinnell F. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 1993;101(1):64-8 (Pubitemid 23213014)
153. Rogers AA, Burnett S, Moore JC, et al. Involvement of proteolytic enzymes-plasminogen activators and matrix metalloproteinases-in the pathophysiology of pressure ulcers. Wound Repair Regen 1995;3(3):273-83
154. Kowalewski R, Sobolewski K, Wolanska M, Gacko M. Matrix metalloproteinases in the vein wall. Int Angiol 2004;23(2):164-9 (Pubitemid 39419779)
155. Trengove NJ, Stacey MC, MacAuley S, et al. Analysis of the acute and chronic wound environments: The role of proteases and their inhibitors. Wound Repair Regen 1999;7(6):442-52 (Pubitemid 30027566)
156. Agren MS. Gelatinase activity during wound healing. Br J Dermatol 1994;131(5): 634-40 (Pubitemid 24344047)
157. Bullen EC, Longaker MT, Updike DL, et al. Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. J Invest Dermatol 1995;104(2): 236-40
158. Wysocki AB, Kusakabe AO, Chang S, Tuan TL. Temporal expression of urokinase plasminogen activator, plasminogen activator inhibitor and gelatinase-B in chronic wound fluid switches from a chronic to acute wound profile with progression to healing. Wound Repair Regen 1999;7(3):154-65 (Pubitemid 29331919)
159. Wysocki AB, Grinnell F. Fibronectin profiles in normal and chronic wound fluid. Lab Invest 1990;63(6):825-31
160. Palolahti M, Lauharanta J, Stephens RW, et al. Proteolytic activity in leg ulcer exudate. Exp Dermatol 1993;2(1):29-37 (Pubitemid 23244485)
161. McCarty SM, Cochrane CA, Clegg PD, Percival SL. The role of endogenous and exogenous enzymes in chronic wounds: A focus on the implications of aberrant levels of both host and bacterial proteases in wound healing. Wound Repair Regen 2012; 20(2):125-36
162. Nwomeh BC, Liang HX, Cohen IK, Yager DR. MMP-8 is the predominant collagenase in healing wounds and nonhealing ulcers. J Surg Res 1999;81(2): 189-95 (Pubitemid 29397810)
163. Grinnell F, Zhu M, Parks WC. Collagenase-1 complexes with alpha2-macroglobulin in the acute and chronic wound environments. J Invest Dermatol 1998;110(5):771-6 (Pubitemid 28194026)
164. Weckroth M, Vaheri A, Lauharanta J, et al. Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers. J Invest Dermatol 1996;106(5):1119-24 (Pubitemid 26155102)
165. Amato B, Coretti G, Compagna R, et al. Role of matrix metalloproteinases in non-healing venous ulcers. Int Wound J (in press 2014
166. Yager DR, Zhang LY, Liang HX, et al. Wound fluids from human pressure ulcers contain elevated matrix metalloproteinase levels and activity compared to surgical wound fluids. J Invest Dermatol 1996; 107(5):743-8 (Pubitemid 26371092)
167. Moues CM, van Toorenenbergen AW, Heule F, et al. The role of topical negative pressure in wound repair: Expression of biochemical markers in wound fluid during wound healing. Wound Repair Regen 2008; 16(4):488-94 (Pubitemid 352000314)
168. Rayment EA, Upton Z, Shooter GK. Increased matrix metalloproteinase-9 (MMP-9) activity observed in chronic wound fluid is related to the clinical severity of the ulcer. Br J Dermatol 2008;158(5): 951-61 (Pubitemid 351521431)
169. Serra R, Buffone G, Falcone D, et al. Chronic venous leg ulcers are associated with high levels of metalloproteinases-9 and neutrophil gelatinase-Associated lipocalin. Wound Repair Regen 2013;21(3):395-401
170. Tarlton JF, Bailey AJ, Crawford E, et al. Prognostic value of markers of collagen remodeling in venous ulcers. Wound Repair Regen 1999;7(5):347-55 (Pubitemid 29523010)
171. Agren MS, Jorgensen LN, Andersen M, et al. Matrix metalloproteinase 9 level predicts optimal collagen deposition during early wound repair in humans. Br J Surg 1998;85(1):68-71 (Pubitemid 28034115)
172. Hoffman R, Noble J, Eagle M. The use of proteases as prognostic markers for the healing of venous leg ulcers. J Wound Care 1999;8(6):273-6
173. Hoffman R, Starkey S, Coad J. Wound fluid from venous leg ulcers degrades plasminogen and reduces plasmin generation by keratinocytes. J Invest Dermatol 1998; 111(6):1140-4 (Pubitemid 29115188)
174. Ladwig GP, Robson MC, Liu R, et al. Ratios of activated matrix metalloproteinase-9 to tissue inhibitor of matrix metalloproteinase-1 in wound fluids are inversely correlated with healing of pressure ulcers. Wound Repair Regen 2002; 10(1):26-37 (Pubitemid 34496479)
175. Mwaura B, Mahendran B, Hynes N, et al. The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2 and PDGF-AA on the chronicity of venous leg ulcers. Eur J Vasc Endovasc Surg 2006; 31(3):306-10 (Pubitemid 43263515)
176. Barone EJ, Yager DR, Pozez AL, et al. Interleukin-1alpha and collagenase activity are elevated in chronic wounds. Plast Reconstr Surg 1998;102(4):1023-7 (Pubitemid 128723393)
177. Brook I, Frazier EH. Aerobic and anaerobic microbiology of chronic venous ulcers. Int J Dermatol 1998;37(6):426-8 (Pubitemid 28284869)
178. Grayson LS, Hansbrough JF, Zapata-Sirvent RL, et al. Quantitation of cytokine levels in skin graft donor site wound fluid. Burns 1993;19(5):401-5 (Pubitemid 23283646)
179. Gohel MS, Taylor M, Earnshaw JJ, et al. Risk factors for delayed healing and recurrence of chronic venous leg ulcers-An analysis of 1324 legs. Eur J Vasc Endovasc Surg 2005;29(1):74-7 (Pubitemid 39618995)
180. Gohel MS, Windhaber RA, Tarlton JF, et al. The relationship between cytokine concentrations and wound healing in chronic venous ulceration. J Vasc Surg 2008;48(5):1272-7
181. Harris IR, Yee KC, Walters CE, et al. Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. Exp Dermatol 1995;4(6):342-9
182. Tian YW, Stacey MC. Cytokines and growth factors in keratinocytes and sweat glands in chronic venous leg ulcers. An immunohistochemical study. Wound Repair Regen 2003;11(5):316-25 (Pubitemid 37122562)
183. Tisato V, Zauli G, Voltan R, et al. Endothelial cells obtained from patients affected by chronic venous disease exhibit a pro-inflammatory phenotype. PLoS One 2012;7(6):e39543
184. Fivenson DP, Faria DT, Nickoloff BJ, et al. Chemokine and inflammatory cytokine changes during chronic wound healing. Wound Repair Regen 1997;5(4):310-22 (Pubitemid 127689592)
185. Beidler SK, Douillet CD, Berndt DF, et al. Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy. J Vasc Surg 2009;49(4):1013-20
186. Tisato V, Zamboni P, Menegatti E, et al. Endothelial PDGF-BB produced ex vivo correlates with relevant hemodynamic parameters in patients affected by chronic venous disease. Cytokine 2013;63(2):92-6
187. Peschen M, Grenz H, Brand-Saberi B, et al. Increased expression of platelet-derived growth factor receptor alpha and beta and vascular endothelial growth factor in the skin of patients with chronic venous insufficiency. Arch Dermatol Res 1998; 290(6):291-7 (Pubitemid 28369385)
188. Peschen M, Grenz H, Grothe C, et al. Patterns of epidermal growth factor receptor, basic fibroblast growth factor and transforming growth factor-beta3 expression in skin with chronic venous insufficiency. Eur J Dermatol 1998;8(5):334-8
189. Agren MS, Steenfos HH, Dabelsteen S, et al. Proliferation and mitogenic response to PDGF-BB of fibroblasts isolated from chronic venous leg ulcers is ulcer-Age dependent. J Invest Dermatol 1999;112(4): 463-9 (Pubitemid 29171936)
190. Cowin AJ, Hatzirodos N, Holding CA, et al. Effect of healing on the expression of transforming growth factor beta(s) and their receptors in chronic venous leg ulcers. J Invest Dermatol 2001;117(5):1282-9 (Pubitemid 34205930)
191. Vasquez R, Marien BJ, Gram C, et al. Proliferative capacity of venous ulcer wound fibroblasts in the presence of platelet-derived growth factor. Vasc Endovascular Surg 2004;38(4):355-60 (Pubitemid 39079941)
192. Gillespie DL, Kistner B, Glass C, et al. Venous ulcer diagnosis, treatment, and prevention of recurrences. J Vasc Surg 2010; 52(5 Suppl):8S-14S
193. Hasan A, Murata H, Falabella A, et al. Dermal fibroblasts from venous ulcers are unresponsive to the action of transforming growth factor-beta 1. J Dermatol Sci 1997; 16(1):59-66
194. Kim BC, Kim HT, Park SH, et al. Fibroblasts from chronic wounds show altered TGF-beta-signaling and decreased TGF-beta Type II receptor expression. J Cell Physiol 2003;195(3):331-6 (Pubitemid 36529861)
195. Seidman C, Raffetto JD, Marien B, et al. bFGF-induced alterations in cellular markers of senescence in growth-rescued fibroblasts from chronic venous ulcer and venous reflux patients. Ann Vasc Surg 2003;17(3): 239-44 (Pubitemid 36687571)
196. Kowalewski R, Malkowski A, Sobolewski K, Gacko M. Evaluation of aFGF/bFGF and FGF signaling pathway in the wall of varicose veins. J Surg Res 2009;155(1): 165-72
197. Seidman C, Raffetto JD, Overman KC, Menzoian JO. Venous ulcer fibroblasts respond to basic fibroblast growth factor at the cell cycle protein level. Ann Vasc Surg 2006;20(3):376-80
198. Mast BA, Schultz GS. Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen 1996;4(4):411-20 (Pubitemid 126670858)
199. Lim M, Goldstein MH, Tuli S, Schultz GS. Growth factor, cytokine and protease interactions during corneal wound healing. Ocul Surf 2003;1(2):53-65 (Pubitemid 41263905)
200. Schultz GS, Wysocki A. Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen 2009;17(2):153-62
201. Schultz GS, Davidson JM, Kirsner RS, et al. Dynamic reciprocity in the wound microenvironment. Wound Repair Regen 2011;19(2):134-48
202. McDaniel JC, Roy S, Wilgus TA. Neutrophil activity in chronic venous leg ulcers-A target for therapy? Wound Repair Regen 2013;21(3):339-51
203. Lauer G, Sollberg S, Cole M, et al. Expression and proteolysis of vascular endothelial growth factor is increased in chronic wounds. J Invest Dermatol 2000; 115(1):12-18 (Pubitemid 30470185)
204. Raffetto JD, Vasquez R, Goodwin DG, Menzoian JO. Mitogen-Activated protein kinase pathway regulates cell proliferation in venous ulcer fibroblasts. Vasc Endovascular Surg 2006;40(1):59-66 (Pubitemid 43201916)
205. Raffetto JD, Gram CH, Overman KC, Menzoian JO. Mitogen-Activated protein kinase p38 pathway in venous ulcer fibroblasts. Vasc Endovascular Surg 2008; 42(4):367-74
206. Moore K, Ruge F, Harding KG. T lymphocytes and the lack of activated macrophages in wound margin biopsies from chronic leg ulcers. Br J Dermatol 1997;137(2):188-94 (Pubitemid 27333350)
207. Boyce DE, Jones WD, Ruge F, et al. The role of lymphocytes in human dermal wound healing. Br J Dermatol 2000;143(1): 59-65 (Pubitemid 30485245)
208. Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol 2011;11(11):723-37
209. Cirino G, Napoli C, Bucci M, Cicala C. Inflammation-coagulation network: Are serine protease receptors the knot? Trends Pharmacol Sci 2000;21(5):170-2
210. Overall CM, Lopez-Otin C. Strategies for MMP inhibition in cancer: Innovations for the post-Trial era. Nat Rev Cancer 2002; 2(9):657-72 (Pubitemid 37328917)
211. Raffetto JD, Khalil RA. Ca(2+)-dependent contraction by the saponoside escin in rat vena cava: Implications in venotonic treatment of varicose veins. J Vasc Surg 2011;54(2):489-96
212. Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation 2005;111(18): 2398-409 (Pubitemid 40647076)
213. Mannello F, Medda V, Ligi D, Raffetto JD. Glycosaminoglycan sulodexide inhibition of MMP-9 gelatinase secretion and activity: Possible pharmacological role against collagen degradation in vascular chronic diseases. Curr Vasc Pharmacol 2013;11(3): 354-65
214. Mannello F, Ligi D, Raffetto JD. Glycosaminoglycan sulodexide modulates inflammatory pathways in chronic venous disease. IntAngiol in press 2014
215. Katz MH, Alvarez AF, Kirsner RS, et al. Human wound fluid from acute wounds stimulates fibroblast and endothelial cell growth. J Am Acad Dermatol 1991; 25(6 Pt 1):1054-8
216. Tarnuzzer RW, Schultz GS. Biochemical analysis of acute and chronic wound environments. Wound Repair Regen 1996; 4(3):321-5 (Pubitemid 126670847)
217. Cooper DM, Yu EZ, Hennessey P, et al. Determination of endogenous cytokines in chronic wounds. Ann Surg 1994;219(6): 688-91
218. Kirsner RS, Marston WA, Snyder RJ, et al. Spray-Applied cell therapy with human allogeneic fibroblasts and keratinocytes for the treatment of chronic venous leg ulcers: A phase 2, multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2012;380(9846):977-85
219. Lantis JC, Marston WA, Farber A, et al. The influence of patient and wound variables on healing of venous leg ulcers in a randomized controlled trial of growth-Arrested allogeneic keratinocytes and fibroblasts. J Vasc Surg 2013;58(2):433-9
220. Grinnell F, Zhu M. Fibronectin degradation in chronic wounds depends on the relative levels of elastase, alpha1-proteinase inhibitor, and alpha2-macroglobulin. J Invest Dermatol 1996;106(2):335-41 (Pubitemid 26094619)
221. Herrick S, Ashcroft G, Ireland G, et al. Up-regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation. Lab Invest 1997;77(3):281-8 (Pubitemid 27413540)
222. Schmidtchen A. Degradation of antiproteinases, complement and fibronectin in chronic leg ulcers. Acta Derm Venereol 2000;80(3):179-84
223. Vaalamo M, Leivo T, Saarialho-Kere U. Differential expression of tissue inhibitors of metalloproteinases (TIMP-1,-2,-3, and-4) in normal and aberrant wound healing. Hum Pathol 1999;30(7):795-802 (Pubitemid 29325786).