Vacuum-assisted Closure Therapy Attenuates the Inflammatory Response in a Porcine Acute Wound Healing Model
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Disclosure: Financial support for this study was provided by KCI.
Initial injury to the skin triggers coagulation and an acute inflammatory response followed by cell recruitment, proliferation, and matrix synthesis. Disruption in any of these stages of the healing response can either delay or significantly impair wound healing. For example, failure to resolve inflammation can lead to chronic nonhealing wounds, whereas uncontrolled matrix accumulation, often involving aberrant pathways, can lead to excess scarring and fibrotic sequelae. Pro-inflammatory cytokines, growth factors, and proteases have been implicated as key regulators of wound healing.1,2 By investigating the complex roles of biomolecules in wound healing, the pathways that result in their inhibition or enhancement can be better understood and wound healing better controlled or modulated.
Vacuum-assisted Closure® (V.A.C.® Therapy, KCI, San Antonio, Tex), also referred to as V.A.C.® Brand Negative Pressure Wound Therapy (NPWT), is a relatively new and increasingly established treatment for promoting wound healing.3–5 Considerable interest has centered on elucidating the mechanism of action for this treatment modality. Early clinical evidence that NPWT affects the amount of cytokines and proteases in wounds includes altered expression of genes for inflammatory cytokines,6 and reduced matrix metalloproteases.7–9 More recently, it has been shown that levels of tumor necrosis factor-alpha (TNF-a), a pro-inflammatory cytokine, decreased in wound fluid from adults with chronic pressure ulcers treated with NPWT over a 7-day period.8
Application of NPWT to full-thickness excisional wounds in young, otherwise healthy swine has been shown to accelerate the rate of granulation tissue formation, allowing for earlier wound closure.10,11 Preliminary studies in swine have indicated that the levels of selected cytokines are altered by NPWT,12,13 suggesting that this treatment may have systemic effects on cytokine levels in the blood. Immediate use of NPWT on pigs with large scald burns (> 15% body surface area) prevented the typical post-burn decrease in mesenteric artery blood flow, which correlated with changes in serum concentrations of IL-6 and IL-8 over the first 4 hours after wounding.12 More recently, Kilpadi et al13 reported that increases in serum levels of IL-10 occurred within the first 2 hours following creation of an excisional wound, whereas IL-6 levels were maintained throughout the 4 hours of treatment with NPWT.
In the present study using a porcine wound healing model, the potential systemic effects of NPWT were measured between 12 and 180 hours after wounding. The primary focus of this work was to examine the effect of NPWT on the pro-inflammatory phase of wound healing. Levels of selected pro-inflammatory cytokines, namely interferon-gamma (IFN-g), IL-1b, IL-4, IL-6, IL-8, transforming growth factor-beta1 (TGF-b1), and tumor necrosis factor-alpha (TNF-a), in serum and in wound fluid were assessed in this study in an effort to characterize how NPWT may attenuate the acute pro-inflammatory response.
Materials and Methods
1. 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):64–68.
2. Schultz G. Molecular regulation of the wound environment. In: Bryant RA, ed. Acute and Chronic Wounds. 2nd ed. St. Louis, Mo: Mosby; 1994:413–429.
3. Joseph E, Hamori CA, Bergman S, Road E, Swann NF, Anastasi GW. New therapeutic approaches in wound care. A prospective randomized trial of vacuum-assisted closure versus standard therapy of chronic nonhealing wounds. WOUNDS. 2000;12(3):60–67.
4. McCallon SK, Knight CA, Valiulus JP, Cunningham MW, McCulloch JM, Farinas LP. Vacuum-assisted closure versus saline-moistened gauze in the healing of postoperative diabetic foot wounds. Ostomy Wound Manage. 2000;46(8):28–32.
5. Argenta LC, Morykwas MJ. Vacuum-assisted closure: a new method for wound control and treatment: clinical experience. Ann Plast Surg. 1997;38(6):563–576.
6. Bennett D, Komorowska-Timek E, Gabriel A, et al. Characterizing the changing gene statement of chronic wounds treated with subatmospheric pressure therapy. Presented at the Plastic Surgery Research Council Annual Meeting, 2002.
7. Badier-Commander C. Verbeuren T, Lebard C, Michel JB, Jacob MP. Increased TIMP/MMP ratio in varicose veins: a possible explanation for extracellular matrix accumulation. J Pathol. 2000;192(1):105–112.
8. Stechmiller JK, Kilpadi DV, Childress B, Shultz GS. Effect of vacuum-assisted closure therapy on the expression of cytokines and proteases in wound fluid of adults with pressure ulcers. Wound Repair Regen. 2006;14(3):371–373.
9. Vanwijck R, Manicourt, D, Feruzi-Lukina, G. Biological monitoring of wounds treated by negative pressure. Presented at the European Tissue Repair Society Meeting, Nice, France, 2002.
10. Morykwas MJ, Argenta LC, Shelton-Brown EI, McGuirt W. Vacuum-assisted closure: a new method for wound control and treatment: animal studies and basic foundation. Ann Plast Surg. 1997;38(6):553–562.
11. Morykwas MJ, Faler BJ, Pearce DJ, Argenta LC. Effects of varying levels of subatmospheric pressure on the rate of granulation tissue formation in experimental wounds in swine. Ann Plast Surg. 2001;47(5):547–551.
12. Kremers L, Wanner M, Webb K, et al. Serum interleukin levels post-burn with and without application of sub-atmospheric pressure. Presented at the American Burn Association Meeting, Miami, Fla, 2003.
13. Kilpadi DV, Bower CE, Reade CC, et al. Effect of vacuum assisted closure therapy on early systemic cytokine levels in a swine model. Wound Repair Regen. 2006;14(2):210–215.
14. Pirone LA, Monte KA, Shannon RJ, Bolton LL. Wound healing under occlusion and non-occlusion in partial-thickness and full-thickness wounds in swine. WOUNDS. 1990;2(2):74–81.
15. Sullivan TP, Eaglstein WH, Davis SC, et al. The pig as a model for human wound healing. Wound Rep Regen. 2001;9(2):66–76.
16. Davidson JM. Experimental animal wound models. WOUNDS. 2001;13(1):9–23.
17. Gottrup F, Agren MS, Karlsmark T. Models for use in wound healing research: a survey focusing on in vitro and in vivo adult soft tissue. Wound Rep Regen. 2000;8(2):83–96.
18. Dubravec DB, Spriggs DR, Mannick JA, Rodrick ML. Circulating human peripheral blood granulocytes synthesize and secrete tumor necrosis factor alpha. Proc Natl Acad Sci U S A. 1990;87(17):6758–6761.
19. Klebanoff SJ, Vadas MA, Harlan JM, et al. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986;136(11):4220–4225.
20. Dovi JV, He LK, DiPetro LA. Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol. 2003;73(4):448–455.
21. Luster AD. Chemokines—chemotactic cytokines that mediate inflammation. N Engl J Med. 1998;338(7):436–445.
22. Taub DD, Proost P, Murphy WJ, et al. Monocyte chemotactic protein-1 (MCP-1), -2, and -3 are chemotactic for human T lymphocytes. J Clin Invest. 1995;95(3):1370–1376.
23. Lu B, Rutledge BJ, Gu L, et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med. 1998;187(4):601–608.
24. Charo IF, Taubman MB. Chemokines in the pathogenesis of vascular disease. Circ Res. 2004;95(9):858–866.
25. Gallucci RM, Simeonova PP, Matheson JM, et al. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J. 2000;14(15):2525–2531.
26. Goodman GJ. Post-acne scarring: a short review of its pathophysiology. Australas J Dermatol. 2001;42(2):84–90.
27. Jacob CI, Dover JS, Kaminer MS. Acne scarring: a classification system and review of treatment options. J Am Acad Dermatol. 2001;45(1):109–117.
28. Wilgus TA, Vodovotz Y, Vittadini E, Clubbs EA, Oberyszyn TM. Reduction of scar formation in full-thickness wounds with topical celecoxib treatment. Wound Repair Regen. 2003;11(1):25–34.
29. Suh DY, Hunt TK. Time line of wound healing. Clin Podiatr Med Surg. 1998;15(1):1–9.
30. Schultz GS, Sibbald RG, Falanga V, et al. Wound bed preparation: a systematic approach to wound management. Wound Repair Regen. 2003;11(Suppl 1):S1–S28.
31. Dovi JV, Szpaderska AM, DiPietro LA. Neutrophil function in the healing wound: adding insult to injury? Thromb Haemost. 2004;92(2):275–280.
32. Leibovich SJ, Ross R. The role of the macrophage in wound repair: a study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78(1):71–100.
33. Adams TST, Herrick S, McGrouther DA. V.A.C.® therapy alters the number and distribution of neutrophils in acute dermal wounds. Topical Negative Pressure. European Tissue Research Society Focus Group Meeting, London, UK; 2003:212.
34. Henry G, Garner WL. Inflammatory mediators in wound healing. Surg Clin N Am. 2003;83(3):483–507.
35. Hamilton JA, Anderson GP. GM-CSF biology. Growth Factors. 2004;22(4):225–231.
36. Roberts AW. G-CSF: a key regulator of neutrophil production, but that’s not all! Growth Factors. 2005;23(1):33–41.
37. Lenhoff S, Sallerfors B, Olofsson T. T lymphocytes downregulate granulocyte-macrophage colony-stimulating factor secretion from stimulated monocytes by increasing the secretion of monocyte-derived interleukin-10. Exp Hematol. 1999;27(3):410–415.
38. Belardelli F. Role of interferons and other cytokines in the regulation of the immune response. APMIS. 1995;103(3):161–179.
39. Fujiwara N, Kobayashi K. Macrophages in inflammation. Curr Drug Targets Inflamm Allergy. 2005;4(3):281–286.
40. Coico R, Sunshine G, Benjamini E. Cytokines. In: Coico R, Sunshine G, Benjamini E, eds. Immunology. 5th ed. Hoboken, NJ: John Wiley and Sons; 2003;149–164.
41. Sandler NG, Mentink-Kane MM, Cheever AW, WYNN TA. Global gene expression profiles during acute pathogen-induced pulmonary inflammation reveal divergent roles for Th1 and Th2 responses in tissue repair. J Immunol. 2003;171(7):3655–3667.
42. Tarnuzzer RW, Schultz GS. Biochemical analysis of acute and chronic wound environments. Wound Repair Regen. 1996;4(3):321–325.
43. Kumar S, Wong PF, Leaper DJ. What is new in wound healing? Turk J Med Sci. 2004;3:147–160.
44. Kishimoto T. The biology of interleukin-6. Blood. 1989;74(1):1–10.
45. Barton BE. IL-6: insights into novel biological activities. Clin Immunol Immunopathol. 1997;85(1):16–20.
46. Lin ZQ, Kondo T, Ishida Y, Takayasu T, Mukaida N. Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice. J Leukoc Biol. 2003;73(6):713–721.
47. Montero-Julian FA. The soluble IL-6 receptors: serum levels and biological function. Cell Mol Biol. 2001;47(4):583–597.
48. Omoigui S. Cholesterol synthesis is the trigger and isoprenoid dependent interleukin-6 mediated inflammation is the common causative factor and therapeutic target for atherosclerotic vascular disease and age-related disorders including osteoporosis and type 2 diabetes. Med Hypotheses. 2005;65(3):559–569.
49. Mast BA, Schultz GS. Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Repair Regen. 1996;4(4):411–420.
50. Kitamura M, Suto TS. TGF-beta and glomerulonephritis: anti-inflammatory versus prosclerotic actions. Nephrol Dial Transplant. 1997;12(4):669–679.
51. Wahl SM, Transforming growth factor: the good, the bad, and the ugly. J Exp Med. 1994;180(5):1587–1590.
52. Yao F, Visovatti S, Johnson CS, et al. Age and growth factors in porcine full-thickness wound healing. Wound Repair Regen. 2001;9(5):371–377.
53. Breuing K, Andree C, Helo G, Slama J, Liu PY, Eriksson E. Growth factors in the repair of partial-thickness porcine skin wounds. Plast Reconstr Surg. 1997;100(3):657–664.
54. Kilpadi DV, Kall S, Comerio M, et al. Concentration of VEGF, TGF-b1, and BMP-2 in fluid from acute wounds during V.A.C.® Therapy. Abstract presented at the Wound Healing Society Annual Meeting, Scottsdale, Ariz, 2006.
55. Banwell PE. The biochemical wound environment and topical negative pressure therapy. European Tissue Repair Society TNP Focus Group Meeting, London, UK, December, 2003.
56. Graves DT, Nooh N, Gillen T, et al. IL-1 plays a critical role in oral, but not dermal, wound healing. J Immunol. 2001;167(9):5316–5320.
57. Hack CE, Aarden LA, Thijs LG. Role of cytokines in sepsis. Adv Immunol. 1997;66:101–195.
58. Norbury K, Ness-Piacente M, Damaj B, et al. Systemic effect of vacuum-assisted closure (V.A.C.® Therapy) in swine with full-thickness acute wounds. Abstract presented at the Wound Healing Society Meeting, Chicago Ill, 2005.
