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Protease and pro-inflammatory cytokine concentrations are elevated in chronic compared to acute wounds and can be modulated by collagen type I in vitro

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Abstract

Physiological wound repair is a highly regulated, complex process, which leads to formation of new tissue after injury. However, the healing process is not perfect and healing impairments can occur. Delayed healing and formation of chronic wounds has been linked to the excessive production of proteolytic enzymes leading to reduced amounts of growth factors and successive destruction of the extracellular matrix. It has been implied that there is an alteration in the normal control mechanisms regulating the levels of these enzymes. The study presented provides data on the concentration of proteases and cytokines in wound fluid from chronic when compared with acute wounds. Levels of proteases such as PMN elastase, matrix metalloproteinases-2 (MMP-2), and MMP-13 were found to be profoundly elevated in chronic when compared with acute wound fluids. In addition, concentrations of IL-1β, IL-6, and IL-8 were shown to be significantly higher in chronic than in acute wounds. Furthermore, the ability of a wound dressing, consisting of bovine collagen type I, to bind pro-inflammatory cytokines was investigated. Collagen type I was able to bind significant amounts of the pro-inflammatory cytokines in vitro. Thus, it should be able to establish a more physiological wound milieu in vivo and promote healing.

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Abbreviations

ECM:

Extracellular matrix

EGF:

Epidermal growth factor

FGF:

Fibroblast growth factor

IL-1:

Interleukin-1

IL-6:

Interleukin-6

IL-8:

Interleukin-8

MMPs:

Matrix metalloproteases

PMN granulocytes:

Polymorphonuclear granulocytes

PDGF:

Platelet-derived growth factor

ROS:

Reactive oxygen species

TGF:

Tumor growth factor

TIMPs:

Tissue inhibitor of matrix metalloproteases

TNF-α:

Tumor necrosis factor-α

VEGF:

Vascular endothelial growth factor

References

  1. Barone EJ, Yager DR, Pozez AL, Olutoye OO, Crossland MC, Diegelmann RF et al (1998) Interleukin-1(alpha) and collagenase activity are elevated in chronic wounds. Plas Recon Surg 102:1023–1027

    Article  CAS  Google Scholar 

  2. Barrick B, Campbell EJ, Owen CA (1999) Leukocyte proteinases in wound healing: roles in physiologic and pathologic processes. Wound Rep Reg 7:410–422

    Article  CAS  Google Scholar 

  3. Baum CL, Arpey CJ (2005) Normal cutaneous wound healing: clinical correlation with cellular and molecular events. Dermatol Surg 31:674–686

    Article  CAS  PubMed  Google Scholar 

  4. Diegelmann RF (2003) Excessive neutrophils characterize chronic pressure ulcers. Wound Rep Reg 11:490–495

    Article  Google Scholar 

  5. Dinarello CA (1991) Interleukin-1 and interleukin-1 antagonism. Blood 77:1627–1652

    CAS  PubMed  Google Scholar 

  6. Dissemond J (2006) Wann ist eine Wunde chronisch? Hautarzt 57:55

    Article  CAS  PubMed  Google Scholar 

  7. Farndale RW, Sixma JJ, Barnes MJ, de Groot PG (2004) The role of collagen in thrombosis and hemostasis. J Thromb Haemost 2:561–573

    Article  CAS  PubMed  Google Scholar 

  8. Friess W (1998) Collagen—biomaterial for drug delivery. Eur J Pharm Biopharm 45:113–136

    Article  CAS  PubMed  Google Scholar 

  9. Gallucci RM, Simeonova PP, Metheson JM, Kommineni C, Guriel JL, Sugawara T et al (2000) Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J 14:2525–2531

    Article  CAS  PubMed  Google Scholar 

  10. Gillitzer R, Goebeler M (2001) Chemokines in cutaneous wound healing. J Leukoc Biol 69:513–521

    CAS  PubMed  Google Scholar 

  11. Giuliani AL, Spisani S, Cavalletti T, Reali E, Melchiorri L, Ferrari L et al (1993) Fibroblasts increase adhesion to neutrophils after stimulation with phorbol ester and cytokines. Cell Immunol 149:208–222

    Article  CAS  PubMed  Google Scholar 

  12. Goren I, Müller E, Pfeilschnifter F, Frank S (2006) Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice—a potential role of tumor necrosis factor-α. Am J Pathol 168:765–777

    Article  CAS  PubMed  Google Scholar 

  13. Grinnel F, Ho CH, Wysocki A (1992) Degradation of fibronectin and vitronectin in chronic wound fluid: analysis by cell blotting, immunoblotting, and cell adhesion assays. J Invest Dermatol 98:410–416

    Article  Google Scholar 

  14. Haernandez-Quintero M, Robles AG, Kuri-Harcuch W, Castro-Munozledo F (2006) Interleukin-6 promotes human epidermal keratinocyte proliferation and keratin cytoskeleton reorganization in culture. Cell Tissue Res 325:77–90

    Article  Google Scholar 

  15. Hamada Y, Kondoh T, Holmlund AB, Yamamoto M, Horie A, Saito T et al (2006) Inflammatory cytokines correlated with clinical outcome of temporomandibular joint irrigation in patients with chronic closed lock. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:596–601

    Article  PubMed  Google Scholar 

  16. Han Y-P, Tuan T-L, Wu H, Hughes M, Garner WL (2001) TNF-α stimulates activation of pro-MMP2 in human skin through NF-κB mediated induction of MT1-MMP. J Cell Sci 114:131–139

    CAS  PubMed  Google Scholar 

  17. Harris IR, Yee KC, Walters CE, Cunliffe WJ, Kearney JN, Wood EJ et al (1995) Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. Exp Dermatol 4:342–349

    Article  CAS  PubMed  Google Scholar 

  18. Herrick S, Ashcroft G, Ireland G, Horan M, MaCollum C, Ferguson M (1997) Up-regulation of elastase in acute wounds of healthy aged humans and chronic venous leg ulcers are associated with matrix degradation. Lab Invest 77:281–288

    CAS  PubMed  Google Scholar 

  19. Lie J, Kirsner R (2007) Pathophysiology of acute wound healing. Clin Dermatol 25:9–18

    Article  Google Scholar 

  20. Mast BA, Schultz GS (1996) Interactions of cytokines, growth factors, and proteases in acute and chronic wounds. Wound Rep Reg 4:411–420

    Article  CAS  Google Scholar 

  21. Mayer W, Jochmann W, Partsch H (1994) Ulcus cruris: Abheilung unter konservativer Therapie. Eine prospektive Studie. Wien Med Wschr 44:250–252

    Google Scholar 

  22. Metzmacher I, Ruth P, Abel M, Friess W (2007) In vitro binding of matrix metalloproteinases-2 (MMP-2), MMP-13, and bacterial collagenase on collagenous wound dressings. Wound Rep Reg 15:549–555

    Article  Google Scholar 

  23. Nezu T, Winnik FM (2000) Interaction of water-soluble collagen with poly(acrylic acid). Biomaterials 21:415–419

    Article  CAS  PubMed  Google Scholar 

  24. Nwomeh BC, Liang HX, Cohen IK, Yager DR (1999) MMP-8 is the predominant collagenase in healing wounds and nonhealing ulcers. J Surg Res 81:189–195

    Article  CAS  PubMed  Google Scholar 

  25. Pachence JM (1996) Collagen-based devices for soft tissue repair. Biomed Mater Res 33:35–40

    Article  CAS  Google Scholar 

  26. Persikov AV, Ramshaw JA, Kirkpatrick A, Brodsky B (2002) Peptide investigations of pairwise interactions in the collagen triple-helix. J Mol Biol 316:385–394

    Article  CAS  PubMed  Google Scholar 

  27. Ramshaw JAM, Werkmeister JA, Glattauer V (1996) Collagen-based biomaterials. Biotechnol Genet Eng Rev 13:335–382

    CAS  PubMed  Google Scholar 

  28. Saarialho-Kere UK (1998) Patterns of matrix metalloproteinases and TIMP expression in chronic ulcers. Arch Dermatol Res 290(Suppl):547–554

    Google Scholar 

  29. Sandler NA, Buckley MJ, Cillo JE, Braun TW (1998) Correlation of inflammatory cytokines with arthroscopic findings in patients with temporomandibular joint internal derangements. J Oral Maxillofac Surg 56:534–543

    Article  CAS  PubMed  Google Scholar 

  30. Schönfelder U, Abel M, Wiegand C, Klemm D, Elsner P, Hipler U-C (2005) Influence of selected wound dressings on PMN elastase in chronic wound fluid and their antioxidative potential in vitro. Biomaterials 26:6664–6673

    Article  PubMed  Google Scholar 

  31. Takahashi T, Kondoh T, Fukuda M, Yamazaki Y, Toyosaki T, Suzuki R (1998) Proinflammatory cytokines detectable in synovial fluids from patients with temporomandibular disorders. Oral Surg Oral Pathol Oral Radiol Endod 85:135–141

    Article  CAS  Google Scholar 

  32. Taravel MN, Domard A (1993) Relation between the physicochemical characteristics of collagen and its interactions with chitosan: I. Biomaterials 14:930–938

    Article  CAS  PubMed  Google Scholar 

  33. Trengrove NJ, Stacey MC, MacAuley S, Bennett N, Gibson J, Burslem F et al (1999) Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Rep Reg 7:442–452

    Article  Google Scholar 

  34. Vaalamo M, Mattila L, Johansson N, Kariniemi AL, Karjalainen-Lindsberg ML, Kähäri VM et al (1997) Distinct populations of stromal cells express collagenase-3 (MMP-13) and collagenase-1 (MMP-1) in chronic ulcers but not in normally healing wounds. J Invest Dermatol 109:96–101

    Article  CAS  PubMed  Google Scholar 

  35. Vaalamo M, Weckroth M, Puolakkainen P, Kere J, Saarinen P, Lauharanta J et al (1996) Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol 135:52–59

    Article  CAS  PubMed  Google Scholar 

  36. Vaidyanathan J, Chinnaswamy K, Vaidyanathan TK (2003) Biomimetic recognition and immunochemical assay of ligand binding to collagen. J Adhes Dent 5:7–17

    CAS  PubMed  Google Scholar 

  37. Venugopal MG, Ramshaw JAM, Braswell E, Zhu D, Brodsky B (1994) Electrostatic interactions in collagen-like triple-helical peptides. Biochemistry 33:7948–7956

    Article  CAS  PubMed  Google Scholar 

  38. Wagner WR, Pachence JM, Ristich J, Johnson PC (1996) Comparative in vitro analysis of topical hemostatic agents. J Surg Res 66:100–108

    Article  CAS  PubMed  Google Scholar 

  39. Weckroth M, Vaheri A, Lauharanta J, Sorsa T, Konttinen YT (1996) Matrix metalloproteinases, gelatinase and collagenase, in chronic leg ulcers. J Invest Dermatol 106:1119–1124

    Article  CAS  PubMed  Google Scholar 

  40. Whitney JD (2005) Overview: acute and chronic wounds. Nurs Clin N Am 40:191–205

    Article  Google Scholar 

  41. Wiegand C, Abel M, Ruth P, Wilhelms T, Schulze D, Norgauer J, Hipler UC (2009) Effects of the sterilization method on the performance of collagen type I on chronic wound parameters in vitro. J Biomed Mater Res Part B: Appl Biomater 90B:710–719

    Article  CAS  Google Scholar 

  42. Wiegand C, Heinze T, Hipler UC (2009) Comparative in vitro study on cytotoxicity, antimicrobial activity, and binding capacity for pathophysiological factors in chronic wounds of alginate and silver-containing alginate. Wound Rep Reg 17:511–521

    Article  Google Scholar 

  43. Winter GD (1962) Formation of the scab and the rate of epithelisation of superficial wounds in the skin of the young domestic pig. Nature 193:293–294

    Article  CAS  PubMed  Google Scholar 

  44. Wysocki AB, Grinnel F (1990) Fibronectin profiles in normal and chronic wound fluid. Lab Invest 63:825–831

    CAS  PubMed  Google Scholar 

  45. Wysocki AB, Staiano-Coico L, Grinnell F (1993) Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 101:64–68

    Article  CAS  PubMed  Google Scholar 

  46. Yager DR, Chen SM, Ward SI, Olutoye OO, Diegelman RF, Cohen IK (1997) Ability of chronic wound fluids to degrade peptide growth factors is associated with increased levels of elastase activity and diminished levels of proteinase inhibitors. Wound Rep Reg 5:23–32

    Article  Google Scholar 

  47. Yager DR, Nwomeh BC (1999) The proteolytic environment of chronic wounds. Wound Rep Reg 7:433–441

    Article  CAS  Google Scholar 

  48. Yagmur Y, Ozturk H, Unaldi M, Gedik E (2005) Relation between severity of injury and the early activation of interleukins in multiple-injured patients. Eur Surg Res 37:360–364

    Article  CAS  PubMed  Google Scholar 

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Conflict of interest statement

This study was in part financially supported by Lohmann & Rauscher GmbH & Co. KG, Rengsdorf (Germany). The authors Dr. Abel and Dr. Ruth are employees of Lohmann & Rauscher GmbH & Co. KG.

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Authors and Affiliations

  1. Department of Dermatology and Dermatological Allergy, University Hospital Jena, Erfurter Str. 35, 07740, Jena, Germany

    Cornelia Wiegand, Ute Schönfelder, Martin Kaatz & Uta-Christina Hipler

  2. Lohmann & Rauscher GmbH & Co. KG, 56579, Rengsdorf, Germany

    Martin Abel

  3. Lohmann & Rauscher GmbH & Co. KG, 56564, Neuwied, Germany

    Peter Ruth

Authors
  1. Cornelia Wiegand
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  2. Ute Schönfelder
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  6. Uta-Christina Hipler
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Correspondence to Cornelia Wiegand.

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Wiegand, C., Schönfelder, 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 302, 419–428 (2010). https://doi.org/10.1007/s00403-009-1011-1

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  • DOI: https://doi.org/10.1007/s00403-009-1011-1

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