The Biological Mechanisms Behind Injury and Inflammation: How They Can Affect Treatment Strategy, Product Performance, and Heali
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Disclosure: Dr. Parenteau and Dr. Young are principals of Parenteau BioConsultants, Inc. This article represents a synopsis of some findings from a report series published and sold by the firm.
The scientific understanding of wound healing has advanced significantly over the last 20 years. In the last 5 to 10 years alone, the biology of inflammation, repair, and regeneration has been advanced by the tremendous effort to understand factors and signaling mechanisms involved in inflammation, angiogenesis, and cell proliferation—particularly as they relate to cancer progression1–3 and cardiovascular disease.4–6 While cutaneous healing research has certainly contributed to this body of information,7,8 product development and clinical practice has not benefitted from recent advances in the scientific understanding of these processes as much as it could have benefitted. An extensive review and analysis of the available biological data regarding the biological mechanisms and the relationships between biological processes that could impact wound repair was undertaken.9 Presented is a synopsis of findings regarding the role of injury and innate immunity and how each has the potential to impact healing and the practice of wound care.
The difficulty in dissecting cutaneous healing has always been compounded by the fact that the biological processes are being carried out in an environment where physical factors can have almost as much impact as physiological factors. There is no doubt that practically speaking, the management of the physical environment, (ie, a moist healing environment, control of wound exudate, and control of bacterial contamination), has an impact on healing. For normal acute healing, this management may be all that is necessary to enable an optimum outcome. However, chronic wound conditions like a chronic venous ulcer or a hard to heal diabetic foot ulcer can be biologically and physiologically far removed from the norm. While environmental conditions are still a factor, they are more likely to be superseded by underlying pathological processes in these cases. To significantly improve healing in chronic wounds requires going beyond the physical environment to address the biological mechanisms affected by the pathological causes of tissue failure and ultimately, the inadequate response mechanisms that undermine the ability to heal. In the chronic wound, the interaction and relationship of the biological processes of repair and regeneration are more likely to be the final arbiters of success for any treatment regimen or therapeutic product.
Although the response mechanisms of the chronic wound may be altered,10–15 the native processes and biological relationships between them still serve as the foundation for cellular behavior and interaction. This synopsis focuses on the biological mechanisms underlying the acute injury and innate immune responses. The analysis draws from available knowledge of injury and inflammatory signaling and cell response. The mechanisms concerned with injury and inflammation and how they impact the biological goals of wound repair are examined. Examples are given to illustrate ways in which a biological perspective can affect how one might view and ultimately treat wounds in different situations.
The Connection of Injury and Inflammation
1. Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science. 2002;296(5573):1634–1635.
2. Karin M. Inflammation and cancer: the long reach of Ras. Nat Med. 2005;11(1):20–21.
3. Karin M, Greten FR. NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol. 2005;5(10):749–759.
4. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest. 2005;115(12):3378–3384.
5. Penn MS, and Topol EJ. Tissue factor, the emerging link between inflammation, thrombosis, and vascular remodeling. Circ Res. 2001;89(1):1–2.
6. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407(6801):258–264.
7. Banno T, Gazel A, Blumenberg M. Effects of tumor necrosis factor-alpha (TNF alpha) in epidermal keratinocytes revealed using global transcriptional profiling. J Biol Chem. 2004;279(31):32633–32642.
8. Szpaderska AM, Zuckerman JD, DiPietro LA. Differential injury responses in oral mucosal and cutaneous wounds. J Dent Res. 2003;82(8):621–626.
9. Parenteau NA, Hardin-Young J. Cutaneous healing. In: Achieving Medical and Commercial Success in Wound Repair and Regeneration. Vol 1. Fair Haven, Vt: Parenteau BioConsultants, LLC; 2006:1–396.
10. 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):463–469.
11. Cook H, Davies KJ, Harding KG, Thomas DW. Defective extracellular matrix reorganization by chronic wound fibroblasts is associated with alterations in TIMP-1, TIMP-2, and MMP-2 activity. J Invest Dermatol. 2000;115(2):225–233.
12. 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):1282–1289.
13. Galkowska H, Wojewodzka U, Olszewski WL. Low recruitment of immune cells with increased expression of endothelial adhesion molecules in margins of the chronic diabetic foot ulcers. Wound Repair Regen. 2005;13(3):248–254.
14. He C, Hughes MA, Cherry GW, Arnold F. Effects of chronic wound fluid on the bioactivity of platelet-derived growth factor in serum-free medium and its direct effect on fibroblast growth. Wound Repair Regen. 1999;7(2):97–105.
15. Dalton SJ, Mitchell DC, Whiting CV, Tarlton JF. Abnormal extracellular matrix metabolism in chronically ischemic skin: a mechanism for dermal failure in leg ulcers. J Invest Dermatol. 2005;125(2):373–379.
16. Han YP, Tuan TL, Wu H, Hughes M, Garner WL. TNF-alpha stimulates activation of pro-MMP2 in human skin through NF-(kappa)B mediated induction of MT1-MMP. J Cell Sci. 2001;114(Pt 1):131–139.
17. Engelhardt E, Toksoy A, Goebeler M, Debus S, Brocker EB, Gillitzer R. Chemokines IL-8, GROalpha, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am J Pathol. 1998;153(6):1849–1860.
18. Groves RW, Rauschmayr T, Nakamura K, Sarkar S, Williams IR, Kupper TS. Inflammatory and hyperproliferative skin disease in mice that express elevated levels of the IL-1 receptor (type I) on epidermal keratinocytes. Evidence that IL-1-inducible secondary cytokines produced by keratinocytes in vivo can cause skin disease. J Clin Invest. 1996;98(2):336–344.
19. Miller LS, Sorensen OE, Liu PT, et al. TGF-alpha regulates TLR expression and function on epidermal keratinocytes. J Immunol. 2005;174(10):6137–6143.
20. Baugh JA, Donnelly SC. Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation. J Endocrinol. 2003;179(1):15–23.
21. Camerer E, Gjernes E, Wiiger M, Pringle S, Prydz H. Binding of factor VIIa to tissue factor on keratinocytes induces gene expression. J Biol Chem. 2000;275(9):6580–6585.
22. Camerer E, Huang W, Coughlin SR. Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A. 2000;97(10):5255–5260.
23. Chen J, Kasper M, Heck T, et al. Tissue factor as a link between wounding and tissue repair. Diabetes. 2005;54(7):2143–2154.
24. Poulsen LK, Jacobsen N, Sorensen BB, et al. Signal transduction via the mitogen-activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor. J Biol Chem. 1998;273(11):6228–6232.
25. Versteeg HH, Ruf W. Emerging insights in tissue factor-dependent signaling events. Semin Thromb Hemost. 2006;32(1):24–32.
26. Chambers RC, Dabbagh K, McAnulty RJ, Gray AJ, Blanc-Brude OP, Laurent GJ. Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-activated receptor 1. Biochem J. 1998;333(Pt 1):121–127.
27. Lang R, Song PI, Legat FJ, et al. Human corneal epithelial cells express functional PAR-1 and PAR-2. Invest Ophthalmol Vis Sci. 2003;44(1):99–105.
28. D'Andrea MR, Derian CK, Santulli RJ, Andrade-Gordon P. Differential expression of protease-activated receptors-1 and -2 in stromal fibroblasts of normal, benign, and malignant human tissues. Am J Pathol. 2001;158(6):2031–2041.
29. Chung AW, Jurasz P, Hollenberg MD, Radomski MW. Mechanisms of action of proteinase-activated receptor agonists on human platelets. Br J Pharmacol. 2002;135(5):1123–1132.
30. Riewald M, Ruf W. Science review: role of coagulation protease cascades in sepsis. Crit Care. 2003;7(2):123–129.
31. Uehara A, Muramoto K, Takada H, Sugawara S. Neutrophil serine proteinases activate human nonepithelial cells to produce inflammatory cytokines through protease-activated receptor 2. J Immunol. 2003;170(11):5690–5696.
32. Chambers RC, Leoni P, Blanc-Brude OP, Wembridge DE, Laurent GJ. Thrombin is a potent inducer of connective tissue growth factor production via proteolytic activation of protease-activated receptor-1. J Biol Chem. 2000;275(45):35584–35591.
33. Shimizu T, Nishihira J, Watanabe H, et al. Macrophage migration inhibitory factor is induced by thrombin and factor Xa in endothelial cells. J Biol Chem. 2004;279(14):13729–13737.
34. Xue M, Campbell D, Sambrook PN, Fukudome K, Jackson CJ. Endothelial protein C receptor and protease-activated receptor-1 mediate induction of a wound-healing phenotype in human keratinocytes by activated protein C. J Invest Dermatol. 2005;125(6):1279–1285.
35. Camerer E, Rottingen JA, Gjernes E, et al. Coagulation factors VIIa and Xa induced cell signaling leading to up-regulation of the egr-1 gene. J Biol Chem. 1999;274(45):32225–32233.
36. Neves SR, Ram PT, Iyengar R. G protein pathways. Science. 2002;296(5573):1636–1639.
37. Drew AF, Liu H, Davidson JM, Daugherty CC, Degen JL. Wound-healing defects in mice lacking fibrinogen. Blood. 2001;97(12):3691–3698.
38. Jurk K, Kehrel BE. Platelets: physiology and biochemistry. Semin Thromb Hemost. 2005;31(4):381–392.
39. Liu L, Cara DC, Kaur J, et al. LSP1 is an endothelial gatekeeper of leukocyte transendothelial migration. J Exp Med. 2005;201(3):409–418.
40. McLoughlin RM, Witowski J, Robson RL, et al. Interplay between IFN–gamma and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation. J Clin Invest. 2003;112(4):598–607.
41. Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev. 2004;18(18):2195–2224.
42. Li M, Carpio DF, Zheng Y, et al. An essential role of the NF-kappa B/Toll-like receptor pathway in induction of inflammatory and tissue-repair gene expression by necrotic cells. J Immunol. 2001;166(12):7128–7135.
43. Tak PP, Firestein GS. NF-kappaB: a key role in inflammatory diseases. J Clin Invest. 2001;107(1):7–11.
44. Danon D, Kowatch MA, Roth GS. Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci U S A. 1989;86(6):2018–2020.
45. Ross R, Odland G. Human wound repair. II. Inflammatory cells, epithelial-mesenchymal interrelations, and fibrogenesis. J Cell Biol. 1968;39(1):152–168.
46. Meszaros AJ, Reichner JS, Albina JE. Macrophage-induced neutrophil apoptosis. J Immunol. 2000;165(1):435–441.
47. Seely AJ, Pascual JL, Christou NV. Science review: Cell membrane expression (connectivity) regulates neutrophil delivery, function and clearance. Crit Care. 2003;7(4):291–307.
48. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;6(12):1191–1197.
49. Ashcroft GS, Mills SJ, Lei K, et al. Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor. J Clin Invest. 2003;111(9):1309–1318.
50. Mills SJ, Ashworth JJ, Gilliver SC, Hardman MJ, Ashcroft GS. The sex steroid precursor DHEA accelerates cutaneous wound healing via the estrogen receptors. J Invest Dermatol. 2005;125(5):1053–1062.
51. Ashcroft GS, Mills SJ. Androgen receptor-mediated inhibition of cutaneous wound healing. J Clin Invest. 2002;110(5):615–624.
52. Belting M, Dorrell MI, Sandgren S, et al. Regulation of angiogenesis by tissue factor cytoplasmic domain signaling. Nat Med. 2004;10(5):502–509.
53. Mechtcheriakova D, Schabbauer G, Lucerna M, et al. Specificity, diversity, and convergence in VEGF and TNF-alpha signaling events leading to tissue factor up-regulation via EGR-1 in endothelial cells. FASEB J. 2001;15(1):230–242.
54. Mechtcheriakova D, Wlachos A, Holzmuller H, Binder BR, Hofer E. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1. Blood. 1999;93(11):3811–3823.
55. Versteeg HH, Peppelenbosch MP, Spek CA. Tissue factor signal transduction in angiogenesis. Carcinogenesis. 2003;24(6):1009–1013.
56. Albina JE, Mastrofrancesco B, Vessella JA, Louis CA, Henry WL Jr, Reichner JS. HIF-1 expression in healing wounds: HIF-1alpha induction in primary inflammatory cells by TNF-alpha. Am J Physiol Cell Physiol. 2001;281(6):C1971–C1977.
57. Fukuda R, Kelly B, Semenza GL. Vascular endothelial growth factor gene expression in colon cancer cells exposed to prostaglandin E2 is mediated by hypoxia-inducible factor 1. Cancer Res. 2003;63(9):2330–2334.
58. Frechette JP, Martineau I, Gagnon G. Platelet-rich plasmas: growth factor content and roles in wound healing. J Dent Res. 2005;84(5):434–439.
59. Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin JA. Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. Diabetes Care. 2001;24(3):483–488.
60. 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.
61. Saap LJ, Falanga V. Debridement performance index and its correlation with complete closure of diabetic foot ulcers. Wound Repair Regen. 2002;10(6):354–359.
62. Shi C, Zhu Y, Ran X, Wang M, Su Y, Cheng T. Therapeutic potential of chitosan and its derivatives in regenerative medicine. J Surg Res. 2006;133(2):185–192.
63. Mori T, Murakami M, Okumura M, Kadosawa T, Uede T, Fujinaga T. Mechanism of macrophage activation by chitin derivatives. J Vet Med Sci. 2005;67(1):51–56.
64. Falanga V, Sabolinski M. A bilayered living skin construct (APLIGRAF) accelerates complete closure of hard-to-heal venous ulcers. Wound Repair Regen. 1999;7(4):201–207.
65. Sabolinski ML, Alvarez O, Auletta M, Mulder G, Parenteau NL. Cultured skin as a 'smart material' for healing wounds: experience in venous ulcers. Biomaterials. 1996;17(3):311–320.
66. Cavorsi J, Vicari F, Wirthllin DJ, et al. Best-practice algorithms for the use of a bilayered living cell therapy (Apligraf) in the treatment of lower-extremity ulcers. Wound Repair Regen. 2006;14(2):102–109.
