Complements and the wound healing cascade: an updated review

Hani Sinno, Satya Prakash, Hani Sinno, Satya Prakash

Abstract

Wound healing is a complex pathway of regulated reactions and cellular infiltrates. The mechanisms at play have been thoroughly studied but there is much still to learn. The health care system in the USA alone spends on average 9 billion dollars annually on treating of wounds. To help reduce patient morbidity and mortality related to abnormal or prolonged skin healing, an updated review and understanding of wound healing is essential. Recent works have helped shape the multistep process in wound healing and introduced various growth factors that can augment this process. The complement cascade has been shown to have a role in inflammation and has only recently been shown to augment wound healing. In this review, we have outlined the biology of wound healing and discussed the use of growth factors and the role of complements in this intricate pathway.

Figures

Figure 1
Figure 1
Cytokines and complements involved in inflammation. The three phases of wound healing are associated with different growth factors and subsequent cellular infiltration. Although the complement system is involved in inflammation, its role in wound healing has never been proposed. Complements C3 and C5, epidermal growth factor (EGF), transforming growth factor (TGF), platelet-derived growth factor (PDGF), tumor necrosis factor (TNF), vascular endothelial growth factor (VEGF), and insulin-like growth factor (IGF).
Figure 2
Figure 2
Complement cascade. The complement system converges with the activation of complements C3 and C5 with the subsequent formation of the membrane attack complex. The C3a and C5a proteins are responsible for chemotaxis. The C3b and C5b are responsible for the continued proliferation of the complement cascade.
Figure 3
Figure 3
Cutaneous wound healing in time. A schematic representation of cutaneous wound healing and the growth factors and cellular participants in the first 72 hours of injury. The complement cascade appears to be involved in many stages of the wound healing. Platelets, macrophages, fibroblasts, and the formation of the fibrin clot are the major cellular players in early cutaneous, tendon, ligament, muscle, and bone healing.

References

    1. Brigham PA, McLoughlin E. Burn incidence and medical care use in the United States: estimates, trends, and data sources. Journal of Burn Care and Rehabilitation. 1996;17(2):95–107.
    1. U.S. markets for wound management products. Medical Data International, Irvine, Calif, USA, August 1997.
    1. Ashcroft GS, Mills SJ, Ashworth JJ. Ageing and wound healing. Biogerontology. 2002;3(6):337–345.
    1. Heldin C-H, Westermark B. Role of Platelet-Derived Growth Factor in Vivo. 2nd edition. New York, NY, USA: Plenum Press; 1996.
    1. Bjork J, Hugli TE, Smedegard G. Microvascular effects of anaphylatoxins C3a and C5a. Journal of Immunology. 1985;134(2):1115–1119.
    1. Clark RAF, Henson PM. The Molecular and Cellular Biology of Wound Repair. 2nd edition. New York, NY, USA: Plenum Press; 1996.
    1. Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. American Journal of Pathology. 1975;78(1):71–100.
    1. Brown EJ. Phagocytosis. BioEssays. 1995;17(2):109–117.
    1. Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis? Cell. 1996;87(7):1153–1155.
    1. Iruela-Arispe ML, Dvorak HF. Angiogenesis: a dynamic balance of stimulators and inhibitors. Thrombosis and Haemostasis. 1997;78(1):672–677.
    1. Risau W. Mechanisms of angiogenesis. Nature. 1997;386(6626):671–674.
    1. Roberts AB. Transforming Growth Factor-Beta. 2nd edition. New York, NY, USA: Plenum Press; 1996.
    1. Xu J, Clark RAF. Extracellular matrix alters PDGF regulation of fibroblast integrins. Journal of Cell Biology. 1996;132(1-2):239–249.
    1. Levenson SM, Geever EF, Crowley LV, Oates JF, III, Berard CW, Rosen H. The healing of rat skin wounds. Annals of surgery. 1965;161:293–308.
    1. Loos M. Classical pathway of activation. In: Rother KTG, editor. The Complement System. Berlin, Germany: Springer; 1985. pp. 136–154.
    1. Holmskov U, Malhotra R, Sim RB, Jensenius JC. Collectins: collagenous C-type lectins of the innate immune defense system. Immunology Today. 1994;15(2):67–74.
    1. Gotze O. The alternate pathway of activation. In: Rother KTG, editor. The Complement System. Berlin: Springer; 1985. pp. 154–168.
    1. Imagawa DK, Osifchin NE, Paznekas WA. Consequences of cell membrane attack by complement: release of arachidonate and formation of inflammatory derivatives. Proceedings of the National Academy of Sciences of the United States of America. 1983;80(21 I):6647–6651.
    1. Hicks PS, Saunero-Nava L, Du Clos TW, Mold C. Serum amyloid P component binds to histones and activates the classical complement pathway. Journal of Immunology. 1992;149(11):3689–3694.
    1. Hugli TE, Marceau F, Lundberg C. Effects of complement fragments on pulmonary and vascular smooth muscle. American Review of Respiratory Disease. 1987;135(6):S9–13.
    1. Fernandez HN, Henson PM, Otani A, Hugli TE. Chemotactic response to human C3a and C5a anaphylatoxins. I. Evaluation of C3a and C5a leukotaxis in vitro and under simulated in vivo conditions. Journal of Immunology. 1978;120(1):109–115.
    1. Hugli TE. Biochemistry and biology of anaphylatoxins. Complement. 1986;3(3):111–127.
    1. Schupf N, Williams CA, Berkman A, Cattell WS, Kerper L. Binding specificity and presynaptic action of anaphylatoxin C5a in rat brain. Brain Behavior and Immunity. 1989;3(1):28–38.
    1. Foreman KE, Vaporciyan AA, Bonish BK, et al. C5a-induced expression of P-selectin in endothelial cells. Journal of Clinical Investigation. 1994;94(3):1147–1155.
    1. Sinno H, Malholtra M, Lutfy J, et al. Topical application of complement C3 in collagen formulation increases early wound healing. Journal of Dermatological Treatment. 2011;24(2):141–147.
    1. Sinno H, Malhotra M, Lutfy J, et al. Accelerated wound healing with topical application of complement C5. Plastic and Reconstructive Surgery. 130(3):523–529.
    1. Sinno H, Malhotra M, Lutfy J, et al. Complements c3 and c5 individually and in combination increase early wound strength in a rat model of experimental wound healing. Plastic Surgery International. 2013;2013:5 pages.243853
    1. Porras-Reyes BH, Mustoe TA. Platelet-activating factor: improvement in wound healing by a chemotactic factor. Surgery. 1992;111:416–423. Erratum in Surgery, vol. 112, no. 3, pp. 612, 1992.
    1. Mustoe TA, Purdy J, Gramates P, Deuel TF, Thomason A, Pierce GF. Reversal of impaired wound healing in irradiated rats by platelet-derived growth factor-BB. American Journal of Surgery. 1989;158(4):345–350.
    1. Mustoe TA, Pierce GF, Thomason A. Accelerated healing of incisional wounds in rats induced by transforming growth factor-β . Science. 1987;237(4820):1333–1336.
    1. Crovetti G, Martinelli G, Issi M, et al. Platelet gel for healing cutaneous chronic wounds. Transfusion and Apheresis Science. 2004;30(2):145–151.
    1. Tarnuzzer RW, Schultz GS. Biochemical analysis of acute and chronic wound environments. Wound Repair and Regeneration. 1996;4(3):321–325.
    1. Streit M, Beleznay Z, Braathen LR. Topical application of the tumour necrosis factor-α antibody infliximab improves healing of chronic wounds. International Wound Journal. 2006;3(3):171–191.
    1. Galiano RD, Tepper OM, Pelo CR, et al. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow-derived cells. American Journal of Pathology. 2004;164(6):1935–1947.
    1. Zhang F, Lei MP, Oswald TM, et al. The effect of vascular endothelial growth factor on the healing of ischaemic skin wounds. British Journal of Plastic Surgery. 2003;56(4):334–341.
    1. Porras-Reyes BH, Mustoe TA. Platelet-activating factor: improvement in wound healing by a chemotactic factor. Surgery. 1992;111(4):416–423.
    1. Edwards DR, Murphy G, Reynolds JJ, et al. Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO Journal. 1987;6(7):1899–1904.
    1. Cordeiro MF, Mead A, Ali RR, et al. Novel antisense oligonucleotides targeting TGF-β inhibit in vivo scarring and improve surgical outcome. Gene Therapy. 2003;10(1):59–71.
    1. Huang JS, Wang Y-H, Ling T-Y, Chuang S-S, Johnson FE, Huang SS. Synthetic TGF-beta antagonist accelerates wound healing and reduces scarring. The FASEB Journal. 2002;16(10):1269–1270.
    1. Powers WE, Ogura JH, Palmer LA. Radiation therapy and wound healing delay. Animals and man. Radiology. 1967;89(1):112–115.
    1. Robson MC, Phillips LG, Thomason A, Robson LE, Pierce GF. Platelet-derived growth factor BB for the treatment of chronic pressure ulcers. Lancet. 1992;339(8784):23–25.
    1. Mustoe TA, Cutler NR, Allman RM, et al. A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers. Archives of Surgery. 1994;129(2):213–219.
    1. Robson MC, Phillips LG, Thomason A, et al. Recombinant human platelet-derived growth factor-BB for the treatment of chronic pressure ulcers. Annals of Plastic Surgery. 1992;29(3):193–201.
    1. Yilgor Huri P, Huri G, Yasar U, et al. A biomimetic growth factor delivery strategy for enhanced regeneration of iliac crest defects. Biomedical Materials. 8(4)045009

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera