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Thromb Haemost 2004; 92(02): 275-280
DOI: 10.1160/TH03-11-0720
Theme Issue Article
Schattauer GmbH

Neutrophil function in the healing wound: adding insult to injury?

Julia V. Dovi
1   Burn and Shock Trauma Institute, Department of Surgery, Loyola University Medical Center Maywood, Illinois, USA
,
Anna M. Szpaderska
1   Burn and Shock Trauma Institute, Department of Surgery, Loyola University Medical Center Maywood, Illinois, USA
,
Luisa A. DiPietro
1   Burn and Shock Trauma Institute, Department of Surgery, Loyola University Medical Center Maywood, Illinois, USA
› Author AffiliationsFinancial support: Supported by NIH GM55238 and the Dr. Ralph and Marion C. Falk Medical Research Trust.
Further Information

Publication History

Received 26 November 2003

Accepted after revision 04 May 2004

Publication Date:
30 November 2017 (online)

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Summary

Cells of the innate immune system, including neutrophils and macrophages, are a highly visible component of normal wound healing in adult mammals. The role of inflammatory cells in the healing wound has been widely investigated, and evidence for both positive and negative influences exists. Several recent investigations support the emerging paradigm that robust inflammation is detrimental to wound closure. This developing information suggests that the functional role of inflammatory cells in wound healing must be reevaluated.

Keywords

Wound healing - neutrophils - macrophages - inflammation
 

  • References

  • 1 Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 1975; 78: 71-100.
    PubMedGoogle Scholar
  • 2 Moore A. Biology of the chronic wound. J Wound Care 1999; 08: 345-355.
    PubMedGoogle Scholar
  • 3 Pierce GF. Inflammation in nonhealing diabetic wounds: the space-time continuum does matter. Am J Pathol 2001; 159: 399-403.
    CrossrefPubMedGoogle Scholar
  • 4 Wetzler C, Kampfer H, Stallmeyer B. et al. Large and sustained induction of chemokines during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the latephase of repair. J Invest Dermatol 2000; 115: 245-253.
    CrossrefPubMedGoogle Scholar
  • 5 Simpson DM, Ross R. The neutrophilic leukocyte in wound repair a study with antineutrophil serum. J Clin Invest 1972; 51: 2009-2023.
    CrossrefPubMedGoogle Scholar
  • 6 Dovi JV, He LK, DiPietro LA. Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol 2003; 73: 448-455.
    CrossrefPubMedGoogle Scholar
  • 7 Rennekampff HO, Hansbrough JF, Kiessig V. et al. Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J Surg Res 2000; 93: 41-54.
    CrossrefPubMedGoogle Scholar
  • 8 McCourt M, Wang JH, Sookhai S. et al. Proinflammatory mediators stimulate neutrophil-directed angiogenesis. Arch Surg 1999; 134: 1325-31 discussion 1331-2.
    CrossrefPubMedGoogle Scholar
  • 9 Ashcroft GS, Yang X, Glick AB. et al. Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1999; 01: 260-266.
    CrossrefPubMedGoogle Scholar
  • 10 Ashcroft GS, Lei K, Jin W. et al. Secretory leukocyte protease inhibitor mediates nonredundant functions necessary for normal wound healing. Nat Med 2000; 06: 1147-1153.
    CrossrefPubMedGoogle Scholar
  • 11 Briggaman RA, Schechter NM, Fraki J. et al. Degradation of the epidermal-dermal junction by proteolytic enzymes from human skin and human polymorphonuclear leukocytes. J Exp Med 1984; 160: 1027-1042.
    CrossrefPubMedGoogle Scholar
  • 12 Katayama H, Hase T, Yaoita H. Detachment of cultured normal human keratinocytes by contact with TNF alpha-stimulated neutrophils in the presence of platelet-activating factor. J Invest Dermatol 1994; 103: 187-190.
    CrossrefPubMedGoogle Scholar
  • 13 Danon D, Kowatch MA, Roth GS. Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci USA 1989; 86: 2018-2020.
    CrossrefPubMedGoogle Scholar
  • 14 Burrington JD. Wound healing in the fetal lamb. J Pediatr Surg 1971; 06: 523-528.
    CrossrefPubMedGoogle Scholar
  • 15 Rowlatt U. Intrauterine wound healing in a 20 week human fetus. Virchows Arch A 1979; 381: 353-361.
    CrossrefPubMedGoogle Scholar
  • 16 Longaker MT, Whitby DJ, Adzick NS. et al. Studies in fetal wound healing, VI. Second and early third trimester fetal wounds demonstrate rapid collagen deposition without scar formation. J Pediatr Surg 1990; 25: 63-8 discussion 68-9.
    CrossrefPubMedGoogle Scholar
  • 17 Goss RJ. Regeneration versus repair. In: Cohen I, Diegelmann R, Lindblad W. editors. Wound healing: Biochemical and clinical aspects. Philadelphia: W.B. Saunders Co; 1992: 20-39.
    Google Scholar
  • 18 Goss RJ. The evolution of regeneration: adaptive or inherent?. J Theor Biol 1992; 159: 241-260.
    CrossrefPubMedGoogle Scholar
  • 19 Adzick NS, Harrison MR, Glick PL. et al. Comparison of fetal, newborn, and adult wound healing by histologic, enzyme-histo-chemical, and hydroxyproline determinations. J Pediatr Surg 1985; 20: 315-319.
    CrossrefPubMedGoogle Scholar
  • 20 Krummel TM, Nelson JM, Diegelmann RF. et al. Fetal response to injury in the rabbit. J Pediatr Surg 1987; 22: 640-644.
    CrossrefPubMedGoogle Scholar
  • 21 Armstrong JR, Ferguson MW. Ontogeny of the skin and the transition from scar-free to scarring phenotype during wound healing in the pouch young of a marsupial, Monodelphis domestica. Dev Biol 1995; 169: 242-260.
    CrossrefPubMedGoogle Scholar
  • 22 Longaker MT, Whitby DJ, Ferguson MW. et al. Adult skin wounds in the fetal environment heal with scar formation. Ann Surg 1994; 219: 65-72.
    CrossrefPubMedGoogle Scholar
  • 23 Harty M, Neff AW, King MW. et al. Regeneration or scarring: an immunologic perspective. Dev Dynam 2003; 226: 268-279.
    CrossrefPubMedGoogle Scholar
  • 24 Hopkinson-Woolley J, Hughes D, Gordon S. et al. Macrophage recruitment during limb development and wound healing in the embryonic and foetal mouse. J Cell Sci 1994; 107: 1159-1167.
    PubMedGoogle Scholar
  • 25 McCallion R, Ferguson M. Fetal wound healing and the development of anti-scarring therapies for adult wound healing. In: Clark R. editor. The molecular biology of wound repair. New York: Plenum; 1996: 561-600.
    Google Scholar
  • 26 Liechty KW, Kim HB, Adzick NS. et al. Fetal wound repair results in scar formation in interleukin-10-deficient mice in a syngeneic murine model of scarless fetal wound repair. J Pediatr Surg 2000; 35: 866-72 discussion 872-3.
    CrossrefPubMedGoogle Scholar
  • 27 Martin P, D’Souza D, Martin J. et al. Wound healing in the PU.1 null mouse – tissue repair is not dependent on inflammatory cells. Curr Biol 2003; 13: 1122-1128.
    CrossrefPubMedGoogle Scholar
  • 28 Szpaderska AM, Zuckerman JD, DiPietro LA. et al. Differential injury responses in oral mucosal and cutaneous wounds. J Dent Res 2003; 82: 621-626.
    CrossrefPubMedGoogle Scholar
  • 29 Yager DR, Nwomeh BC. The proteolytic environment of chronic wounds. Wnd Rep Regen 1999; 07: 433-441.
    PubMedGoogle Scholar
  • 30 Nwomeh BC, Yager DR, Cohen IK. Physiology of the chronic wound. Clin Plast Surg 1998; 25: 341-356.
    CrossrefPubMedGoogle Scholar
  • 31 Rosner K, Ross C, Karlsmark T. et al. Role of LFA-1/ICAM-1, CLA/E-selectin and VLA-4/ VCAM-1 pathways in recruiting leukocytes to the various regions of the chronic leg ulcer. Acta Derm-Venereol 2001; 81: 334-339.
    PubMedGoogle Scholar
  • 32 Goren I, Kampfer H, Podda M. et al. Leptin and wound inflammation in diabetic ob/ob mice: differential regulation of neutrophil and macrophage influx and a potential role for the scab as a sink for inflammatory cells and mediators. Diabetes 2003; 52: 2821-2832.
    CrossrefPubMedGoogle Scholar
  • 33 Ashcroft GS, Horan MA, Ferguson MW. Aging is associated with reduced deposition of specific extracellular matrix components, an upregulation of angiogenesis, and an altered inflammatory response in a murine incisional wound healing model. J Invest Dermatol 1997; 108: 430-437.
    CrossrefPubMedGoogle Scholar
  • 34 Swift ME, Burns AL, Gray KL. et al. Agerelated alterations in the inflammatory response to dermal injury. J Invest Dermatol 2001; 117: 1027-1035.
    CrossrefPubMedGoogle Scholar
  • 35 Weiss SJ. Tissue destruction by neutrophils. New Engl J Med 1989; 320: 365-376.
    CrossrefPubMedGoogle Scholar
  • 36 Thiagarajan RR, Winn RK, Harlan JM. The role of leukocyte and endothelial adhesion molecules in ischemia-reperfusion injury. Thromb Haemost 1997; 78: 310-314.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Vender RL. Therapeutic potential of neutrophil-elastase inhibition in pulmonary disease. J Invest Med 1996; 44: 531-539.
    PubMedGoogle Scholar
  • 38 Carden D, Xiao F, Moak C. et al. Neutrophil elastase promotes lung microvascular injury and proteolysis of endothelial cadherins. Am J Physiol 1998; 275: H385-92.
    PubMedGoogle Scholar
  • 39 Ginzberg HH, Cherapanov V, Dong Q. et al. Neutrophil-mediated epithelial injury during transmigration: role of elastase. Am J Physiol 2001; 281: G705-17.
    PubMedGoogle Scholar
  • 40 Yang JJ, Preston GA, Pendergraft WF. et al. Internalization of proteinase 3 is concomitant with endothelial cell apoptosis and internalization of myeloperoxidase with generation of intracellular oxidants. Am J Pathol 2001; 158: 581-592.
    CrossrefPubMedGoogle Scholar
  • 41 Jennette JC. Antineutrophil cytoplasmic autoantibody-associated diseases: a pathologist’s perspective. Am J Kidney Dis 1991; 18: 164-170.
    CrossrefPubMedGoogle Scholar
  • 42 Yuspa SH. The pathogenesis of squamous cell cancer: lessons learned from studies of skin carcinogenesis—thirty-third G. H. A. Clowes Memorial Award Lecture. Cancer Res 1994; 54: 1178-1189.
    PubMedGoogle Scholar
  • 43 Tazawa H, Okada F, Kobayashi T. et al. Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells: implication of inflammation-associated carcinogenesis and tumor progression. Am J Pathol 2003; 163: 2221-2232.
    CrossrefPubMedGoogle Scholar
  • 44 Slattery MJ, Dong C. Neutrophils influence melanoma adhesion and migration under flow conditions. Int J Cancer 2003; 106: 713-722.
    CrossrefPubMedGoogle Scholar
  • 45 Meszaros AJ, Reichner JS, Albina JE. Macrophage-induced neutrophil apoptosis. J Immunol 2000; 165: 435-441.
    CrossrefPubMedGoogle Scholar
  • 46 Meszaros AJ, Reichner JS, Albina JE. Macrophage phagocytosis of wound neutrophils. J Leukoc Biol 1999; 65: 35-42.
    CrossrefPubMedGoogle Scholar
  • 47 Ramer-Quinn DS, Swanson MA, Lee WT. et al. Cytokine production by naive and primary effector CD4+ T cells exposed to norepinephrine. Brain Behav Immun 2000; 14: 239-255.
    CrossrefPubMedGoogle Scholar
  • 48 Sanders VM, Kohm AP. Sympathetic nervous system interaction with the immune system. Int Rev Neurobiol 2002; 52: 17-41.
    PubMedGoogle Scholar
  • 49 Swanson MA, Lee WT, Sanders VM. IFNgamma production by Th1 cells generated from naive CD4+ T cells exposed to norepinephrine. J Immunol 2001; 166: 232-240.
    CrossrefPubMedGoogle Scholar