, Volume 30, Issue 1, pp 11–19 | Cite as

Neutrophil depletion delays wound repair in aged mice

  • Naomi Nishio
  • Yayoi Okawa
  • Hidetoshi Sakurai
  • Ken-ichi Isobe


One of the most important clinical problems in caring for elderly patients is treatment of pressure ulcers. One component of normal wound healing is the generation of an inflammatory reaction, which is characterized by the sequential infiltration of neutrophils, macrophages and lymphocytes. Neutrophils migrate early in the wound healing process. In aged C57BL/6 mice, wound healing is relatively inefficient. We examined the effects of neutrophil numbers on wound healing in both young and aged mice. We found that the depletion of neutrophils by anti-Gr-1 antibody dramatically delayed wound healing in aged mice. The depletion of neutrophils in young mice had less effect on the kinetics of wound healing. Intravenous G-CSF injection increased the migration of neutrophils to the wound site. While the rate of wound repair did not change significantly in young mice following G-CSF injection, it increased significantly in old mice.


Aging Neutrophil Wound healing 


  1. Ashcroft GS, Mills SJ, Ashworth JJ (2002) Ageing and wound healing. Biogerontology Rev 3(6):337–345CrossRefGoogle Scholar
  2. Ballas CB, Davidson JM (2001) Delayed wound healing in aged rats is associated with increased collagen gel remodeling and contraction by skin fibroblasts, not with differences in apoptotic or myofibroblast cell populations. Wound Repair Regen 9(3):223–237PubMedCrossRefGoogle Scholar
  3. Bourke E, Cassetti A, Villa A, Fadlon E, Colotta F, Mantovani A (2003) IL-1 beta scavenging by the type II IL-1 decoy receptor in human neutrophils. J Immunol 170(12):5999–6005PubMedGoogle Scholar
  4. Cohen BJ, Cutler RG, Roth GS (1987) Accelerated wound repair in old deer mice (Peromyscus maniculatus) and white-footed mice (Peromyscus leucopus). J Gerontol 42(3):302–307PubMedGoogle Scholar
  5. Danon D, Kowatch MA, Roth GS (1989) Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci USA 86(6):2018–2020PubMedCrossRefGoogle Scholar
  6. Dovi JV, He LK, DiPietro LA (2003) Accelerated wound closure in neutrophil-depleted mice. J Leukoc Biol 73:448–455PubMedCrossRefGoogle Scholar
  7. Fulop T, Larbi A, Douziech N, Fortin CF, Guerard KP, Lesur O, Khalil A, Dupuis G (2004) Signal transduction and functional changes in neutrophils with aging. Aging Cell 3:217–226PubMedCrossRefGoogle Scholar
  8. Grove GL, Kligman AM (1983) Age-associated changes in human epidermal cell renewal. J Gerontol 38:137–142PubMedGoogle Scholar
  9. Hellemans L, Corstjens H, Neven A, Declercq L, Maes D (2003) Antioxidant enzyme activity in human stratum corneum shows seasonal variation with an age-dependent recovery. J Invest Dermatol 120:434–439PubMedCrossRefGoogle Scholar
  10. Hubner G, Brauchle M, Smola H, Madlener M, Fassler R, Werner S (1996) Differential regulation of pro-inflammatory cytokines during wound healing in normal and glucocorticoid-treated mice. Cytokine 8(7):548–556PubMedCrossRefGoogle Scholar
  11. Larbi A, Douziech N, Fortin CF, Linteau A, Dupuis G, Fulop T (2005) The role of the MAPK pathway alterations in GM-CSF modulated human neutrophil apoptosis with aging. Immun Ageing 2(1):6PubMedCrossRefGoogle Scholar
  12. Leibovich SJ, Ross R (1975) The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol 78(1):71–100PubMedGoogle Scholar
  13. Leibovich SJ, Ross R (1976) A macrophage-dependent factor that stimulates the proliferation of fibroblasts in vitro. Am J Pathol 84(3):501–514PubMedGoogle Scholar
  14. Martin P (1997) Wound healing-aiming for perfect skin regeneration. Sci Rev 276(5309):75–81Google Scholar
  15. Ross R, Benditt EP (1962a) Wound healing and collagen formation. II. Fine structure inexperimental scurvy. J Cell Biol 12:533–551PubMedCrossRefGoogle Scholar
  16. Ross R, Benditt EP (1962b) Wound healing and collagen formation. III. A quantitative radioautographic study of the utilization of proline-H3 in wounds from normal and scorbutic guinea pigs. J Cell Biol 15:99–108PubMedCrossRefGoogle Scholar
  17. Schroder AK, von der Ohe M, Kolling U, Altstaedt J, Uciechowski P, Fleischer D, Dalhoff K, Ju X, Zenke M, Heussen N, Rink L (2006) Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators. Immunology 119(3):317–327PubMedCrossRefGoogle Scholar
  18. Simpson DM, Ross R (1972) The neutrophilic leukocyte in wound repair a study with antineutrophil serum. J Clin Invest 51(8):2009–2023PubMedCrossRefGoogle Scholar
  19. Swift ME, Burn AL, Gray KL, DiPietro LA (2001) Age-related alterations in the inflammatory response to dermal injury. J Invest Dermatol 117(5):1027–1035PubMedCrossRefGoogle Scholar
  20. Yuli I, Tomonaga A, Synderman R (1982) Chemoattractant receptor functions in human polymorphonuclear leukocytes are divergently altered by membrane fluidizers. Proc Natl Acad Sci USA 79(19):5906–5910PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association, Media, PA, USA 2007

Authors and Affiliations

  • Naomi Nishio
    • 1
  • Yayoi Okawa
    • 2
  • Hidetoshi Sakurai
    • 1
  • Ken-ichi Isobe
    • 1
  1. 1.Department of ImmunologyNagoya University Graduate School of MedicineAichiJapan
  2. 2.Department of Functioning ActivationNational Institute for Longevity Sciences, National Center for Geriatrics GerontologyAichiJapan

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