Molecular pathology of wound healing

https://doi.org/10.1016/j.forsciint.2010.07.004Get rights and content

Abstract

Skin-wound healing is an orchestrated biological phenomena consisting of three sequential phases, inflammation, proliferation, and maturation. Many biological substances are involved in the process of wound repair, and this short and simplified overview of wound healing can be adopted to determine wound vitality or wound age in forensic medicine. With the development of genetically engineered animals, essential molecules for skin-wound healing have been identified. Especially, cytokines, and growth factors are useful candidates and markers for the determination of wound vitality or age. Moreover, bone marrow-derived progenitor cells would give significant information to wound age determination. In this review article, some interesting observations are presented, possibly contributing to the future practice of forensic pathologists.

Introduction

The primary function of the skin is to serve as a protective barrier against the environment. Loss of the integrity of large portions of the skin as a result of injury or illness may lead to major disability or even death. Skin-wound healing starts immediately after injury and consists of three phases: inflammation, proliferation, and maturation (Fig. 1). These phases proceed with complicated but well-organized interaction between various tissues and cells [1], [2]. Lots of cellular and molecular-biological studies demonstrated that many cytokines, growth factors, and proteases are closely involved in the wound-healing process to complete normal tissue repair after damage [1], [2].

In forensic practice, it is necessary to evaluate the causal relationship between death and any wounds, and forensic pathologists are always required to discriminate antemortem wounds from postmortem damage. Moreover, when the wound is vital, it is necessary to determine how long before death it was sustained. The short and simplified overview of wound healing can be adopted to determine wound vitality or wound age in forensic medicine.

Section snippets

Inflammation

The disruption of the epidermal barrier occurs the release of prestored interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) from keratinocytes. IL-1 and TNF-α alert surrounding cells to barrier damage. In addition, the extravasation of blood constituents follows the disruption of blood vessels by tissue injury causes. The resulting clot induces hemostasis and provides a matrix for the influx of inflammatory cells. Platelets also secrete growth factors such as: epidermal growth factor

Historical background of wound age determination

The short and simplified overview of wound healing can be adopted to determine wound vitality or wound age in forensic medicine. Walcher [11] and Orsos [12] first emphasized, based on their practical experiences, that the determination of wound vitality or wound age was indispensable in forensic practice. In the 1960s, Raekallio developed the biological evidences in wound age determination, with the investigation of the activity of several enzymes at wound sites [13]. Some years later, Berg et

Simultaneous detection of several factors

Recently, Takamiya et al. [43], [44] simultaneously analyzed several cytokines such as IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFN-γ, and TNF-α in human dermal wounds for wound age estimation by the use of multiplex beaded array system. IL-10, GM-CSF, IFN-γ, and TNF-α increased from the early phase of dermal wound healing, IL-6 exclusively in the middle phase, IL-2, IL-4, and IL-8 from the middle phase to the late phase [43]. In another combination, IL-5, IL-12p70, IL-13, and IL-17 increased

Bone marrow cells and skin-wound healing

It is well known that hematopoietic stem cells are present in bone marrow for the renewal of circulating hematopoietic cells. Several lines of accumulating evidence demonstrated that bone marrow-derived stem cells/progenitor cells were essentially involved in tissue repair including skin-wound healing [57], [58]. These progenitor cells are recruited to the injured sites from the bone marrow via peripheral circulation under the guidance of chemotactic cytokines. In particular, Bucala et al.

Acknowledgements

We are grateful to Prof. Dr. Wolfgang Eisenmenger (Institute for Legal Medicine, University of Munich, Germany) and Prof. Dr. Peter Betz (Institute for Legal Medicine, University of Erlangen-Nürunberg, Germany) for their critical and instructive supports to our scientific research. We would like to express my sincere thanks to Prof. Dr. Burkhard Madea (Institute for Legal Medicine, University of Bonn, Germany) and Prof. Dr. Pekka Saukko (Department of Forensic Medicine, University of Turku) for

References (70)

  • J. Becker et al.

    MOR1 receptor mRNA expression in human brains of drug-related fatalities—a real-time PCR quantification

    Forensic Sci. Int.

    (2004)
  • K. Ishida et al.

    Novel approach to quantitative reverse transcription PCR assay of mRNA component in autopsy material using the TaqMan fluorogenic detection system: dynamics of pulmonary surfactant apoprotein A

    Forensic Sci. Int.

    (2000)
  • K. Shinone et al.

    Molecular-biological analysis of the effect of methamphetamine on the heart in restrained mice

    Leg. Med. (Tokyo)

    (2010)
  • A. Matsuo et al.

    C-fos, fos-B, c-jun and dusp-1 expression in the mouse heart after single and repeated methamphetamine administration

    Leg. Med. (Tokyo)

    (2009)
  • H. Takahashi et al.

    Increase in dual specificity phosphatase 1, TGF-beta stimulated gene 22, domain family protein 3 and Luc7 homolog (S. cerevisiae)-like messenger RNA after mechanical asphyxiation in the mouse lung

    Leg. Med. (Tokyo)

    (2009)
  • M. Takamiya et al.

    A study on mRNA expressions of interleukin 10 during fracture healing for wound age determination

    Leg. Med. (Tokyo)

    (2008)
  • R. Bai et al.

    The time-dependent expressions of IL-1beta, COX-2, MCP-1 mRNA in skin wounds of rabbits

    Forensic Sci. Int.

    (2008)
  • Y. Ishida et al.

    Essential roles of the CC chemokine ligand 3-CC chemokine receptor 5 axis in bleomycin-induced pulmonary fibrosis through regulation of macrophage and fibrocyte infiltration

    Am. J. Pathol.

    (2007)
  • A.J. Singer et al.

    Cutaneous wound healing

    N. Engl. J. Med.

    (1999)
  • P. Martin

    Wound healing—aiming for perfect skin regeneration

    Science

    (1997)
  • R. Grose et al.

    Wound-healing studies in transgenic and knockout mice

    Mol. Biotechnol.

    (2004)
  • S. Werner et al.

    Regulation of wound healing by growth factors and cytokines

    Physiol. Rev.

    (2003)
  • S. Barrientos et al.

    Growth factors and cytokines in wound healing

    Wound Repair Regen.

    (2008)
  • Z.Q. Lin et al.

    Essential involvement of IL-6 in the skin wound-healing process as evidenced by delayed wound healing in IL-6-deficient mice

    J. Leukoc. Biol.

    (2003)
  • Y. Ishida et al.

    Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-κB activation and a reciprocal suppression of TGF-β signal pathway

    J. Immunol.

    (2006)
  • R. Mori et al.

    Accelerated wound healing in tumor necrosis factor receptor p55-deficient mice with reduced leukocyte infiltration

    FASEB J.

    (2002)
  • Y. Ishida et al.

    The essential involvement of cross-talk between IFN-γ and TGF-β in the skin wound-healing process

    J. Immunol.

    (2004)
  • Y. Ishida et al.

    Chemokine receptor CX3CR1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function

    J. Immunol.

    (2008)
  • K. Walcher

    Über vitale Reaktionen

    Dtsch. Z. Gesamte. Gerichtl. Med.

    (1930)
  • F. Orsos

    Die vitalen Reaktionen und ihre gerichtsmedizinische Bedeutung

    Beitr. Pathol. Anat.

    (1935)
  • J. Raekallio

    Timing of wounds in forensic medicine

    Jpn. J. Legal Med.

    (1976)
  • S. Berg et al.

    Möglichkeiten der biochemischen Wundaltersbestimmung

    Dtsch. Z. Gerichtl. Med.

    (1968)
  • S. Berg et al.

    Praktische Erfahrungen mit der biochemischen Wundaltersbestimmung

    Beitr. Gerichtl. Med.

    (1971)
  • W. Eisenmenger et al.

    Die Bedeutung des Kollagens bei der Wundaltersbestimmung

    Z. Rechtsmed.

    (1988)
  • M. Oehmichen

    Die Wundheilung

    (1990)
  • Cited by (289)

    • Anti-inflammatory potential of ulvan

      2023, International Journal of Biological Macromolecules
    View all citing articles on Scopus

    This paper is part of the special issue entitled: Molecular Pathology in Forensic Medicine, Guest-edited by Burkhard Madea and Pekka Saukko.

    View full text