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Episodic Binge Ethanol Exposure Impairs Murine Macrophage Infiltration and Delays Wound Closure by Promoting Defects in Early Innate Immune Responses

Authors

  • Brenda J. Curtis,

    1. Health Sciences Division , Alcohol Research Program, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    2. Health Sciences Division , Department of Surgery, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
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    • These authors contributed equally.

  • Sara Hlavin,

    1. Health Sciences Division , Department of Surgery, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    2. Health Sciences Division , Department of Microbiology and Immunology, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    3. Health Sciences Division , Integrative Cell Biology Program, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    4. Health Sciences Division , Infectious Disease and Immunology Research Institute, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
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    • These authors contributed equally.

  • Aleah L. Brubaker,

    1. Health Sciences Division , Department of Surgery, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    2. Health Sciences Division , Integrative Cell Biology Program, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    3. Health Sciences Division , Stritch School of Medicine, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
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  • Elizabeth J. Kovacs,

    1. Health Sciences Division , Alcohol Research Program, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    2. Health Sciences Division , Department of Surgery, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    3. Health Sciences Division , Department of Microbiology and Immunology, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    4. Health Sciences Division , Integrative Cell Biology Program, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    5. Health Sciences Division , Stritch School of Medicine, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
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  • Katherine A. Radek

    Corresponding author
    1. Health Sciences Division , Alcohol Research Program, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    2. Health Sciences Division , Department of Surgery, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    3. Health Sciences Division , Department of Microbiology and Immunology, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    4. Health Sciences Division , Integrative Cell Biology Program, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    5. Health Sciences Division , Infectious Disease and Immunology Research Institute, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    6. Health Sciences Division , Stritch School of Medicine, The Burn and Shock Trauma Research Institute, Loyola University Chicago, Maywood, Illinois
    • Reprint requests: Katherine A. Radek, PhD, Burn and Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Campus, 2160 S. First Avenue, Maywood, IL 60153; Tel.: 708-327-2360; Fax: 708-327-2813; E-mail: kradek1@lumc.edu

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Abstract

Background

Exacerbation of cutaneous wound infections and delayed wound closure are frequent complications seen in alcohol exposed subjects who sustain injuries. We previously reported that acute alcohol exposure alters the early dermal inflammatory phase of wound healing and also several parameters of the proliferative wound healing phase in wounds from ethanol (EtOH)-treated mice for several days or weeks after EtOH exposure. Hence, it is likely that the cumulative defects arising in the early phases of the wound healing process directly contribute to the increased complications observed in intoxicated patients at the time of injury.

Methods

C57BL/6 mice were given intraperitoneal EtOH (2.2 g/kg body weight) or vehicle (saline) EtOH using our episodic binge EtOH exposure protocol (3 days EtOH, 4 days off, 3 days EtOH) to yield a blood alcohol concentration (BAC) of 300 mg/dl at the time of wounding. Mice were subjected to six 3 mm full-thickness dorsal wounds and immediately treated topically with 10 μl of sterile saline (control) or diluted Staphylococcus aureus corresponding to 1 × 104 CFU/wound. Wounds were harvested at 24 hours post injury to evaluate wound area, neutrophil and macrophage accumulation, and the protein levels of cytokines, interleukin-6 (IL-6), IL-1β, and IL-10, and chemokines, macrophage inflammatory protein-2 (MIP-2) and MIP-1α, monocyte chemotactic protein-1 (MCP-1), and keratinocyte-derived chemokine (KC). The abundance and localization of cathelicidin-related antimicrobial peptide (CRAMP) and the kallikrein epidermal proteases (KLK5 and KLK7) were also determined.

Results

Compared to control mice, EtOH-treated mice exhibited delayed wound closure, decreased macrophage accumulation, and impaired production of MIP-1α. Furthermore, skin from EtOH-treated mice demonstrated a reduction in the abundance of epidermal CRAMP and KLK7.

Conclusions

These findings suggest that EtOH exposure hinders several distinct components of the innate immune response, including phagocyte recruitment and chemokine/cytokine and AMP production. Together, these effects likely contribute to delayed wound closure and enhanced infection severity observed in intoxicated patients.

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