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Impaired healing of nitrogen mustard wounds in CXCR2 null mice
Snjezana Milatovic1, Lillian B Nanney, Yingchun Yu
1Department of Cancer Biology, Vanderbilt University School of Medicine, and Department of Veterans Affairs, Nashville, Tennessee 37232, USA.
Abstract:
To examine the significance of chemokine activation of CXCR2 in wound healing after chemical burn, cutaneous injury was created by topical application of nitrogen mustard on CXCR2 wild type (+/+), heterozygous (+/-), and knockout (-/-) mice. Wounds were analyzed histologically for neutrophil and monocyte infiltration and for reepithelialization at postwound days 4, 7, and 10. Neutrophil recruitment to the wound site was reduced through postwound day 7 in CXCR2 -/- mice as indicated by myeloperoxidase assay and by visual quantitation. Because there is always concern that mice with targeted deletion of a specific receptor may undergo developmental adaptations to offset the loss of the receptor, we also accessed chemical wound repair in the presence of a small molecule antagonist of CXCR2. Dietary supplementation with a CXCR2 antagonist (SB-265610) during the wound repair process also markedly delayed healing parameters in CXCR2 +/+ mice, even greater than treatment with glucocorticoids. These parallel studies further establish that mice deficient in CXCR2 function exhibit delayed cutaneous wound healing that may be primarily linked to impaired neutrophil recruitment after chemical burn with nitrogen mustard. Thus, there may be a potential therapeutic benefit of treating nitrogen mustard-induced skin lesions with agonists of CXCR2 to facilitate the wound repair process.
Insights
Chemokine receptor CXCR2 is crucial for effective wound healing after chemical burns. Blocking CXCR2 significantly delays skin repair by impairing neutrophil recruitment, suggesting CXCR2 agonists may aid healing.
Area of Science:
- Immunology
- Dermatology
- Wound Healing Research
Background:
- Chemical burns, such as those caused by nitrogen mustard, present significant challenges in cutaneous wound healing.
- The role of chemokine signaling, specifically via CXCR2, in orchestrating the inflammatory response during skin repair is not fully understood.
Purpose of the Study:
- To investigate the functional significance of chemokine receptor CXCR2 activation in the context of chemical burn wound healing.
- To determine the impact of CXCR2 deficiency and antagonism on neutrophil infiltration and reepithelialization following nitrogen mustard-induced skin injury.
Main Methods:
- Utilized a murine model of chemical burn using topical nitrogen mustard application on CXCR2 wild-type, heterozygous, and knockout mice.
- Assessed wound healing parameters including neutrophil and monocyte infiltration (via myeloperoxidase assay and histology) and reepithelialization at multiple time points (days 4, 7, 10).
- Administered a small molecule CXCR2 antagonist (SB-265610) to wild-type mice to corroborate findings from knockout models.
Main Results:
- CXCR2 knockout mice exhibited significantly reduced neutrophil recruitment to the wound site up to postwound day 7.
- Pharmacological inhibition of CXCR2 in wild-type mice also markedly delayed wound healing parameters, surpassing the effect of glucocorticoids.
- These findings indicate that impaired neutrophil recruitment due to CXCR2 deficiency is a key factor in delayed cutaneous wound healing after chemical burn.
Conclusions:
- CXCR2 signaling is essential for efficient neutrophil recruitment and subsequent cutaneous wound healing following nitrogen mustard-induced chemical burns.
- Targeting CXCR2 with agonists presents a potential therapeutic strategy for accelerating the repair of nitrogen mustard-induced skin lesions.