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Norepinephrine Modulates the Inflammatory and Proliferative Phases of Wound Healing

Gosain, Ankush MD; Jones, Stephen B. PhD; Shankar, Ravi PhD; Gamelli, Richard L. MD; DiPietro, Luisa A. DDS, PhD

Journal of Trauma and Acute Care Surgery: April 2006 - Volume 60 - Issue 4 - p 736-744
doi: 10.1097/
Original Articles

Background: Injury results in the massive release of norepinephrine (NE) into the peripheral circulation. Recent investigations have demonstrated functional adrenoreceptors on the cellular mediators of cutaneous wound healing and NE-induced phenotypic alterations in immune cells have been demonstrated in vitro. Despite this, there is little description of how NE might alter the phases of wound healing in vivo. The purpose of this study was to compare cutaneous wound healing in norepinephrine-intact and norepinephrine-depleted mice.

Methods: Norepinephrine-depleted (NED) mice were generated by chemical axotomy with 6-hydroxydopamine and compared with norepinephrine-intact (NEI) animals (n = 6–12 per group, per time point). Using an excisional wound model, neutrophil recruitment was measured by myeloperoxidase assay. Macrophage recruitment and angiogenesis were measured by immunohistochemistry and re-epithelialization was determined histologically. The development of incisional wound disruption strength was determined over time. Finally, macrophage scavenger function was assessed by an in vitro latex bead phagocytosis assay.

Results: Wounds from NEI mice demonstrated greater neutrophil infiltration than NED wounds (24, 72 hours; p < 0.05). Wound macrophage recruitment was initially higher in NEI animals (24 hours, p < 0.05), but was eventually surpassed by that of NED animals (120 hours, p < 0.05). Angiogenesis was decreased while re-epithelialization was accelerated in NEI animals (p < 0.05). Wound disruption strength and macrophage scavenger function were unaltered between NED and NEI mice.

Conclusions: Norepinephrine modulates the inflammatory and proliferative phases of wound healing in a temporally defined, cell-specific manner. By increasing recruitment of innate immune cells and expediting wound closure, norepinephrine appears to play a protective role in defense against infection.

From the Burn and Shock Trauma Institute (A.G., S.B.J., R.S., R.L.G., L.A.D.), Department of Cell Biology, Neurobiology, and Anatomy (A.G.), Department of Physiology (S.B.J.), Department of Microbiology and Immunology (L.A.D.), and Department of Surgery (S.B.J., R.S., R.L.G., L.A.D.), Loyola University Medical Center, Maywood, Illinois.

Submitted for publication November 8, 2005.

Accepted for publication January 12, 2006.

This study was supported by grants from the National Institutes of Health (T32-GM08750 to A.G., and R01-GM50875 and R01-GM55238 to L.A.D.).

Presented at Experimental Biology 2005, San Diego, California; and the 63rd Annual Meeting of the American Association for the Surgery of Trauma, September 29–October 2, 2004, Maui, Hawaii.

Address for reprints: Luisa A. DiPietro, DDS, PhD, Loyola University Medical Center, Burn and Shock Trauma Institute, 2160 S. First Avenue, Maywood, IL 60153; email:

© 2006 Lippincott Williams & Wilkins, Inc.