Non-healing is associated with persistent stimulation of the innate immune response in chronic venous leg ulcers

Pukstad, Brita S.; Ryan, Liv; Flo, Trude H.; Stenvik, Jørgen; Moseley, Ryan; Harding, Keith; Thomas, David W.; Espevik, Terje

doi:10.1016/j.jdermsci.2010.05.003

« Previous Next »Journal of Dermatological Science
Volume 59, Issue 2 , Pages 115-122, August 2010

Non-healing is associated with persistent stimulation of the innate immune response in chronic venous leg ulcers

Brita S. Pukstad
- Institute of Cancer Research and Molecular Medicine, Norwegian University of Technology and Science, 7089 Trondheim, Norway
- Department of Dermatology, St. Olavs Hospital HF, Trondheim University Hospital, 7006 Trondheim, Norway
- Corresponding author at: Institute of Cancer Research and Molecular Medicine, Norwegian University of Technology and Science, 7089 Trondheim, Norway. Tel.: +47 95878012; fax: +47 73598801.
Liv Ryan
- Institute of Cancer Research and Molecular Medicine, Norwegian University of Technology and Science, 7089 Trondheim, Norway
Trude H. Flo
- Institute of Cancer Research and Molecular Medicine, Norwegian University of Technology and Science, 7089 Trondheim, Norway
Jørgen Stenvik
- Institute of Cancer Research and Molecular Medicine, Norwegian University of Technology and Science, 7089 Trondheim, Norway
Ryan Moseley
- School of Dentistry, Cardiff University, Heath Park, Cardiff CF14 4XY, Wales, UK
Keith Harding
- Wound Healing Research Unit, Cardiff University, Heath Park, Cardiff CF14 4XY, Wales, UK
David W. Thomas
- School of Dentistry, Cardiff University, Heath Park, Cardiff CF14 4XY, Wales, UK
Terje Espevik
- Institute of Cancer Research and Molecular Medicine, Norwegian University of Technology and Science, 7089 Trondheim, Norway

Received 1 December 2009; received in revised form 27 April 2010; accepted 14 May 2010. published online 12 July 2010.

Abstract

Background

The molecular pathogenesis of chronic skin wounds is complex and not fully understood. Although these wounds are often characterized as being in a state of persistent inflammation, the impact and participation of the innate immune responses in sustaining this inflammation needs further investigation.

Objective

We investigated the cytokine profiles, Toll-like receptor (TLR)-stimulating activities and the levels of the antibacterial peptide Lipocalin-2 (Lcn-2) in a series of healing and non-healing chronic venous leg ulcers (CVLUs) through a study time of 8 weeks.

Methods

Wound fluids from healing and non-healing CVLUs were run on a Human Cytokine Antibody Array, and Lcn-2 levels measured with ELISA. HEK 293 cells transfected with TLR2 or TLR4 and their respective co-receptors, and human peripheral blood monocytes were then stimulated with the wound fluids from healing and non-healing venous leg ulcers.

Results

Healing wounds were associated with decreasing levels of IL-1α, IL-1β and MIP-1δ, whereas in non-healing wounds decreasing levels of IL-8 and MIP-1α were found. Accordingly, wound fluid from non-healing CVLUs contained persistent Lcn-2 levels and TLR2- and TLR4-stimulating activities, while, in healing wounds, the TLR-stimulating activities decreased over time with significantly diminished levels of Lcn-2 (p<0.005).

Conclusions

Innate immune responses contribute to the chronic inflammation in non-healing CVLUs through participation of Toll-like receptors. The levels of the antimicrobial peptide Lcn-2 in wound fluids from these ulcers are elevated as a reflection of this contribution.

Keywords: Chronic venous leg ulcer (CVLU), Toll-like receptor (TLR), Wound fluid, Lipocalin-2 (Lcn-2)