Abstract
The pathogenesis of complex regional pain syndrome (CRPS) is unresolved, but tumor
necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are elevated in experimental
skin blister fluid from CRPS-affected limbs, as is tryptase, a marker for mast cells.
In the rat fracture model of CRPS, exaggerated sensory and sympathetic neural signaling
stimulate keratinocyte and mast cell proliferation, causing the local production of
high levels of inflammatory cytokines leading to pain behavior. The current investigation
used CRPS patient skin biopsies to determine whether keratinocyte and mast cell proliferation
occur in CRPS skin and to identify the cellular source of the up-regulated TNF-α,
IL-6, and tryptase observed in CRPS experimental skin blister fluid. Skin biopsies
were collected from the affected skin and the contralateral mirror site in 55 CRPS
patients and the biopsy sections were immunostained for keratinocyte, cell proliferation,
mast cell markers, TNF-α, and IL-6. In early CRPS, keratinocytes were activated in
the affected skin, resulting in proliferation, epidermal thickening, and up-regulated
TNF-α and IL-6 expression. In chronic CRPS, there was reduced keratinocyte proliferation,
leading to epidermal thinning in the affected skin. Acute CRPS patients also had increased
mast cell accumulation in the affected skin, but there was no increase in mast cell
numbers in chronic CRPS.
Perspective
The results of this study support the hypotheses that CRPS involves activation of
the innate immune system, with keratinocyte and mast cell activation and proliferation,
inflammatory mediator release, and pain.
Key words
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Article info
Publication history
Published online: January 24, 2014
Accepted:
January 8,
2014
Received in revised form:
January 3,
2014
Received:
October 17,
2013
Footnotes
Supported by National Institutes of Health grant NS072168, Department of Veterans Affairs Rehabilitation Research and Development Merit grant F7137R, German Research Foundation Bi579/8, EU FP7, Foundation Rhineland-Palatinate Project 936, the Hopp Stiftung, National Health and Medicine Research Council of Australia grants 437205 and APP1030379, and Australian and New Zealand College of Anaesthetics grant 10/21.
The authors do not have financial or other relationships that might lead to conflict of interest.
This study contains essential parts of the MD thesis of N.A., which will be submitted to the Faculty of Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
Identification
Copyright
Published by Elsevier Inc.
