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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-07-2248.
Submitted July 31, 2002
Accepted February 19, 2003
The heme-heme oxygenase system: a molecular switch in wound healing
Frank A Wagener*, Hugo E van Beurden, Johannes W Von den Hoff, Gosse J Adema, and Carl G Figdor
Department of Tumor Immunology, UMC Nijmegen, Nijmegen, The Netherlands
Department of Orthodontics & Oral Biology, UMC Nijmegen, Nijmegen, The Netherlands
* Corresponding author; email: f.wagener{at}ncmls.kun.nl.
When cells get injured, they release their content resulting in a local accumulation of free heme proteins and heme. Here, we investigated the involvement of heme and its degrading enzyme heme oxygenase (HO) in the inflammatory process during wound healing. We observed that heme directly accumulates at the edges of the wound after inflicting a wound in the palate of Wistar rats. This coincided with an increased adhesion molecule expression, and the recruitment of leukocytes. To prove that heme is responsible for the recruitment of leukocytes, heme was intradermally administered 24 hours prior to injury. A clear heme-induced influx of both macrophages and granulocytes was observed. When examining the HO-isoforms, HO-1 and HO-2, we found that HO-2 was present in the entire submucosa. Surprisingly, we observed that also HO-1 is significantly expressed in the epithelium of both the mucosa and the skin of non-wounded animals. Upon inflammation, HO-1 expression increased particularly in infiltrating cells during the resolution phase of inflammation. Interestingly, we observed that heme-induced influx of leukocytes was highly elevated after pharmacological inhibition of HO activity. These observations suggest that the heme-heme oxygenase system is tightly involved in the control of wound healing. In conclusion, our results demonstrate that the local release of heme may be a physiological trigger to start inflammatory processes, whereas HO-1 antagonizes inflammation by attenuating adhesive interactions and cellular infiltration. Moreover, the basal level of HO expression in the skin may serve as a first protective environment against acute oxidative and inflammatory insults.
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