HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The heme-heme oxygenase system: a molecular switch in wound healing

When cells are injured they release their contents, 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 administered intradermally 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 also that HO-1 is significantly expressed in the epithelium of both the mucosa and the skin of animals without wounds. On 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 pharmacologic inhibition of HO activity. These observations suggest that the heme-HO system is closely involved in the control of wound healing. Our results demonstrate that the local release of heme may be a physiologic 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. (Blood. 2003;102: 521-528)