Abstract
Expression and enzymatic activity of heme oxygenase (HO) has been implicated in the development, as well as in the resolution, of inflammatory conditions. Because inflammation is central to tissue repair, we investigated the presence and potential functions of HO in an excisional model of normal and diabetes-impaired wound repair in mice. Expression of HO-1 during cutaneous healing was analyzed by RNase protection assay, Western blot, and immunohistochemical techniques in a murine model of excisional repair. Furthermore, we determined HO-1-dependent release of proinflammatory cytokines from RAW 264.7 macrophages by enzyme-linked immunosorbent assay (ELISA). Upon injury, we observed a rapid and strong increase in HO-1 mRNA and protein levels at the wound site. By contrast to normal repair, late stages of diabetes-impaired repair were associated with elevated HO-1 expression. Besides a few keratinocytes of the hyperproliferative epithelium, immunohistochemistry revealed infiltrating macrophages as the predominant and major source of HO-1 at the wound site. In vitro studies demonstrated the potency of exogenous and also endogenous nitric oxide (NO) to strongly induce HO-1 expression in RAW 264.7 macrophages. However, L-NIL-mediated enzymatic inhibition of inducible NO-synthase (iNOS) at the wound site in vivo was not paralleled by decreased HO-1 levels. In vitro inhibition of HO-1 enzymatic activity by tin protoporphyrin IX (SnPPIX) in RAW 264.7 macrophages markedly attenuated tumor necrosis factor-alpha (TNF-alpha), but strongly increased interleukin-1beta (IL-1beta) release in RAW 264.7 macrophages in vitro. The observed injury-mediated increase in HO-1 mRNA and protein at the wound site was due to infiltrating HO-1 expressing monocytic cells. Macrophage-derived HO-1 expression was not under regulatory control by NO in skin repair. We provide evidence that HO-1 might exert a regulatory role in macrophage-derived cytokine release.
Highlights
Cutaneous wound healing represents a special situation to the body, as an injury of body surfaces more or less interferes with normal skin integrity that usually provides protection against different environmental conditions
Because expression of heme oxygenase (HO)-1 is discussed as contributing to inflammatory processes associated with different pathologic conditions [5], we postulated a potential presence of HO-1 during the inflammatory phase of skin regeneration
Expression of HO has long been known to participate in inflammatory conditions
Summary
Cutaneous wound healing represents a special situation to the body, as an injury of body surfaces more or less interferes with normal skin integrity that usually provides protection against different environmental conditions. Skin repair comprises tissue movements such as hemostasis, inflammation, granulation tissue formation, and re-epithelialization. These phases of tissue repair are well known to overlap in a temporal and spatial manner [1]. The inflammatory phase of repair, initiated a few hours after injury by infiltration of immune cells from the vasculature, is of central importance for wound closure. Results: Upon injury, we observed a rapid and strong increase in HO-1 mRNA and protein levels at the wound site. Conclusions: The observed injury-mediated increase in HO-1 mRNA and protein at the wound site was due to infiltrating HO-1 expressing monocytic cells. We provide evidence that HO-1 might exert a regulatory role in macrophage-derived cytokine release
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