The heme-heme oxygenase system: a molecular switch in wound healing

Abstract

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)

Peanut lipids display potential adjuvanticity by triggering a pro‐inflammatory response in human keratinocytes

“…HO‐1 mRNA levels (Figure 1), but not proteins (data not shown), were also increased upon PNL treatment. HO‐1 is highly expressed in KC and is increased in response to stress and inflammatory stimuli 9. The capacity of PNL to activate human KC was further supported by our results demonstrating stress‐related morphological changes appearing after 24 hours of PNL treatment in the presence or absence of allergens (Figure S4) without affecting cell viability (Figure S5).…”

IL-22 Inhibits Epidermal Differentiation and Induces Proinflammatory Gene Expression and Migration of Human Keratinocytes

“…The modulation of two other genes is also in favor of the proinflammatory and chemotactic roles of IL-22. Indeed, the induction of neutrophil attractant chemokine CXCL5/epithelial-derived neutrophil-activating peptide 78, together with the down-regulation of heme oxygenase 1, which antagonizes inflammation by attenuating adhesive interaction and cellular infiltration in the skin, could contribute to the neutrophil influx in the skin (33,43).…”

“…DNase treatment, poly(A) ϩ RNA enrichment, 33 P-labeled cDNA probe synthesis, and purification and hybridization to custom Atlas array membranes (24) were performed according to Clontech's recommendations (Clontech). Membranes were exposed for 4 days to a Molecular Dynamics Storm storage screen and scanned using a phosphorimager scanner (Molecular Dynamics Storm analyser; Amersham Biosciences).…”

Overexpression of Heme Oxygenase-1 in Murine Melanoma

“…Strong expression of HO-1 is often observed in tissues with a high rate of cell proliferation, such as epidermis during cutaneous wound healing, 39 psoriatic skin lesions, 11 or tumors including adenocarcinoma, hepatoma, sarcoma, glioblastoma, melanoma, and squamous carcinoma. 14,40 -42 Contradictory results published so far indicate that the role of HO-1 in regulation of cell cycle is strongly tissue-type-dependent.…”