No abstract

Post-menopausal women have an increased risk of developing a number of degenerative pathological conditions, linked by the common theme of excessive inflammation. Systemic estrogen replacement (in the form of hormone replacement therapy) is able to accelerate healing of acute cutaneous wounds in elderly females, linked to its potent antiinflammatory activity. However, in contrast to many other age-associated pathologies, the detailed mechanisms through which estrogen modulates skin repair, particularly the cell type–specific role of the two estrogen receptors, ERα and ERβ, has yet to be determined. Here, we use pharmacological activation and genetic deletion to investigate the role of both ERα and ERβ in cutaneous tissue repair. Unexpectedly, we report that exogenous estrogen replacement to ovariectomised mice in the absence of ERβ actually delayed wound healing. Moreover, healing in epidermal-specific ERβ null mice (K14-cre/ERβL2/L2) largely resembled that in global ERβ null mice. Thus, the beneficial effects of estrogen on skin wound healing are mediated by epidermal ERβ, in marked contrast to most other tissues in the body where ERα is predominant. Surprisingly, agonists to both ERα and ERβ are potently antiinflammatory during skin repair, indicating clear uncoupling of inflammation and overall efficiency of repair. Thus, estrogen-mediated antiinflammatory activity is not the principal factor in accelerated wound healing.

No abstract

Impaired wound healing states in the elderly lead to substantial morbidity and mortality, and a cost to the health services of over $9 billion per annum. In addition to intrinsic ageing processes that per se cause delayed healing, studies have suggested marked differences in wound repair between the sexes. We have previously reported that, castration of male mice results in a striking acceleration of local cutaneous wound healing and dampens the associated inflammatory response. In this study, we report that systemic 5α-reductase inhibition, which blocks the conversion of testosterone to its more active metabolite 5α-dihydrotestosterone, mimics the effects of castration in a rat model of cutaneous wound healing. The mechanisms underlying the observed effects involve a direct, cell-specific upregulation of pro-inflammatory cytokine expression by macrophages, but not fibroblasts, in response to androgens. Androgens require the transforming growth factor β signalling intermediate Smad3 to be present in order to influence repair and local pro-inflammatory cytokine levels. That reducing 5α-dihydrotestosterone levels through 5α-reductase antagonism markedly accelerates healing suggests a specific target for future therapeutic intervention in impaired wound healing states in elderly males.

That endogenous sex steroid hormones profoundly influence the response to cutaneous injury is well established. How they and other factors combine to direct repair in male and female animals is much less well understood. Using a murine incisional wound-healing model, we investigated the roles of circulating sex steroids, macrophage migration inhibitory factor (MIF) (the mediator of delayed healing in ovariectomized animals), and hormone- and MIF-independent factors in controlling repair. We report that d 3 wounds, of comparable size in intact male and female mice, are significantly larger in ovariectomized female animals than in castrated males, suggesting that native sex hormones mask inherent underlying differences in the ways in which males and females respond to wounding. Wound MIF levels were comparable in intact male and female mice but greater in ovariectomized females than castrated males. Furthermore, wound levels of Jun activation domain-binding protein 1 (JAB1), a key factor by which MIF activates intracellular responses, were increased through ovariectomy and greater in ovariectomized females than castrated males. This difference in wound JAB1 levels may underscore the marked sex difference we observed in the responses of MIF knockout mice to the local application of MIF: healing was impaired in ovariectomized females but not castrated males. Separately, systemic treatment with androgens and estrogens yielded contrasting effects on repair in male and female animals. Collectively, the presented data indicate sex divergence in wound healing to be multifaceted, being strongly influenced by MIF and seemingly limited by the combined actions of gonadal steroids.

Immigrants to Sweden are a mixed group with differing, but often increased, risks of mental disorders. Targeted qualitative and intervention studies may facilitate efforts to develop and implement preventive methods for immigrants at high risk of mental ill health, and to tailor treatment to the specific needs of different immigrant groups.

Owing to its implication in a range of pathological conditions, including asthma, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease and cancer, the pleiotropic cytokine macrophage migration inhibitory factor (MIF) has been the subject of intensive recent investigation. In the field of dermatology, MIF is believed to be a detrimental factor in diseases such as systemic sclerosis, atopic dermatitis, psoriasis, eczema and UV radiation damage. However, its contribution to other aspects of cutaneous biology is currently unclear. Although its expression in intact skin is well characterized, little is known about MIF's role in cutaneous homoeostasis. However, recent data do identify MIF as a key player in the immune privilege of hair follicles. Similarly, although MIF is rapidly released and its local expression significantly induced upon wounding, its primary role in the ensuing repair process remains a source of contention. MIF has been identified as being a key effector of the beneficial effects of estrogen on wound repair, yet studies employing Mif null mice, recombinant MIF, and neutralizing anti-MIF antibodies have failed to provide a consensus as to whether it benefits or inhibits healing. In fact MIF appears to be able to exert both positive and negative effects, with the cell-specific relevancy of MIF in wound healing still unclear. Thus, if MIF and ⁄ or its downstream targets are to be therapeutically useful in the context of cutaneous repair, more needs to be done to establish the nature and mechanism of action of MIF and its receptors in healing wounds.

Age-related impaired wound healing states lead to substantial morbidity and cost, with treatment in the USA resulting in an expenditure of over $9 billion per annum. Dehydroepiandrosterone (DHEA) is a ubiquitous adrenal hormone with immunomodulatory properties whose levels decline significantly with advanced age in humans. Conversion of DHEA locally to downstream steroid hormones leads to estrogenic and/or androgenic effects which may be important in age-related skin homeostasis, and which would avoid systemic adverse effects related to estrogen. We report that systemic DHEA levels are strongly associated with protection against chronic venous ulceration in humans. DHEA accelerated impaired healing in an impaired healing model (mice rendered hypogonadal) associated with increased matrix deposition and dampens the exaggerated inflammatory response. Such effects were mediated by local conversion of DHEA to estrogen, acting through the estrogen receptor, and vitro studies suggest a direct effect on specific pro-inflammatory cytokine production by macrophages via mitogen activated kinase (MAP) and phosphatidylinositol 3 (PI3) kinase pathways. In addition, we show that local injection of DHEA accelerates impaired healing in an ageing mouse colony. We suggest that exogenous application of DHEA accelerates impaired wound repair, results which may be applicable to the prophylaxis and treatment of human impaired wound healing states.