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The role of estrogen and MIF in cutaneous wound healing

Emmerson, Elaine

[Thesis]. Manchester, UK: The University of Manchester; 2010.

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Abstract

The complex process of wound repair becomes disrupted in the elderly with a profound effect on patient morbidity and huge financial implications for the NHS. While age itself is a risk factor for delayed healing recent work implicates estrogen decline, rather than intrinsic ageing per se, as the critical regulator of delayed healing in elderly subjects. In women estrogen levels fall dramatically post-menopause and with increasing life expectancy most women in the developed now world spend at least a third of their lives in a state of estrogen deprivation. Estrogen replacement can reverse this delay, but unfortunately long term estrogen treatment (HRT) increases breast cancer risk such that steroidal estrogen is now listed as a carcinogen. The aim of this study has been to functionally dissect the role of estrogen signalling during repair at the molecular, cellular and physiological levels. New data presented within this thesis reveal estrogen to be a global regulator of healing with pleiotropic effects on multiple wound cell types. By combining pharmacological manipulation and genetic ablation my data reveals novel diametrically opposed roles for the two estrogen receptor isoforms, ERalpha and ERbeta, during healing. I have further exploited this to demonstrate the in vivo therapeutic potential of compounds with receptor selective agonistic/antagonistic activity. Additionally, I have further investigated the mechanism of action of estrogen and these selective compounds implicating the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) in beneficial effects on healing. This research leads the way toward translation into human studies with the ultimate aim of developing targeted therapeutics for the treatment of delayed acute and chronic wounds, particularly in the elderly.