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Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor
Gillian S. Ashcroft, … , Sharon M. Wahl, Toshinori Nakayama
Gillian S. Ashcroft, … , Sharon M. Wahl, Toshinori Nakayama
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1309-1318. https://doi.org/10.1172/JCI16288.
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Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor

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Abstract

Characteristic of both chronic wounds and acute wounds that fail to heal are excessive leukocytosis and reduced matrix deposition. Estrogen is a major regulator of wound repair that can reverse age-related impaired wound healing in human and animal models, characterized by a dampened inflammatory response and increased matrix deposited at the wound site. Macrophage migration inhibitory factor (MIF) is a candidate proinflammatory cytokine involved in the hormonal regulation of inflammation. We demonstrate that MIF is upregulated in a distinct spatial and temporal pattern during wound healing and its expression is markedly elevated in wounds of estrogen-deficient mice as compared with intact animals. Wound-healing studies in mice rendered null for the MIF gene have demonstrated that in the absence of MIF, the excessive inflammation and delayed-healing phenotype associated with reduced estrogen is reversed. Moreover, in vitro assays have shown a striking estrogen-mediated decrease in MIF production by activated murine macrophages, a process involving the estrogen receptor. We suggest that estrogen inhibits the local inflammatory response by downregulating MIF, suggesting a specific target for future therapeutic intervention in impaired wound-healing states.

Authors

Gillian S. Ashcroft, Stuart J. Mills, KeJian Lei, Linda Gibbons, Moon-Jin Jeong, Marisu Taniguchi, Matthew Burow, Michael A. Horan, Sharon M. Wahl, Toshinori Nakayama

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Figure 3

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Reduced estrogen has no effect on wound healing in mice null for MIF. Da...
Reduced estrogen has no effect on wound healing in mice null for MIF. Day 3 wounds were wider in OVX wild-type mice (c) with an increased inflammatory response as compared with intact littermates (a). In marked contrast, no differences were observed between wounds from MIF null intact mice (b) and MIF null OVX mice (d). Arrows demarcate wound edges. In (c), the panniculus carnosus muscle is at the extreme edges of the image. Scale bars for a–d represent 100 μm. In the OVX MIF null wounds at day 7 (f), increased collagen I deposition was observed as compared with wounds from OVX wild-type mice (e). An absence of staining on parallel sections using an isotype control antibody is shown (g). Scale bars for e–g represent 10 μm. Wound areas were significantly greater in OVX wild-type mice than in OVX MIF null mice at day 3 after wounding (h). Results represent means ± SEM (n = 3–5 for each group, *P < 0.05). Wound strength evaluated by disruption of day-3, -5, and -7 wounds in vivo using a BTC1000 device is shown (i). A significant increase in wound strength was observed at days 5 and 7 as compared with day 3. Results represent means ± SEM (n = 4–5 for each group, *P < 0.05 compared to day-3 data). At day 7 after wounding (j), the ultimate breaking strength (mmHg) was significantly reduced in the OVX wild-type mice as compared with OVX MIF null mice and wild-type intact mice. Results represent means ± SEM (n = 4, *P < 0.05).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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