From an Enhanceosome to a Repressosome: Molecular Antagonism between Glucocorticoids and EGF Leads to Inhibition of Wound Healing

Lee, Brian; Vouthounis, Constantinos; Stojadinović, Olivera; Brem, Harold; Im, Mark J.; Tomic‐Canic, Marjana

doi:10.1016/j.jmb.2004.11.027

Cited by 66 publications

(87 citation statements)

References 44 publications

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“…Studies by Filaretova demonstrated that glucocorticoid had a gastric protective role during stress and administration of nonsteroidal anti-inflammatory drugs in rats (Filaretova et al, 1998(Filaretova et al, , 2002. In our opinion, our results and their observations on the functional role of glucocorticoid on ulcer healing are not contradictory since endogenous glucocorticoids may have a physiologically protective role (Filaretova et al, 1998(Filaretova et al, , 2002, whereas its administration in pharmacological doses would in turn delay ulcer repair and wound healing (Carpani de Kaski et al, 1995;Luo et al, 2003;Lee et al, 2005).…”

Section: Discussionsupporting

confidence: 51%

Dexamethasone Inhibits Epidermal Growth Factor-Stimulated Gastric Epithelial Cell Proliferation

Luo

Wen

Lin

et al. 2006

J Pharmacol Exp Ther

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Epidermal growth factor (EGF) is essential to heal gastric ulcers, whereas glucocorticoid delays rat gastric ulcer healing. We found that dexamethasone inhibited EGF-stimulated rat gastric epithelial cell (RGM-1) proliferation by cell count and DNA synthesis analysis of flow cytometry and attempted to elucidate the possible mechanistic pathway via Western blot analysis. EGF (10 ng/ml) treatment for 24 h significantly increased RGM-1 cell proliferation, and dexamethasone (10 Ϫ8and 10 Ϫ6 M) markedly suppressed EGF-stimulated cell proliferation. Western blotting results demonstrated that the phosphorylated extracellular signal-regulated kinase (pERK) (pERK1/pERK2) significantly increased at 10 min after EGF treatment. This was followed by increase of cyclooxygenase (COX)-2 expression at 3 h after EGF treatment. The continued increase of COX-2 (up to 18 h) resulted in increased intracellular prostaglandin E 2 and cyclin D1 expression significantly after 8 and 12 h of EGF treatment. Dexamethasone substantially reduced EGF-stimulated COX-2 expression at 3 and 6 h and cyclin D1 expression at 8 and 12 h. Pretreatment of RGM-1 cells with dexamethasone or 2Ј-amino-3Ј-methoxyflavone (PD98059)-mitogen-activated protein kinase kinase inhibitor (5 ϫ 10 Ϫ5 M) significantly reduced EGF-stimulated pERK1/ pERK2 expression. Simultaneous treatment of RGM-1 cells with PD98059 and EGF also markedly decreased EGF-stimulated COX-2 expression at 6 h. These findings indicate that dexamethasone significantly suppresses EGF-stimulated gastric epithelial cell proliferation, and one of the pathways involved is via inhibiting activation of ERK1/ERK2, followed by inhibition of COX-2, cyclin D1 expression, and finally DNA synthesis.

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Section: Discussionsupporting

confidence: 51%

Dexamethasone Inhibits Epidermal Growth Factor-Stimulated Gastric Epithelial Cell Proliferation

Luo

Wen

Lin

et al. 2006

J Pharmacol Exp Ther

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“…Twenty-four hours before the experiment, cells were transferred to basal medium containing DMEM with 5% stripped serum (23). To eliminate proliferation, on day 0, cells were treated with 8 g mL -1 Mitomycin C (ICN) for 1 h, washed with 1ϫPBS prior to scratch, as previously described (24). Scratches were performed using sterile yellow pipette tips and photographed using a Carl Zeiss microscope and a Sony digital camera (DKC -500).…”

Section: Wound Scratch Assaysmentioning

confidence: 99%

Molecular Markers in Patients with Chronic Wounds to Guide Surgical Debridement

Brem

Stojadinović

Diegelmann

et al. 2007

Mol Med

Self Cite

285

257

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“…At a cellular level, dermal collagen content in human skin is decreased following topical and systemic GC treatment (3,8,9) and is similarly decreased in rats following subcutaneous dexamethasone injection (10). Subsequently, there is a profound increase in the transparency of skin with a tissue paper-like consistency, increased fragility, tearing and bruising (7), increased transepidermal water loss (TEWL) (11), poor wound healing (12,13), and increased infection risk (14).…”

Section: Introductionmentioning

confidence: 99%

11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

Tiganescu

Tahrani²,

Morgan³

et al. 2013

J. Clin. Invest.

117

120

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Glucocorticoid (GC) excess adversely affects skin integrity, inducing thinning and impaired wound healing. Aged skin, particularly that which has been photo-exposed, shares a similar phenotype. Previously, we demonstrated age-induced expression of the GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in cultured human dermal fibroblasts (HDFs). Here, we determined 11β-HSD1 levels in human skin biopsies from young and older volunteers and examined the aged 11β-HSD1 KO mouse skin phenotype. 11β-HSD1 activity was elevated in aged human and mouse skin and in PE compared with donor-matched photo-protected human biopsies. Age-induced dermal atrophy with deranged collagen structural organization was prevented in 11β-HSD1 KO mice, which also exhibited increased collagen density. We found that treatment of HDFs with physiological concentrations of cortisol inhibited rate-limiting steps in collagen biosynthesis and processing. Furthermore, topical 11β-HSD1 inhibitor treatment accelerated healing of full-thickness mouse dorsal wounds, with improved healing also observed in aged 11β-HSD1 KO mice. These findings suggest that elevated 11β-HSD1 activity in aging skin leads to increased local GC generation, which may account for adverse changes occurring in the elderly, and 11β-HSD1 inhibitors may be useful in the treatment of age-associated impairments in dermal integrity and wound healing.

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From an Enhanceosome to a Repressosome: Molecular Antagonism between Glucocorticoids and EGF Leads to Inhibition of Wound Healing

Cited by 66 publications

References 44 publications

Dexamethasone Inhibits Epidermal Growth Factor-Stimulated Gastric Epithelial Cell Proliferation

Dexamethasone Inhibits Epidermal Growth Factor-Stimulated Gastric Epithelial Cell Proliferation

Molecular Markers in Patients with Chronic Wounds to Guide Surgical Debridement

11β-Hydroxysteroid dehydrogenase blockade prevents age-induced skin structure and function defects

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