Chemically modified tetracycline (CMT‐8) and estrogen promote wound healing in ovariectomized rats: Effects on matrix metalloproteinase‐2, membrane type 1 matrix metalloproteinase, and laminin‐5 γ2‐chain

Pirilä, Emma; Parikka, Mataleena; Ramamurthy, N. S.; Maisi, Päivi; McClain, Steve A.; Kucine, Allan; Tervahartiala, Taina; Prikk, Kaiu; Golub, Lorne M.; Salo, Tuula; Sorsa, Timo

doi:10.1046/j.1524-475x.2002.10605.x

Cited by 54 publications

(41 citation statements)

References 37 publications

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“…C, no injection at wound site; PBS, vehicle control. estrogen in maintaining a rapid rate of healing in both animal and human models, suggesting that the marked reduction of estrogen with age in both females and males plays a major role in age-related impaired woundhealing states (2)(3)(4)(5)(6)(7)(8). Moreover, evidence suggests that a crucial mechanism underlying the responses to estrogen involves a dampening of the inflammatory response, resulting in reduced proteolytic activity and enhanced matrix deposition (6).…”

Section: Discussionmentioning

confidence: 99%

Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor

Ashcroft¹,

Mills²,

Lei³

et al. 2003

J. Clin. Invest.

284

184

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IntroductionBecause of a complex interaction of medical and epidemiological factors, there has been a rapid increase in the size of the elderly population. With this, there has also been a parallel increase in morbidity associated with age-related delayed wound healing, which costs the health services over $9 billion per year. Cutaneous wound healing is characterized by an initial inflammatory response, followed by reformation of the epithelial barrier and matrix deposition. Accumulating evidence implicates inflammation, and the resultant proteolysis of matrix, as a causative factor in age-related delayed healing and suggests that in the absence of infection, the inflammatory response is inappropriately excessive (1, 2). There is striking evidence from animal studies dating back to 1962 that estrogens play a crucial role in cutaneous wound healing and repair is significantly delayed in its absence, an event characterized by profound leukocyte recruitment during the initial stages of injury and tissue destruction (3-6). Moreover, exogenous estrogen replacement in these animal and human models reverses the effects on healing (6-8). In this regard, recent reports have shown that hormonereplacement therapy (HRT) prevents the development of chronic wounds (both pressure ulcers and venous ulcers) in postmenopausal women (9, 10). Intriguingly, the positive effect of topical estrogen has been shown in both elderly women and men, reflecting the marked decrease in local estrogenic activity secondary to reduced ovarian activity in women, a decline in the adrenal estrogenic precursor dehydroepiandrosterone (DHEA) in men and women, and altered aromatization of systemic precursors to local active estrogen (6).In excessive and chronic inflammatory disorders, the influx of leukocytes occurs unabated, leading to enhanced cytokine and chemokine production, further unchecked leukocyte recruitment, and ultimately proteolytic tissue destruction. Estrogen accelerates the cutaneous wound-healing process, associated with enhanced matrix deposition, rapid epithelialization, and a dampening of the inflammatory response (2-8).One potential downstream target for hormonal effects 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 agerelated 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 associ...

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Section: Discussionmentioning

confidence: 99%

Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor

Ashcroft¹,

Mills²,

Lei³

et al. 2003

J. Clin. Invest.

284

184

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“…17␤-Estradiol 3-benzoate was demonstrated to be pro-proliferative in connective tissue (25) and in skin and lung fibroblasts (26) but to diminish cell proliferation in the renal ablation model (5). Estrogens normalized wound bed collagen contents and structure in the OVX rat model (27). In mesangial cell cultures, genistein, a selective estrogen receptor modulator (14), and 17␤-estradiol 3-benzoate reduced expression of collagen types I and IV (28).…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Estrogens on Indices of Renal Damage in Uninephrectomized SHRsp Rats

Gross¹,

Adamczak

Rabe

et al. 2004

Journal of the American Society of Nephrology

103

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Abstract. Renal diseases tend to be less severe among premenopausal female patients, compared with male patients. Experimental data on the effects of estrogens on renal damage are controversial, and potential underlying mechanisms have not been fully clarified. Three-month-old, female, uninephrectomized (UNX), sham-operated or ovariectomized (OVX) SHRsp rats were left untreated or received either 17␤-estradiol 3-benzoate (25 g/d) or estriol (0.02 mg/d) daily. After 3 mo, indices of renal damage (glomerulosclerosis index and tubulointerstitial damage index) and glomerular geometric parameters were investigated. The expression of desmin, TGF-␤, endothelin-1, collagen IV, endothelial nitric oxide synthase, and estrogen receptors ␣ and ␤ in the glomeruli and tubulointerstitium was immunohistochemically evaluated. Estradiol and estriol did not significantly affect kidney weights or BP. Estradiol and estriol caused significant reductions in albuminuria (vehicle-treated UNX/OVX animals, 25.4 Ϯ 8.52 mg/24 h; estradiol-treated UNX/OVX animals, 15.37 Ϯ 6.12 mg/24 h; estriol-treated UNX/OVX animals, 6.54 Ϯ 2.24 mg/24 h). The glomerulosclerosis index was significantly lower in estriol-and estradiol-treated animals (estradiol-treated UNX/OVX animals, 0.69 Ϯ 0.16; estriol-treated UNX/OVX animals, 0.21 Ϯ 0.12; P Ͻ 0.05), compared with vehicle-treated animals (1.46 Ϯ 0.09); the tubulointerstitial damage index exhibited a similar pattern. The mean glomerular volume was significantly less in estrogen-treated animals. UNX/OVX animals demonstrated significantly greater expression of TGF-␤ and endothelin-1 in immunohistochemical, in situ hybridization, and reverse transcription-PCR assays. This increase was abrogated by estriol but not estradiol. Similarly, significantly higher glomerular and tubulointerstitial expression of proliferating cell nuclear antigen and collagen IV was observed in UNX/OVX animals, and expression was decreased by estriol but not estradiol. It was concluded that, in the UNX model of spontaneous renal damage, glomerular lesions and glomerular hypertrophy were reduced by estriol but less consistently by estradiol. In parallel, loss of podocytes, evidence of podocyte injury (i.e., desmin expression), and expression of mediator systems of glomerular damage were decreased, pointing to a major renoprotective action of estriol.Several studies have demonstrated that the severity and rate of progression of renal diseases tend to be greater among men, compared with women (1). This is true for several types of renal diseases, such as membranous nephropathy (2), IgA nephropathy (3), and polycystic kidney disease (4). The data from experimental studies are controversial, and very few molecular data are available. Estrogens or estrogen metabolites ameliorate renal damage in some (5) but not all (6,7) models of renal damage. The beneficial effect of estrogen was also noted in allograft nephropathy (8). Potential explanations for the discrepancies are that different pathomechanisms operate in the various animal models or th...

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“…Doxycycline can also reduce inflammation by reducing synthesis of nitric oxide (NO) (101,102,115). Evaluation of a chemically tetracycline analogue in an animal study (116) also showed that local therapy reduced levels of MMP-8 and MMP-13 mRNA in dermal wounds of rats. Supporting this concept, an initial report (117) of a randomized controlled trial showed improved healing of chronic diabetic foot ulcers treated with a topical doxycycline gel.…”

Section: Local Therapy With Protease Inhibitorsmentioning

confidence: 99%

Proteases and the Diabetic Foot Syndrome: Mechanisms and Therapeutic Implications

2005

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Chemically modified tetracycline (CMT‐8) and estrogen promote wound healing in ovariectomized rats: Effects on matrix metalloproteinase‐2, membrane type 1 matrix metalloproteinase, and laminin‐5 γ2‐chain

Cited by 54 publications

References 37 publications

Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor

Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor

Beneficial Effects of Estrogens on Indices of Renal Damage in Uninephrectomized SHRsp Rats

Proteases and the Diabetic Foot Syndrome: Mechanisms and Therapeutic Implications

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