Wound Healing in Ovariectomized Rats Effects of Chemically Modified Tetracycline (CMT-8) and Estrogen on Matrix Metalloproteinases -8, -13 and Type I Collagen Expression

Pirilä, Emma; Ramamurthy, N. S.; Maisi, Päivi; McClain, Steve A.; Kucine, Allan; Wahlgren, Jaana; Golub, Lorne M.; Salo, Tuula; Sorsa, Timo

doi:10.2174/0929867013373552

Cited by 74 publications

(76 citation statements)

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“…In 1898, Calzolari observed an enlargement of the thymus when rabbits were castrated before sexual maturity, and documented a relationship between sexual environment and immunity (20). Exogenous E2 replacement in animals and humans promoted wound healing, and hormone replacement therapy in postmenopausal women was reported to prevent the development of chronic wounds (21)(22)(23). Also, E2 supplementation has been shown to reduce or reverse traumahemorrhagic shock-induced organ dysfunction in animal models (4,12).…”

Section: Introductionmentioning

confidence: 99%

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Raju

Bland

Chaudry

2008

Mol Med

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ESTROGEN, MECHANISM OF ACTIONE2, the female hormone, is mainly produced by the ovaries and the placenta. The three major estrogens in women are estradiol, estriol, and estrone ( Figure 1). Estrogens are synthesized from androgens by the loss of C-19 angular methyl group and the formation of an aromatic A ring. Whereas estradiol is derived from testosterone, estrone is derived from androstenedione. The main form of E2 in women Trauma-hemorrhage leads to prolonged immune suppression, sepsis, and multiple organ failure. The condition affects all compartments of the immune system, and extensive studies have been carried out elucidating the immunological events following trauma-hemorrhage. The immune alteration observed following trauma-hemorrhage is gender dependent in both animal models and humans, though some studies in humans are contradictory. Within 30 min after trauma-hemorrhage, splenic and peritoneal macrophages, as well as T-cell function, are depressed in male animals, but not in proestrus females. Studies have also shown that the survival rate and the induction of subsequent sepsis following trauma-hemorrhage are significantly higher in males and ovariectomized females compared with proestrus females. These and other investigations show that sex hormones form the basis of this gender dichotomy, and administration of estrogen can ameliorate the immune depression and increase the survival rate after trauma-hemorrhage. This review specifically elaborates the studies carried out thus far demonstrating immunological alteration after trauma-hemorrhage and its modulation by estrogen. Also, estrogen was shown to produce its salutary effects through nuclear as well as extranuclear receptors. Estrogen rapidly activates several protein kinases and phosphatases, as well as the release of calcium in different cell types. The results of the studies exemplify the promise of estrogen as a therapeutic adjunct in treating adverse pathophysiological conditions following trauma-hemorrhage.

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Section: Introductionmentioning

confidence: 99%

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Raju

Bland

Chaudry

2008

Mol Med

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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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“…Release and activation of MMP-8 without de novo expression of PMNs have thus been considered to be mainly regulated by factors affecting PMN triggering and degranulation (Weiss, 1989). Certain mesenchymal cell lines and plasma cells have recently been demonstrated to express MMP-8 protein and mRNA (Bachmeier et al, 2000;Cole et al, 1996;Hanemaaijer et al, 1997;Palosaari et al, 2000;Pirilä et al, 2001;Tervahartiala et al, 2000;Wahlgren et al, 2001). Furthermore, bronchial epithelial cells express MMP-8 (Prikk et al, 2001) and also other MMPs such as MMP-2, -7, and -9 (Dunsmore et al, 1998;Yao et al, 1996), which can mediate tissue destruction in cascades by activating each other.…”

Section: Discussionmentioning

confidence: 99%

Airway Obstruction Correlates with Collagenase-2 (MMP-8) Expression and Activation in Bronchial Asthma

Prikk

Maisi²,

Pirilä

et al. 2002

Laboratory Investigation

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105

118

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Wound Healing in Ovariectomized Rats Effects of Chemically Modified Tetracycline (CMT-8) and Estrogen on Matrix Metalloproteinases -8, -13 and Type I Collagen Expression

Cited by 74 publications

References 0 publications

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Estrogen: A Novel Therapeutic Adjunct for the Treatment of Trauma-Hemorrhage—Induced Immunological Alterations

Estrogen modulates cutaneous wound healing by downregulating macrophage migration inhibitory factor

Airway Obstruction Correlates with Collagenase-2 (MMP-8) Expression and Activation in Bronchial Asthma

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