The Aromatase Inhibitor, 4-Hydroxyandrostenedione, Restores Immune Responses Following Trauma-Hemorrhage in Males and Decreases Mortality From Subsequent Sepsis

Schneider, Christian; Nickel, E.; Samy, T. S. Anantha; Schwacha, Martin G.; Cioffi, William G.; Bland, Kirby I.; Chaudry, Irshad H.

doi:10.1097/00024382-200014030-00019

Cited by 79 publications

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“…Thus the salutary effects of 4-OHA may be related to prevention of the systemic proinflammatory response after trauma-hemorrhage. Our findings here are also consistent with previous findings that 4-OHA treatment improved survival in a two-hit model of trauma-hemorrhage and sepsis (46). The increased systemic IL-10 levels observed after trauma-hemorrhage were unaffected by 4-OHA, suggesting that the regulation of this cytokine may be androgen independent.…”

Section: Discussionsupporting

confidence: 92%

“…Groups 2 and 4 received a subcutaneous injection of 4-OHA (4-androsten-4-ol-3, 17-dione; Steraloids, Newport, RI) dissolved in corn oil (5 mg/kg body wt) just before resuscitation. The dosage regime of 4-OHA employed was based on previous in vitro studies, the treatment regime for patients with prostatic and breast cancer, and previous work by our laboratory (17,32,46). No deleterious side effects of subcutaneous 4-OHA administrations at this dose were observed in the present study.…”

mentioning

confidence: 87%

“…The animals were killed with methoxyflurane overdose 2 h after the completion of the resuscitation. Spleens were removed aseptically, and splenic macrophages were isolated, as previously described (46). Briefly, the spleen was gently ground to produce a single-cell suspension, and the erythrocytes were lysed by hypotonic shock.…”

Section: Animalsmentioning

confidence: 99%

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Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5α-dihydrotestosterone

Schneider

Schwacha

Samy

et al. 2003

Journal of Applied Physiology

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Androgens have been implicated as the causative factor for the postinjury immune dysfunction in males; however, it remains unknown whether androgens directly affect macrophages. To study this, male mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (mean arterial pressure, 30 ± 5 mmHg for 90 min and then resuscitated). The mice received the 5α-reductase inhibitor 4-hydroxyandrostenedione (4-OHA) before resuscitation. Plasma TNF-α, IL-6, and IL-10 levels were elevated after trauma-hemorrhage and normalized by 4-OHA. TNF-α and IL-6 production by splenic macrophages was decreased after injury, whereas Kupffer cell production of these mediators was enhanced. 4-OHA normalized cytokine production. Androgens suppressed cytokine production by splenic macrophages from hemorrhaged mice, whereas it enhanced TNF-α and IL-6 production by Kupffer cells. The addition of 4-OHA in vitro normalized cytokine production by cells treated with testosterone, but it had no effect on dihydrotestosterone-treated cells. These results indicate that androgens directly affect macrophage function in males after trauma and hemorrhagic shock and that the intracellular conversion of testosterone to dihydrotestosterone is of particular importance in mediating the androgen-induced effects.

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Section: Discussionsupporting

confidence: 92%

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confidence: 87%

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Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5α-dihydrotestosterone

Schneider

Schwacha

Samy

et al. 2003

Journal of Applied Physiology

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“…Une surexpression du REβ a été observée chez des animaux soumis à un trauma et une hémorragie, contexte inflammatoire généralisé, parallèlement à une diminution de la quantité de REα (Schneider et al, 2000). Un stress oxydatif augmente aussi l'expression du REβ dans des cellules endothéliales et des macrophages activés (Tamir et al, 2002) quand il induit une dégradation du REα dans des cellules cancéreuses mammaires (Kurebayashi et al, 2001 ;Stoner et al, 2002).…”

Section: Les Récepteurs Nucléaires Aux Estrogènes : Reα Et Reβunclassified

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

et al. 2012

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Titre : La 7β-hydroxy-épiandrostérone dans des modèles in vitro de cancer du sein : effets anti-estrogéniques et rôle des récepteurs des estrogènes. La 7β-hydroxy-épiandrostérone, stéroïde endogène dérivant de la DHEA, présente des propriétés antiinflammatoires. En effet, elle module la voie des prostaglandines (PGs) en inhibant la production de la PGE2 pro-inflammatoires et en augmentant la production de la 15-Deoxy-∆ 12,14 -PGJ2 cyto-protectrice in vivo et in vitro. Les faibles doses de 7β-hydroxy-épiandrostérone (1nM, 10nM, 100nM) pour lesquelles ces effets sont observés, suggèrent une liaison à un récepteur spécifique. L'inflammation et la production des PGs jouent un rôle important dans le développement et la prolifération des tumeurs mammaires estrogéno-dépendantes. Le 17β-estradiol (E2), en se fixant sur les récepteurs des estrogènes (REs), induit la production de PGE2 et la prolifération cellulaire dans ces cellules tumorales. De ce fait, notre objectif était de tester les effets de la 7β-hydroxy-épiandrostérone sur la prolifération (comptage avec exclusion au bleu trypan), le cycle cellulaire et l'apoptose (cytométrie de flux) dans les lignées cellulaires de cancer du sein MCF-7 (REα+, REβ+, GPR30+) et MDA-MB-231 (REα-, REβ+, GPR30+) et d'identifier une(des) cible(s) potentielle(s) dans ces cellules (transactivation) et dans des cellules négatives pour les REs nucléaires SKBr3 (GPR30+) (études de prolifération). Cette étude a montré que la 7β-hydroxy-épiandrostérone exerce des effets anti-estrogéniques dans les cellules MCF-7 et MDA-MB-231 associés à une inhibition de la prolifération et un arrêt du cycle cellulaire. Les études de transactivation et de prolifération avec les agonistes spécifiques des REs ont montré une interaction avec le REβ. De plus, les résultats des études de proliférations sur les trois lignées cellulaires suggèrent que la 7β-hydroxy-épiandrostérone pourrait également interagir avec le GPR30. Ces résultats indiquent que ce stéroïde androgène agit comme un anti-estrogène. De plus, c'est la première fois qu'un stéroïde androgène à faible dose montre une action anti-proliférative dans des lignées de cancers du sein. De études ultérieures restent à réaliser afin de mieux comprendre ces effets observés. Mots clés : 7β-hydroxy-épiandrostérone, récepteurs des estrogènes, lignées de carcinomes mammaires, prolifération, transactivationThe DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines 7β-hydroxy-epiandrosterone, an endogenous androgenic derivative of DHEA, has previously been shown to exert anti-inflammatory action in vitro and in vivo via a shift from prostaglandin E2 (PGE2) to 15-deoxy-∆ 12,14 -PGJ2 production. This modulation in prostaglandin production was obtained with low concentrations of 7β-hydroxy-epiandrosterone (1-100 nM) and suggested that it might act through a specific receptor. Inflammation and prostaglandin synthesis is important in the development and survival of estrogendependent mammary cancers. Estrogen induced PGE2 ...

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“…However, such suppression in splenocyte function was not observed in proestrus female animals under those conditions [1]. Additional studies have shown that male sex steroids produce deleterious effects on splenocyte function [4], but female sex steroids maintain the splenocyte functions following traumahemorrhage [1]. Studies have also shown that administration of a single dose of 17β-estradiol (E2) following trauma-hemorrhage normalizes splenocyte function [5].…”

Section: Introductionmentioning

confidence: 99%

Mitogen activated protein kinase (MAPK) mediates non-genomic pathway of estrogen on T cell cytokine production following trauma-hemorrhage

Suzuki

Hsieh

et al. 2008

Cytokine

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Although studies have shown 17β-estradiol (E2) administration following trauma-hemorrhage (T-H) attenuates alterations in T cell cytokine production, it remains unknown whether such effects of E2 are mediated via genomic or non-genomic pathways. In this study, we determined the nongenomic effects of E2 on splenic T cell cytokine production and the role of MAPK following T-H. Male Sprague-Dawley rats underwent T-H (mean BP 40 mmHg for 90 min, then resuscitation). E2, E2 conjugated with BSA (E2-BSA, 1 mg/kg E2) with or without an estrogen receptor antagonist (ICI 182 780), or vehicle was administrated during resuscitation. Two hrs thereafter, T cell production of IL-2 and IFN-γ and activation of MAPK (p38, ERK-1/2 and JNK) were determined. The effect of selective MAPK inhibitors on cytokine production was also examined in vitro. IL-2 and IFN-γ production capacity and MAPK activation decreased in T cells following T-H. However, E2 administration normalized these parameters. Although E2-BSA administration also attenuated suppression in cytokine production, the values were lower compared to sham. In contrast, E2-BSA prevented T-H-induced suppression in MAPK activation to the same extent as E2. Co-administration of ICI 182 780 abolished E2-BSA effects. These findings suggest E2 effects on T cell cytokine production following T-H are mediated at least in part via non-genomic pathway and these nongenomic effects are likely mediated via MAPK pathways.

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The Aromatase Inhibitor, 4-Hydroxyandrostenedione, Restores Immune Responses Following Trauma-Hemorrhage in Males and Decreases Mortality From Subsequent Sepsis

Cited by 79 publications

References 0 publications

Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5α-dihydrotestosterone

Androgen-mediated modulation of macrophage function after trauma-hemorrhage: central role of 5α-dihydrotestosterone

The DHEA metabolite 7β-hydroxy-epiandrosterone exerts anti-estrogenic effects on breast cancer cell lines

Mitogen activated protein kinase (MAPK) mediates non-genomic pathway of estrogen on T cell cytokine production following trauma-hemorrhage

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