Estrogen ameliorates sepsis-induced vascular hyporeactivity in thoracic aorta of female rats via permissive effect of GRα expression

Wang, Shan; Wu, Jue; Yang, Kai; Li, Xin; Wu, Liben; Qi, Xiaoqin; Zhang, Ruizhi; Ni, Wenfeng; Pei, Jinlian; Gu, Fangyan; Liu, Bing; Wang, Yan; Tian, Yaping

doi:10.1016/j.bbrc.2023.03.058

Cited by 2 publications

(1 citation statement)

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“…Additionally, recent work in a sepsis model showed that treatment of female animals with E2 increased the expression of corticoid receptor a (GRa) in vascular smooth cells. This receptor was associated with glucocorticoid activation of vascular activity and the upregulation of this receptor by E2, enhanced corticoid-positive action in vascular dysfunction (24).…”

Section: A B Figure 12mentioning

confidence: 96%

17β-estradiol and methylprednisolone association as a therapeutic option to modulate lung inflammation in brain-dead female rats

Vidal-dos-Santos,

Anunciação,

Armstrong-Jr

et al. 2024

Front. Immunol.

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IntroductionBrain death (BD) is known to compromise graft quality by causing hemodynamic, metabolic, and hormonal changes. The abrupt reduction of female sex hormones after BD was associated with increased lung inflammation. The use of both corticoids and estradiol independently has presented positive results in modulating BD-induced inflammatory response. However, studies have shown that for females the presence of both estrogen and corticoids is necessary to ensure adequate immune response. In that sense, this study aims to investigate how the association of methylprednisolone (MP) and estradiol (E2) could modulate the lung inflammation triggered by BD in female rats.MethodsFemale Wistar rats (8 weeks) were divided into four groups: sham (animals submitted to the surgical process, without induction of BD), BD (animals submitted to BD), MP/E2 (animals submitted to BD that received MP and E2 treatment 3h after BD induction) and MP (animals submitted to BD that received MP treatment 3h after BD induction).ResultsHemodynamics, systemic and local quantification of IL-6, IL-1β, VEGF, and TNF-α, leukocyte infiltration to the lung parenchyma and airways, and adhesion molecule expression were analyzed. After treatment, MP/E2 association was able to reinstate mean arterial pressure to levels close to Sham animals (p<0.05). BD increased leukocyte infiltration to the airways and MP/E2 was able to reduce the number of cells (p=0.0139). Also, the associated treatment modulated the vasculature by reducing the expression of VEGF (p=0.0616) and maintaining eNOS levels (p=0.004) in lung tissue.DiscussionData presented in this study show that the association between corticoids and estradiol could represent a better treatment strategy for lung inflammation in the female BD donor by presenting a positive effect in the hemodynamic management of the donor, as well as by reducing infiltrated leukocyte to the airways and release of inflammatory markers in the short and long term.

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Section: A B Figure 12mentioning

confidence: 96%

17β-estradiol and methylprednisolone association as a therapeutic option to modulate lung inflammation in brain-dead female rats

Vidal-dos-Santos,

Anunciação,

Armstrong-Jr

et al. 2024

Front. Immunol.

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Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries

Martinez,

Appleton,

Kipp

et al. 2024

Physiological Reviews

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The normal stress response in humans is governed by the hypothalamic-pituitary-adrenal (HPA) axis through heightened mechanisms during stress, raising blood levels of the glucocorticoid hormone cortisol. Glucocorticoids are quintessential compounds that balance the proper functioning of numerous systems in the mammalian body. They are also generated synthetically and are the preeminent therapy for inflammatory diseases. They act by binding to the nuclear receptor transcription factor, the glucocorticoid receptor (GR), which has two main isoforms (GRα and GRβ). Our classical understanding of glucocorticoid signaling is from the GRα isoform, which binds the hormone, whereas GRβ has no known ligands. With glucocorticoids being involved in many physiological and cellular processes, even small disruptions in their release via the HPA axis, or changes in GR isoform expression, can have dire ramifications on health. Long-term chronic glucocorticoid therapy can lead to a glucocorticoid-resistant state, and we deliberate how this impacts disease treatment. Chronic glucocorticoid treatment can lead to noticeable side effects such as weight gain, adiposity, diabetes, and others that we discuss in detail. There are sexually dimorphic responses to glucocorticoids, and women tend to have a more hyperresponsive HPA axis than men. This review summarizes our understanding of glucocorticoids, critically analyzes the GR isoforms and their beneficial and deleterious mechanisms, and the sexual differences that cause a dichotomy in responses. We also discuss the future of glucocorticoid therapy and propose a new concept of dual GR isoform agonist and postulate why activating both isoforms may prevent glucocorticoid resistance.

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Estrogen ameliorates sepsis-induced vascular hyporeactivity in thoracic aorta of female rats via permissive effect of GRα expression

Cited by 2 publications

References 20 publications

17β-estradiol and methylprednisolone association as a therapeutic option to modulate lung inflammation in brain-dead female rats

17β-estradiol and methylprednisolone association as a therapeutic option to modulate lung inflammation in brain-dead female rats

Glucocorticoids, their uses, sexual dimorphisms, and diseases: new concepts, mechanisms, and discoveries

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