Estradiol-induced inhibition of endoplasmic reticulum stress normalizes splenic CD4 + T lymphocytes following hemorrhagic shock

Wang, Peng; Jiang, Lina; Wang, Chen; Li, Ying; Yin, Meng; Du, Hui-Bo; Zhang, Hong; Fan, Zehua; Liu, Yan-Xu; Zhao, Meng; Kang, An-Ling; Feng, Ding-Ya; Li, Shuguang; Niu, Chun‐Yu; Zhao, Zi‐Gang

doi:10.1038/s41598-021-87159-1

Cited by 5 publications

(9 citation statements)

References 49 publications

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“…Recent studies showed that ethinyl estradiol sulfate, an estrogenic derivative, blunted hemorrhagic shock induced-multiple harmful outcomes in rat and swine, and showed a broad prospect of clinical application (30,31). Our previous studies have demonstrated that E2 prolonged the survival time and normalized CD4 + T lymphocyte function of rats after hemorrhagic shock (19) and attenuated hemorrhagic shock-induced vascular hyporeactivity in mice (25). In this study, we applied the small animal pulmonary function assay system and confirmed that E2 treatment improved the pulmonary function evidenced by these indices including RI, FRC, PEF, and IC of hemorrhagic shock rats.…”

Section: Discussionmentioning

confidence: 99%

“…To confirm the intestinal lymphatic mechanism of E2 therapy on hemorrhagic shock–induced ALI, partial rats with acute hemorrhage received subcutaneous injection of E2 (2 mg/kg) upon resuscitation. The dose of E2 is referenced the previous report (19). The obtained PHSML and E2-PHSML (from E2-treated rats) were centrifuged at 3000 r/min for 10 min for cellular component removal and supernatant collection, which was frozen at −80°C for the next observation.…”

Section: Methodsmentioning

confidence: 99%

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Estrogen Alleviates Posthemorrhagic Shock Mesenteric Lymph-Mediated Lung Injury Through Autophagy Inhibition

Sun

Zhang

et al. 2023

Shock

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Background: Hemorrhagic shock–induced acute lung injury (ALI) is commonly associated with the posthemorrhagic shock mesenteric lymph (PHSML) return. Whether excessive autophagy is involved in PHSML-mediated ALI remains unclear. The relationship between estrogen treatment and PHSML or autophagy needs to verify. The current study will clarify the role of estrogen in reducing PHSML-mediated ALI through inhibition of autophagy. Methods: First, a hemorrhagic shock model in conscious rats was used to observe the effects of 17β-estradiol (E2) on intestinal blood flow, pulmonary function, intestinal and pulmonary morphology, and expression of autophagy marker proteins. Meanwhile, the effect of PHSML and autophagy agonist during E2 treatment was also investigated. Secondly, rat primary pulmonary microvascular endothelial cells were used to observe the effect of PHSML, PHSML plus E2, and E2-PHSML (PHSML obtained from rats treated by E2) on the cell viability. Results: Hemorrhagic shock induced intestinal and pulmonary tissue damage and increased wet/dry ratio, reduced intestinal blood flow, along with pulmonary dysfunction characterized by increased functional residual capacity and lung resistance and decreased inspiratory capacity and peak expiratory flow. Hemorrhagic shock also enhanced the autophagy levels in intestinal and pulmonary tissue, which was characterized by increased expressions of LC3 II/I and Beclin-1 and decreased expression of p62. E2 treatment significantly attenuated these adverse changes after hemorrhagic shock, which was reversed by PHSML or rapamycin administration. Importantly, PHSML incubation decreased the viability of pulmonary microvascular endothelial cells, while E2 coincubation or E2-treated lymph counteracted the adverse roles of PHSML. Conclusions: The role of estrogen reducing PHSML-mediated ALI is associated with the inhibition of autophagy.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Estrogen Alleviates Posthemorrhagic Shock Mesenteric Lymph-Mediated Lung Injury Through Autophagy Inhibition

Sun

Zhang

et al. 2023

Shock

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“…The expression levels of autophagic and phenotypic proteins were detected using western blotting. Primary antibodies, including LC3 II (1:1000, ab192890; Abcam, Cambridge, UK), Beclin 1 (1:1000, ab207612, Abcam), MMP2 (1:1000, 10,373-2-AP; Proteintech, Chicago, IL), Calponin 1 (1:5000, ab46794, Abcam), and β-actin (1:5000, 66009-1-IG, Proteintech), were used as previously described (26,27). Protein bands were visualized using an ultrasensitive luminescent solution sourced from Beijing Puli Gene Technology Co. (Beijing, China).…”

Section: Methodsmentioning

confidence: 99%

STELLATE GANGLION BLOCK REVERSES PHSML-INDUCED VASCULAR HYPOREACTIVITY THROUGH INHIBITING AUTOPHAGY-MEDIATED PHENOTYPIC TRANSFORMATION OF VSMCs

Li,

Du,

Zhao

et al. 2023

Shock

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Post-hemorrhagic shock mesenteric lymph (PHSML) return-contributed excessive autophagy of vascular smooth muscle cells (VSMCs) is involved in vascular hypo-reactivity, which is inhibited by stellate ganglion block (SGB) treatment. The contractile phenotype of VSMCs transforms into a synthetic phenotype after stimulation with excessive autophagy. Therefore, we hypothesized that SGB ameliorates PHSML-induced vascular hypo-reactivity by inhibiting autophagy-mediated phenotypic transformation of VSMCs. To substantiate this hypothesis, a hemorrhagic shock model in conscious rats was employed to observe the effects of SGB intervention or intravenous infusion of the autophagy inhibitor 3-MA on intestinal blood flow and the expression of autophagy- and phenotype-defining proteins in mesenteric secondary artery tissues. We also investigated the effects of intraperitoneal administration of PHSML intravenous infusion and the autophagy agonist rapamycin (RAPA) on the beneficial effect of SGB. The results showed that hemorrhagic shock decreased intestinal blood flow and enhanced the expression of LC3 II/I, Beclin1, and matrix metalloproteinase 2, which were reversed by SGB or 3-MA treatment. In contrast, RAPA and PHSML administration abolished the beneficial effects of SGB. Furthermore, the effects of PHSML or PHSML obtained from rats treated with SGB (PHSML-SGB) on cellular contractility, autophagy, and VSMC phenotype were explored. Meanwhile, the effects of 3-MA on PHSML and RAPA on PHSML-SGB were observed. The results showed that PHSML, but not PHSML-SGB, incubation decreased VSMCs contractility and induced autophagy activation and phenotype transformation. Importantly, 3-MA administration reversed the adverse effects of PHSML, and RAPA treatment attenuated the effects of PHSML-SGB incubation on VSMCs. Taken together, the protective effect of SGB on vascular reactivity is achieved by inhibiting excessive autophagy-mediated phenotypic transformation of VSMCs to maintain their contractile phenotype.

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“…HS model was established as described previously (14). Rats were weighed and anesthetized using 3% iso urane (Hebei Yilin Pharmaceutical Co., LTD., Shijiazhuang, China) by inhalation, and then maintenance of anesthesia with an intraperitoneal injection of 1% pentobarbital sodium (50 mg/kg, Merck, Germany).…”

Section: Hs Model In Ratsmentioning

confidence: 99%

Estrogen activates its receptors to improve lymphatic contractility through suppression of endoplasmic reticulum stress induced by hemorrhagic shock

Zhao

2023

Preprint

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Lymphatic contractility dysfunction is associated with the deterioration of hemorrhagic shock (HS). Endoplasmic reticulum stress (ERS) has been demonstrated to be involved in HS-induced organ injury, while estrogen alleviates HS-induced ERS and organ injury. However, whether estrogen improves lymphatic contraction through inhibition of HS-induced ERS remains unclear. We hypothesized that estrogen activation of its receptors (ERs) promoted mesenteric lymphatic contractility through suppression of HS-induced ERS in lymphatic smooth muscle cells (LSMCs). In a rodent model of HS, 17β-estradiol (E2) administration abrogated HS-induced upregulation of GRP78 in lymphatic tissues. Either E2 or ERS inhibitor 4-phenylbutyric acid (4-PBA) promoted the survival HS rats in the first 72 hours after resuscitation. E2, ER-α agonist PPT, ER-β agonist DPN, GPR30-selective agonist G-1, 4-PBA significantly enhanced the contractility of mesenteric lymphatics following HS in vivo and in vitro. In contrast, ICI 182,780 (ERα and ERβ selective inhibitor) and G-15 (GPR30-selective inhibitor) partly abolished the beneficial effects of E2. Furthermore, ERS agonist XCT-790 abolished the beneficial effects of E2, PPT, DPN, and G-1 on lymphatic contractility. Additionally, E2, PPT, DPN, and G-1 inhibited ERS, and thus ameliorate ERS agonist tunicamycin-induced hypo-contractility in primary LSMCs. Taken together, the data indicates that E2 promotes the lymphatic contractility after HS by inhibiting ERS and estrogen receptor activation mediates the beneficial effect of E2.

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Estradiol-induced inhibition of endoplasmic reticulum stress normalizes splenic CD4 + T lymphocytes following hemorrhagic shock

Cited by 5 publications

References 49 publications

Estrogen Alleviates Posthemorrhagic Shock Mesenteric Lymph-Mediated Lung Injury Through Autophagy Inhibition

Estrogen Alleviates Posthemorrhagic Shock Mesenteric Lymph-Mediated Lung Injury Through Autophagy Inhibition

STELLATE GANGLION BLOCK REVERSES PHSML-INDUCED VASCULAR HYPOREACTIVITY THROUGH INHIBITING AUTOPHAGY-MEDIATED PHENOTYPIC TRANSFORMATION OF VSMCs

Estrogen activates its receptors to improve lymphatic contractility through suppression of endoplasmic reticulum stress induced by hemorrhagic shock

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