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Background: Sepsis-induced acute lung injury (ALI) is associated with poor survival rates. The identification of potential therapeutic targets for preventing sepsis-induced ALI has clinical importance. This study aims to investigate the role of estrogen-related receptor alpha (ERRα) in sepsis-induced ALI., Methods: Lipopolysaccharide (LPS) was used to simulate sepsis-induced ALI model in rat pulmonary microvascular endothelial cells (PMVECs). The effects of ERRα overexpression and knockdown on LPS-induced endothelial permeability, apoptosis and autophagy were determined by horseradish peroxidase permeability assay, TdT-mediated dUTP Nick End Labeling (TUNEL) assay, flow cytometry, immunofluorescence staining, RT-PCR and Western Blotting. The rat model with sepsis-induced ALI was established by cecal ligation and puncture in anesthetized rats to verify the results of in vitro experiments. Animals were randomly assigned to receive intraperitoneal injection of vehicle or ERRα agonist. Lung vascular permeability, pathological injury, apoptosis and autophagy were examined., Results: Overexpression of ERRα ameliorated LPS-induced endothelial hyperpermeability, degradation of adherens junctional molecules, upregulation of bax, cleaved caspase 3 and cleaved caspase 9 levels, downregulation of anti-apoptotic protein Bcl-2 level, and promoted the formation of autophagic flux, while the knockdown of ERRα exacerbated LPS-induced apoptosis and inhibited the activation of autophagy. Administration of ERRα agonist alleviated the pathological damage of lung tissue, increased the levels of tight junction proteins and adherens junction proteins, and decreased the expression of apoptosis-related proteins. Promoting the expression of ERRα significantly enhanced the process of autophagy and reduced CLP-induced ALI. Mechanistically, ERRα is essential to regulate the balance between autophagy and apoptosis to maintain the adherens junctional integrity., Conclusion: ERRα protects against sepsis-induced ALI through ERRα-mediated apoptosis and autophagy. Activation of ERRα provides a new therapeutic opportunity to prevent sepsis-induced ALI., (© 2023. The Author(s).)

This study was undertaken to examine the regulatory role of multidrug resistance-associated protein 4 (MRP4) in an experimental model of sepsis-induced acute lung injury in rats. Sepsis was induced by cecal ligation and puncture in anesthetized rats. Animals were then randomly assigned to receive intravenous injection of vehicle or MRP4 inhibitor (MK571, 20 mg/kg). The pathological changes were observed by hematoxylin and eosin staining. Lung water content, lung vascular permeability and inflammatory cell count in bronchoalveolar lavage fluid (BALF) were quantified. Serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were measured. In addition, lung tissue cyclic adenosine monophosphate (cAMP) levels were examined by enzyme-linked immunosorbent assay. Furthermore, the effects of MRP4 knockdown on lipopolysaccharide (LPS)-induced endothelial permeability and the cytoskeleton of rat pulmonary microvascular endothelial cells (PMVECs) were detected. The protein expression levels of MRP4, Rac1, VE-cadherin, β-catenin and ZO-1 were measured by Western blot analysis. MK571 significantly reduced lung tissue damage, lung water content and lung vascular permeability. Lung tissue cAMP levels were attenuated in MK571-treated animals compared with vehicle controls. MK571 also decreased sepsis-induced inflammatory cell accumulation in BALF. In addition, the MK571 group had significantly lower serum TNF-α and IL-6 levels compared with vehicle controls. Consistently, knockdown of MRP4 protected against LPS-induced increase in the endothelial permeability and the destruction of cytoskeleton in vitro. Furthermore, silencing MRP4 gene significantly reduced MRP4 protein expression and restored the protein expression of Rac1, VE-cadherin, β-catenin and ZO-1 in rat PMVECs in response to LPS stimulation. These data suggest that inhibition of MRP4 significantly alleviates sepsis-induced acute lung injury in rats., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To investigate influences of estrogen-related receptor α(ERRα) on pulmonary vascular endothelium of rats undergoing sepsis., Methods: Male Sprague-Dawley (SD) rats were divided into four groups according to the random number table method (12 in each group): normal control group (NC group), sham operation group (Sham group), sepsis model caused by cecal ligation and puncture (CLP) group (CLP group), XCT790 intervention group (XCT790 group, given the XCT790 2.5 mg/kg via intraperitoneal injection 30 minutes before CLP). After 24 hours, rats were sacrificed and the organs were harvested. The pathological changes of lung tissue were observed using hematoxylin and eosin (HE) staining, and the ultrastructural changes of lung tissue were observed by double staining of uranium citrate with lead acetate, the degree of apoptosis of pulmonary capillary endothelial cells were observed by TdT-mediated dUTP nike end labeling stain (TUNEL), the permeability of lung vascular endothelial was detected by Evans blue (EB) staining, the levels of serum cytokines were detected by enzyme linked immunosorbent assay (ELISA), and white blood cell count in bronchial alveolar lavage fluid (BALF) was detected., Results: Compared with NC group and Sham group, the CLP group and XCT790 group had severe pathological damage and increased lung tissue permeability, the levels of serum cytokines and white blood cell count in BALF were increased. Compared with CLP group, the pathological changes of lung tissue, the degree of ultrastructural damage of lung tissue, the degree of apoptosis of lung capillary endothelial cells in XCT790 group further intensified, the permeability of lung endothelial barrier further increased [the content of EB (μg/g): 116.00±15.46 vs. 60.19±19.79, P < 0.05], and the level of serum cytokines further increased [interleukin-1β (IL-1β, ng/L): 71.38±4.01 vs. 56.58±2.45, interleukin-6 (IL-6, ng/L): 741.62±88.94 vs. 534.22±72.70, tumor necrosis factor-α (TNF-α, ng/L): 188.55±7.41 vs. 143.33±11.27, all P < 0.05], the white blood cell count in the BALF increased further (×10 4 /L: 193.79±27.46 vs. 99.34±36.41, P < 0.05)., Conclusions: ERRα can aggravate inflammation in sepsis rats, destroy lung tissue and increase pulmonary permeability.