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Objectives: To explore the anti-inflammatory effect and the potential mechanism of dexmedetomidine in ARDS/ALI., Materials and Methods: C57BL/6 mice and EL-4 cells were used in this research. The ALI model was established by CLP. The level of inflammatory cytokines in the lung and blood, the severity of lung injury, the expression of Foxp3, and the proportion of Tregs were detected before and after dexmedetomidine treatment. The expression of the AMPK/SIRT1 after dexmedetomidine treatment was detected in vivo and in vitro. After blocking the AMPK/SIRT1 pathway or depleting Tregs in vivo, the level of the inflammatory response, tissue injury, and Tregs differentiation were detected again to clarify the effect of dexmedetomidine., Results: Dexmedetomidine significantly reduced systemic inflammation and lung injury in CLP mice. Dexmedetomidine enhanced the Foxp3 expression in the lungs and the frequency of Tregs in the spleen. Dexmedetomidine up-regulated the protein expression of p-AMPK and SIRT1 in lungs and EL-4 cells and facilitated the differentiation of naïve CD4 + T cells into Tregs in vitro. Meanwhile, DEX also increased the expression of Helios in Treg cells., Conclusions: DEX could improve ARDS/ALI by facilitating the differentiation of Tregs from naïve CD4 + T cells via activating the AMPK/SIRT1 pathway., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a severe form of inflammatory lung disease. Its development and progression are regulated by cytokines. The purpose of this study was to determine the effects of HMGB1 involved in the regulation of Treg cells and IL-35., Methods: A cecal ligation and puncture (CLP)-induced ALI model was used to investigate the changes in IL-35, Tregs, and the expression of RAGE and caspase-11 after HMGB1 inhibition (glycyrrhizin was used as an inhibitor of HMGB1). CD4+ naïve T cells sorted from C57BL/6 mice spleens were cultured to explore the role of HMGB1 in the differentiation from CD4+ naïve T cells to Tregs., Results: HMGB1 promoted lung injury and uncontrolled inflammation in the CLP mouse model. HMGB1, NF-κB p65, RAGE, and caspase-11 expression in the lungs of CLP mice decreased significantly after pretreatment with glycyrrhizin. We found that the Treg proportion and IL-35 expression were upregulated in the serum and lung of CLP mice after inhibiting HMGB1. In our in vitro experiments, we found that recombinant HMGB1 significantly suppressed the proportion of CD4+CD25+FOXP3+Tregs differentiated from CD4+ naïve T cells., Conclusions: The inhibition of HMGB1 increased the proportion of Treg and expression of IL-35 and alleviated lung injury in the CLP-induced ALI model. Furthermore, inhibition of HMGB1 reduced caspase-11-dependent pyroptosis in the lungs of the CLP-induced ALI model., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Rationale: The aim of this study was to analyze the metabolomics of lung with different host inflammation of acute respiratory distress syndrome (ARDS) for the identification of biomarkers for predicting severity under different inflammatory conditions., Methods: Cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)-intratracheal injection induced acute lung injury (ALI) were used. A mouse model was used to explore lung metabolomic biomarkers in ALI/ARDS. The splenectomy model was used as an auxiliary method to distinguish between hyper- and hypo-inflammatory subtypes. Plasma, lung tissue and bronchoalveolar lavage fluid (BALF) samples were collected from mice after CLP/LPS. The severity of lung injury was evaluated. Expression of tumor necrosis factor-α (TNF-α) in mice serum and lung was tested by enzyme-linked immunosorbent assay (ELISA) and polymer chain reaction (PCR). Polymorphonuclear cells in BALF were counted. The lung metabolites were detected by gas chromatography/mass spectrometry (GC/MS), and the metabolic pathways predicted using the KEGG database., Results: The LPS/CLP-Splen group had more severe lung injury than the corresponding ALI group; that in the CLP-Splen group was more serious than in the LPS-Splen group. TNF-α expression was significantly elevated in the serum and lung tissue after LPS or CLP, and higher in the LPS/CLP-Splen group than in the corresponding ALI group. The level of TNF-α in the CLP-Splen group was elevated significantly over that in the LPS-Splen group. Both these groups also showed significant neutrophil exudation within the lungs. During differential inflammation, more differential metabolites were detected in the lungs of the CLP group ALI mice than in the LPS group. A total of 41 compounds were detected in the lungs of the CLP and CLP-Splen groups. Contrastingly, eight compounds were detected in the lungs of the LPS and LPS-Splen groups. The LPS-Splen and CLP-Splen groups had significant neutrophil exudation in the lung. Random forest analysis of lung-targeted metabolomics data indicated 4-hydroxyphenylacetic acid, 1-aminocyclopentanecarboxylic acid (ACPC), cis-aconitic acid, and hydroxybenzoic acid as strong predictors of the hyper-inflammatory subgroup in the CLP group. Furthermore, with splenectomy, 13 differential metabolic pathways between the CLP and LPS groups were revealed., Conclusions: Hyper-inflammatory subgroups of ARDS have a greater inflammatory response and a more active lung metabolism. Combined with the host inflammation background, biomarkers from metabolomics could help evaluate the response severity of ARDS., (© 2020 John Wiley & Sons, Ltd.)

Objectives: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one type of respiratory failure characterized by rapid onset of widespread inflammation in the lungs. Curcumin has been reported to be an anti-inflammatory factor through enhancing the function of regulatory T cells (Tregs). This study aimed to explore the effect of curcumin on the differentiation of Tregs and the role of curcumin in ALI/ARDS., Methods: A cecal ligation and puncture (CLP)-induced acute lung injury mouse model was used to explore the effect of curcumin in ALI/ARDS. The severity of lung injury was evaluated. Immunohistochemistry of IL-17A and MPO in lung tissue was examined. Treg-related cytokine levels in serum and bronchoalveolar lavage fluid (BALF) were tested. The expression of nuclear factor-kappa B (NF-κB) in lung tissue was detected. Macrophages in lung tissue were detected by immunofluorescence. Splenic CD4+CD25+FOXP3+ Tregs were quantified, and the differentiation of Tregs from naïve CD4 + T cell and STAT5 was evaluated. The expression of IL-10 during naïve CD4 + T cell differentiation in vitro was tested., Results: Curcumin alleviated lung injury in the induced CLP mouse model and suppressed inflammation. IL-17A, MPO-producing neutrophils, and NF-κB p65 expression in lungs of CLP mice decreased significantly after pretreatment with curcumin. We found curcumin could regulate M1/M2 macrophage levels in lungs of CLP mice. This may have been through regulating the differentiation of Tregs and the production of Treg-derived IL-10. Treg-derived IL-10 is the main factor that could affect macrophage polarization. We found curcumin could increase Treg proportions in vivo and up-regulate IL-10 expression in serum and BALF of CLP mice. In our in vitro experiments, we found curcumin could promote Treg differentiation and increase the production of IL-10., Conclusions: Curcumin can reduce the degree of severity of ALI and uncontrolled inflammation through promoting the differentiation of naïve CD4 + T cells to CD4+ CD25+ FOXP3+ Tregs. Curcumin promotes the conversion of macrophages from M1 to M2. The differentiation of Tregs induced by curcumin may be one source of IL-10 immune modulation., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they do not have any competing interests.

Objectives: Cytokines participate in the progression of acute respiratory distress syndrome (ARDS), and uncontrolled inflammation is a central issue of acute lung injury (ALI). Interleukin (IL)-33 is a nuclear protein that has been reported to have a proinflammatory role in ARDS. Studies have shown that excessive autophagy may lead to the increased mortality of patients with ARDS, while several investigations indicated that IL-33 and autophagy interact with one another. The present study sought to clarify the relation between autophagy and IL-33's proinflammatory role in ARDS., Methods: We built a lipopolysaccharide (LPS)-induced lung injury mouse model. To study the relationship between IL-33 and autophagy, mice were pretreated with rapamycin (RAPA; a promoter of autophagy) and 3-methyladenine (3-MA; an inhibitor of autophagy) prior to LPS administration. The expression of IL-33 in serum and bronchoalveolar lavage fluid (BALF) was measured. Immunohistochemistry of IL-33 in lung tissue was examined. Th1,Th2 cytokines/chemokine levels in serum and BALF were tested. Further, the severity of lung injury was evaluated. And the nuclear factor-kappa B (NF-κB)'s nuclear translocation in lung tissue was detected., Results: In comparison with the control group, the levels of IL-33 in serum and BALF were increased after LPS injection. Th1 cytokines/chemokine levels were significantly increased in serum and BALF, while Th2 cytokine levels changed only a little. The levels of IL-33 in serum and BALF of the RAPA group was significantly increased after LPS was injected as compared with the LPS group; additionally, the levels of IL-33 in serum and BALF of the 3-MA group was significantly reduced after LPS was injected as compared with the LPS group, and that lung injury was ameliorated after 3-MA pretreatment. Th1 cytokines and chemokines in both serum and BALF were also decreased in the 3-MA group. Furthermore, we found that the nuclear translocation of NF-κB increased after LPS administration, and NF-κB's nuclear translocation was significantly increased in comparison with the LPS group after RAPA pretreatment. In contrast, NF-κB's nuclear translocation decreased after 3-MA pretreatment as compared with the LPS group., Conclusions: These findings showed that autophagy might regulate IL-33 by activating or inhibiting NF-κB to control the uncontrolled inflammation of acute lung injury.

Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome with uncontrolled inflammation that is a central issue. Its main characteristic is inflammatory mediators and cytokines as well as agglutinating chemokines that injure target cells. Interleukin (IL)-35 is a newly identified IL-12 cytokine family member with structural similarities to other IL-12, IL-23, and IL-27 cytokines but unique immunological functions. How IL-35 functions in ARDS is unclear. The purpose of our study was to determine what role IL-35 played in the development of ARDS. Here we found serum IL-35 concentrations were significantly elevated in patients with ARDS relative to healthy people. Moreover, we established a mouse model of lipopolysaccharide- and cecal ligation and puncture-induced ARDS treated with neutralizing antibodies (anti-IL-35 Ebi3 or anti-IL-35 P35); the results showed that lung injury occurred more often than in untreated models and the inflammatory cytokines CXCL-1, tumor necrosis factor alpha, IL-6, and IL-17A increased significantly after neutralizing antibody treatment in bronchoalveolar lavage fluid and serum. Therefore IL-35 can protect against the development of ARDS. Even more interesting in our study was that we discovered IL-35 expression differed between lung and spleen across different ARDS models, which further demonstrated that the spleen likely has an important role in extrapulmonary ARDS model only, improving the ratio of CD4 + /CD4 + CD25 + Foxp3 + (Tregs). Meanwhile in our clinical work, we also found that the concentration of IL-35 and the ratio of CD4 + /Treg in the serum are higher and the mortality is lower than those with the spleen deficiency in patients with extrapulmonary ARDS. Therefore, IL-35 is protective in ARDS by promoting the ratio of splenic CD4 + /Tregs in extrapulmonary ARDS, and as such, may be a therapeutic target., (Copyright © 2018. Published by Elsevier B.V.)

The development and progression of acute respiratory distress syndrome (ARDS) has been shown to be regulated by cytokines. IL-33 and HMGB1 are conventionally considered as nuclear proteins and have a proinflammatory role. Studies have confirmed that HMGB1 has a significant role in ARDS, but few studies have provided direct evidence to confirm that IL33 is involved in ARDS. The purpose of our study was to determine whether IL-33 is elevated in ARDS and the relationship between IL-33 and HMGB1 in ARDS. We established a mouse model of LPS-induced lung inflammation/injury. Serum, bronchoalveolar lavage fluid (BALF) and lung tissues were obtained to determine the related indicators. IL-33 levels in both the serum, BALF and lungs were significantly increased at 24h after LPS administration compared to the control group. We also found that HMGB1 and other Th1 cytokine/chemokine levels in serum and BALF were also significantly elevated, but the Th2 cytokine levels in serum and BALF didn't increase. To further study the relationship between IL-33 and HMGB1, mice were pretreated with glycyrrhizin (an inhibitor of HMGB1) prior to LPS administration. We found that the expression of IL-33 and HMGB1 were markedly lower than those in the LPS group and the lung injury was ameliorated. The levels of other Th1 cytokines and chemokines in serum and BALF were also significantly decreased. The results showed that IL-33 is likely a major factor in ARDS, and the release of HMGB1 may be correlated with up-regulation of IL-33 expression., (Copyright © 2016 Elsevier B.V. All rights reserved.)