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• IL-35 release in clinical ARDS but reduced in non-survivor, suggesting anti-inflammatory potential of IL-35 in clinical ARDS. • Recombinant IL-35 treatment could improve survival in experimental ARDS. • Its protective effect is promoting differentiation of Helios+Foxp3+Tregs to improve uncontrolled inflammation in ARDS. • IL-35 could be a novel cytokine-targeted for the regulation of T cell differentiation in ARDS development. Regulatory T lymphocytes are important targets for the treatment of acute respiratory distress syndrome (ARDS). IL-35 is a newly identified IL-12 cytokine family member that plays an important protective role in a variety of immune system diseases by regulating Treg cell differentiation; however, the role of IL-35 in the pathogenesis of ARDS is still unclear. Here, we found that IL-35 was significantly elevated in adult patients with ARDS compared to controls. Additionally, IL-35 was positively and significantly correlated with IL-6, IL-10 and the oxygenation index (PaO2/FiO2 ratio) but negatively correlated with TNF-α, IL-1β and APACHE II score during ARDS. Moreover, the proportion of Treg/CD4+ cells in the peripheral blood of ARDS patients and the expression of NF-κB in PMBCs were significantly higher than in healthy individuals. Recombinant IL-35 improved survival in a murine model of CLP-induced ARDS. Additionally, IL-35 administration decreased the inflammatory response, as reflected by lower levels of cytokines (including IL-2, TNF-α, IL-1β and IL-6) and less lung damage in CLP-induced ARDS. Furthermore, recombinant IL-35 reduced the apoptosis of lung tissue and the expression of NF-κB signalling in a CLP-induced ARDS model and increased the proportion of Treg cells in spleen and peripheral blood. In vitro experiments revealed that IL-35 can affect the phosphorylation of STAT5 during differentiation of naïve CD4+ T lymphocytes into Foxp3+Helios+ Tregs. Our findings suggest that IL-35 attenuates ARDS by promoting the differentiation of naïve CD4+ T cells into Foxp3+Helios+ Tregs, thereby providing a novel tool for anti-ARDS therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: Inflammatory disease characterized by clinical destructive respiratory disorder is called acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Studies have shown that luteolin exerts anti-inflammatory effects by increasing regulatory T cells (Tregs). In this study, we aimed to determine the effects of luteolin on ALI/ARDS and Treg differentiation.Methods: In this paper, we used cecal ligation puncture (CLP) to generate an ALI mouse model to determine the effects of luteolin on ALI/ARDS. Lung tissues were stained for interleukin- (IL-) 17A and myeloperoxidase (MPO) by immunohistochemical analysis. The levels of Treg-related cytokines in serum and bronchoalveolar lavage fluid (BALF) of mice were detected. The protein levels of NF-κB p65 in lung tissues were measured. Macrophage phenotypes in lung tissues were measured using immunofluorescence. The proportion of Tregs in splenic mononuclear cells and peripheral blood mononuclear cells (PBMCs) was quantified. Furthermore, in vitro, we evaluated the effects of luteolin on Treg differentiation, and the effects of IL-10 immune regulation on macrophage polarization were examined.Results: Luteolin alleviated lung injury and suppressed uncontrolled inflammation and downregulated IL-17A, MPO, and NF-κB in the lungs of CLP-induced mouse models. At this time, luteolin upregulated the level of IL-10 in serum and BALF and the frequency of CD4+CD25+FOXP3+ Tregs in PBMCs and splenic mononuclear cells of CLP mice. Luteolin treatment decreased the proportion of M1 macrophages and increased the proportion of M2 macrophages in lungs of CLP-induced mouse models. In vitro, administration of luteolin significantly induced Treg differentiation, and IL-10 promoted the polarization of M2 macrophages but reduced the polarization of M1 macrophages.Conclusions: Luteolin alleviated lung injury and suppressed uncontrolled inflammation by inducing the differentiation of CD4+CD25+FOXP3+ Tregs and upregulating the expression of IL-10. Furthermore, the anti-inflammatory cytokine IL-10 promoted polarization of M2 macrophages in vitro. Luteolin-induced Treg differentiation from naïve CD4+ T cells may be a potential mechanism for regulating IL-10 production. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Inhibition of HMGB1 increased the proportion of Treg and expression of IL-35. • HMGB1 mediates caspase-11-dependent pyroptosis in acute lung injury. • HMGB1 down-regulates Tregs differentiation from CD4+ naïve T cells. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

As the aging population increases, the focus on elderly patients with acute respiratory distress syndrome (ARDS) is also increasing. In this article, we found progranulin (PGRN) differential expression in ARDS patients and healthy controls, even in young and old ARDS patients. Its expression strongly correlates with several cytokines in both young and elderly ARDS patients. PGRN has comparable therapeutic effects in young and elderly mice with lipopolysaccharide-induced acute lung injury, manifesting as lung injury, apoptosis, inflammation, and regulatory T cells (Tregs) differentiation. Considering that Tregs differentiation relies on metabolic reprogramming, we discovered that Tregs differentiation was mediated by mitochondrial function, especially in the aged population. Furthermore, we demonstrated that PGRN alleviated the mitochondrial damage during Tregs differentiation through the AMPK/PGC-1α pathway in T cells. Collectively, PGRN may regulate mitochondria function to promote Tregs differentiation through the AMPK/PGC-1α pathway to improve ARDS. [Display omitted] • Differential expression of PGRN and mitochondrial respiratory in ARDS patients and healthy controls. • PGRN has an equivalent therapeutic effect on Tregs differentiation in young and old ALI mice induced by LPS intratracheal instillation. • PGRN has a better promotion effect on metabolic reprogramming during the differentiation of old Tregs than that of young. • PGRN promotes mitochondrial function through the AMPK/PGC-1α pathway in T cells. [ABSTRACT FROM AUTHOR]

• Curcumin suppressed inflammatory mediators, alleviated lung injury and increased CD4+CD25+Foxp3+ Tregs in ALI model. • Curcumin can upregulate the differentiation from CD4+ naïve T cells to Tregs in vitro. • Curcumin can promote Tregs ratio and increase Tregs derived IL-10 immune modulation. • Curcumin down-regulates lung M1 macrophages and up-regulates M2 macrophages in ALI. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]