Dexmedetomidine alleviates acute lung injury by promoting Tregs differentiation via activation of AMPK/SIRT1 pathway.

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.

Exploring the metabolic phenotypes associated with different host inflammation of acute respiratory distress syndrome (ARDS) from lung metabolomics in mice.

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.

Progranulin Improves Acute Lung Injury through Regulating the Differentiation of Regulatory T Cells and Interleukin-10 Immunomodulation to Promote Macrophage Polarization.

Progranulin (PGRN), which plays an anti-inflammatory role in acute lung injury (ALI), is promising as a potential drug. Studies have shown that regulatory T cells (Tregs) and interleukin- (IL-) 10 can repress inflammation and alleviate tissue damage during ALI. In this study, we built a lipopolysaccharide- (LPS-) induced ALI mouse model to illustrate the effect of PGRN on regulation of Treg differentiation and modulation of IL-10 promoting macrophage polarization. We found that the proportion of Tregs in splenic mononuclear cells and peripheral blood mononuclear cells was higher after treatment with PGRN. The increased proportion of Tregs after PGRN intratracheal instillation was consistent with the decreased severity of lung injury, the reduction of proinflammatory cytokines, and the increase of anti-inflammatory cytokines. In vitro, the percentages of CD4+CD25+FOXP3+ Tregs from splenic naïve CD4+ T cells increased after PGRN treatment. In further research, it was found that PGRN can regulate the anti-inflammatory factor IL-10 and affect the polarization of M1/M2 macrophages by upregulating IL-10. These findings show that PGRN likely plays a protective role in ALI by promoting Treg differentiation and activating IL-10 immunomodulation.

Different intensity of autophagy regulate interleukin-33 to control the uncontrolled inflammation of acute lung injury.

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.

Inflammation elevated IL-33 originating from the lung mediates inflammation in acute lung injury.

Excessive inflammatory reactions occur with acute respiratory distress syndrome (ARDS), however, the underlying mechanisms of ARDS remain incompletely understood. Here we investigated whether interleukin (IL)-33 was elevated in ARDS patients. Serum samples were obtained from 14 ARDS patients and 24 control healthy volunteers. ELISA was used to measure the concentrations of IL-33. Besides, we established pulmonary ARDS and extrapulmonary ARDS models in mice, and serum and lung tissue samples were collected for analyses. The results showed that serum IL-33 concentrations were significantly higher in pulmonary ARDS patients compared to controls. Also, the levels of IFN-γ and IL-2 were positively correlated with IL-33 levels. We also showed that there were increased IL-33 levels in both the serum and lungs in the pulmonary ARDS model. This was not the case, however, in the extrapulmonary ARDS model. Pulmonary inflammation and injury in the pulmonary ARDS model was reduced with IL-33 neutralizing antibody treatment.

Interleukin-35 is upregulated in response to influenza virus infection and secondary bacterial pneumonia.

Postinfluenza pneumococcal pneumonia is an important cause of global morbidity and mortality. What causes this increased susceptibility is not well elucidated. IL-35 is a newly described cytokine in infectious tolerance. A murine model was established to study postinfluenza pneumococcal pneumonia and evaluate the role of IL-35 in host defense against postinfluenza pneumococcal pneumonia. Pulmonary IL-35 was rapidly up-regulated during murine influenza infection, which was partially mediated by type I IFN-α/ß receptor signaling pathway. Secondary pneumococcal infection led to a synergistic IL-35 response in influenza-infected mice. Clinical analysis showed that IL-35 levels were significantly elevated in the patients with influenza infection compared with healthy individuals and influenza infection could induce IL-35 production from human peripheral blood mononuclear cells. These data suggest that IL-35 contributes to the increased susceptibility to secondary pneumococcal pneumonia at least in part by inhibiting the early immune response.

Cotinine exposure enhances the association of blood manganese and non-alcoholic fatty liver disease in American children: a cross-sectional study.

This cross-sectional survey aims to determine whether cotinine exposure would enhance the relationship between blood manganese (Mn) and non-alcoholic fatty liver disease (NAFLD) in children using the NHANES database. Restricted cubic spline (RCS) and logistic regression analyses were adopted to determine the potential relationship. Besides, we tested the robustness of the results by performing trend tests and subgroup analyses. The study finally enrolled 866 children aged 18 years and below. Blood Mn was linearly linked to NAFLD and the risk of NAFLD was increased with the blood Mn elevation (P < 0.05). There was a notable relationship between blood Mn and NAFLD in crude model 1, which was still significant upon adjustment of all the identified covariates (all P < 0.05). Under Mn exposure, the cotinine-exposed group had a higher risk of NAFLD than the cotinine-unexposed group. In conclusion, blood Mn level is an independent risk factor for pediatric NAFLD, and cotinine exposure can enhance this relationship to some degree. Therefore, reducing cotinine exposure may alleviate detrimental consequences related to exposure to heavy metals in children.

Identifying the risk factors of ICU-acquired fungal infections: clinical evidence from using machine learning.

Background: Fungal infections are associated with high morbidity and mortality in the intensive care unit (ICU), but their diagnosis is difficult. In this study, machine learning was applied to design and define the predictive model of ICU-acquired fungi (ICU-AF) in the early stage of fungal infections using Random Forest. Objectives: This study aimed to provide evidence for the early warning and management of fungal infections. Methods: We analyzed the data of patients with culture-positive fungi during their admission to seven ICUs of the First Affiliated Hospital of Chongqing Medical University from January 1, 2015, to December 31, 2019. Patients whose first culture was positive for fungi longer than 48 h after ICU admission were included in the ICU-AF cohort. A predictive model of ICU-AF was obtained using the Least Absolute Shrinkage and Selection Operator and machine learning, and the relationship between the features within the model and the disease severity and mortality of patients was analyzed. Finally, the relationships between the ICU-AF model, antifungal therapy and empirical antifungal therapy were analyzed. Results: A total of 1,434 cases were included finally. We used lasso dimensionality reduction for all features and selected six features with importance ≥0.05 in the optimal model, namely, times of arterial catheter, enteral nutrition, corticosteroids, broadspectrum antibiotics, urinary catheter, and invasive mechanical ventilation. The area under the curve of the model for predicting ICU-AF was 0.981 in the test set, with a sensitivity of 0.960 and specificity of 0.990. The times of arterial catheter (p = 0.011, OR = 1.057, 95% CI = 1.053-1.104) and invasive mechanical ventilation (p = 0.007, OR = 1.056, 95%CI = 1.015-1.098) were independent risk factors for antifungal therapy in ICU-AF. The times of arterial catheter (p = 0.004, OR = 1.098, 95%CI = 0.855-0.970) were an independent risk factor for empirical antifungal therapy. Conclusion: The most important risk factors for ICU-AF are the six time-related features of clinical parameters (arterial catheter, enteral nutrition, corticosteroids, broadspectrum antibiotics, urinary catheter, and invasive mechanical ventilation), which provide early warning for the occurrence of fungal infection. Furthermore, this model can help ICU physicians to assess whether empiric antifungal therapy should be administered to ICU patients who are susceptible to fungal infections.

Luteolin Regulates the Differentiation of Regulatory T Cells and Activates IL-10-Dependent Macrophage Polarization against Acute Lung Injury.

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.

The predictive value of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide for weaning outcome in mechanical ventilation patients: Evidence from SROC.

OBJECTIVE: Mechanical ventilation is an important treatment for critically ill patients. Physicians generally perform a spontaneous breathing trial (SBT) to determine whether the patients can be weaned from mechanical ventilation, but almost 17% of the patients who pass the SBT still require respiratory support. Cardiac dysfunction is an important cause of weaning failure. The use of brain natriuretic peptide or N-terminal pro-BNP is a simple method to assess cardiac function. We performed a systematic review of investigations of brain natriuretic peptide or N-terminal pro-BNP as predictors of weaning from mechanical ventilation. DATA SOURCES: PubMed (1950 to December 2020), Cochrane, and Embase (1974 to December 2020), and some Chinese databases for additional articles (China Biology Medicine (CBM), China Science and Technology Journal Database (CSTJ), and Wanfang Data and China National Knowledge Infrastructure (CNKI)). STUDY SELECTION: We systematically searched observation studies investigating the predictive value of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide in weaning outcome of patients with mechanical ventilation. DATA EXTRACTION: Two independent reviewers extracted data. The differences are resolved through consultation. DATA SYNTHESIS: We included 18 articles with 1416 patients and extracted six index tests with pooled sensitivity and specificity for each index test. For the BNP change rate predicting weaning success, the pooled sensitivity was 89% (83%-94%) and the pooled specificity was 82% (72%-89%) with the highest pooled AUC of 0.9511. CONCLUSIONS: The brain natriuretic peptide change rate is a reliable predictor of weaning outcome from mechanical ventilation.

HMGB1 suppress the expression of IL-35 by regulating Naïve CD4+ T cell differentiation and aggravating Caspase-11-dependent pyroptosis in acute lung injury.

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.

Coronavirus disease 2019 (COVID-19): cytokine storms, hyper-inflammatory phenotypes, and acute respiratory distress syndrome.

Coronavirus Disease 2019 (COVID-19) was first identified in China at the end of 2019. Acute respiratory distress syndrome (ARDS) represents the most common and serious complication of COVID-19. Cytokine storms are a pathophysiological feature of COVID-19 and play an important role in distinguishing hyper-inflammatory subphenotypes of ARDS. Accordingly, in this review, we focus on hyper-inflammatory host responses in ARDS that play a critical role in the differentiated development of COVID-19. Furthermore, we discuss inflammation-related indicators that have the potential to identify hyper-inflammatory subphenotypes of COVID-19, especially for those with a high risk of ARDS. Finally, we explore the possibility of improving the quality of monitoring and treatment of COVID-19 patients and in reducing the incidence of critical illness and mortality via better distinguishing hyper- and hypo-inflammatory subphenotypes of COVID-19.

Exploring plasma metabolomic changes in sepsis: a clinical matching study based on gas chromatography-mass spectrometry.

BACKGROUND: Sepsis is a deleterious systemic inflammatory response to infection, and despite advances in treatment, the mortality rate remains high. We hypothesized that plasma metabolism could clarify sepsis in patients complicated by organ dysfunction. METHODS: Plasma samples from 31 patients with sepsis and 23 healthy individuals of comparable age, gender, and body mass index (BMI) were collected. Plasma metabolites were detected through gas chromatography-mass spectrometry (GC-MS), and relevant metabolic pathways were predicted using the Kyoto Encyclopedia of Genes and Genomics (KEGG) pathway database. Student's t-test was employed for statistical analysis. In addition, to explore sepsis organ dysfunction, plasma samples of sepsis patients were further analyzed by metabolomics subgroup analysis according to organ dysfunction. RESULTS: A total of 222 metabolites were detected, which included 124 metabolites with statistical significance between the sepsis and control groups. Among these, we found 26 were fatty acids, including 3 branched fatty acids, 10 were saturated fatty acids, and 13 were unsaturated fatty acids that were found in sepsis plasma samples but not in the controls. In addition, 158 metabolic pathways were predicted, 74 of which were significant. Further subgroup analysis identified seven metabolites in acute kidney injury (AKI), three metabolites in acute respiratory distress syndrome (ARDS), seven metabolites in sepsis-induced myocardial dysfunction (SIMD), and four metabolites in acute hepatic ischemia (AHI) that were significantly different. The results showed that the sepsis samples exhibited extensive changes in amino acids, fatty acids, and tricarboxylic acid (TCA)-cycle products. In addition, three metabolic pathways-namely, energy metabolism, amino acid metabolism, and lipid metabolism-were downregulated in sepsis patients. CONCLUSIONS: The downregulated energy, amino acid, and lipid metabolism found in our study may serve as a novel clinical marker for the dysregulated internal environment, particularly involving energy metabolism, which results in sepsis.

Curcumin Promotes the Expression of IL-35 by Regulating Regulatory T Cell Differentiation and Restrains Uncontrolled Inflammation and Lung Injury in Mice.

Interleukin (IL)-35, which has an anti-inflammatory role in acute respiratory distress syndrome (ARDS)/acute lung injury (ALI), is relatively promising as a drug target. Studies have shown that curcumin may play a therapeutic role in ALI and enhance the suppressive function of regulatory T cells (Tregs). To illustrate the effect of curcumin on the regulation of Treg cell differentiation and expression of IL-35, we built a cecal ligation and puncture (CLP)-induced acute lung injury mouse mode with curcumin pretreatment. The expression of IL-35 in serum, severity of lung injury, IL-17A in lung tissue, survival rate, Treg-related cytokines levels in serum, nuclear factor-kappa B (NF-κB)'s nuclear translocation in lung tissue, and splenic CD4+CD25+FOXP3+ Tregs were assessed. Furthermore, the proportion of Tregs, STAT5, and IL-35 expression during naïve CD4+ T cell differentiation in vitro was measured. Compared with the CLP group, the increased IL-35 expression in CLP with the curcumin pretreatment (CLP + Cur) group was consistent with the decreased severity of lung injury, IL-17A protein levels in lung tissue, and Treg-related cytokines levels. Pretreatment with curcumin, the survival rate climbed to 50%, while the mortality rate was 100% in the CLP group. In addition, splenic CD4+CD25+FOXP3+ Treg cells increased in the CLP + Cur group. In vitro, CD4+CD25+FOXP3+ Treg cells from naïve CD4+ T cells, STAT5 proportion, and IL-35 expression increased after curcumin treatment. These findings showed that curcumin might regulate IL-35 by activating the differentiation of Treg cells to control the inflammation in acute lung injury.

Curcumin regulates the differentiation of naïve CD4+T cells and activates IL-10 immune modulation against acute lung injury in mice.

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.

IL-35 interferes with splenic T cells in a clinical and experimental model of acute respiratory distress syndrome.

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.

HMGB1 regulates IL-33 expression in acute respiratory distress syndrome.

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.

The effect of curcumin on sepsis-induced acute lung injury in a rat model through the inhibition of the TGF-ß1/SMAD3 pathway.

Curcumin has the potential to treat inflammatory diseases. This study investigated its effect on sepsis-induced acute lung injury (ALI) in a rat model. 125 healthy rats were randomly divided into five groups, including normal group, sham-operated group, sepsis group, dimethyl sulfoxide group, and curcumin-treated group (25 rats in each subgroup). Sepsis-induced acute lung injury was affected by cecal ligation and puncture surgery. At 0, 6, 12, 24, and 48 h after treatment, the lungs were harvested for histological and protein expression examinations. 24h after the initial treatment, real-time PCR and Western blot analysis showed that the expression of TGF-ß1 and SMAD3-dependent signaling pathway was significantly decreased in the curcumin-treated group than other control groups (P<0.05). Therefore, curcumin played a protective role in sepsis-induced ALI, possibly through the inhibition of the expression of TGF-ß1/SMAD3 pathway which may provide a new strategy for the treatment of sepsis-induced ALI.