international-expert-consensus-recommendations-for-neonatal

International Expert Consensus and Recommendations for Neonatal Pneumothorax Ultrasound Diagnosis and Ultrasound-guided Thoracentesis Procedure

Pneumothorax (PTX) represents accumulation of the air in the pleural space. A large or tension pneumothorax can collapse the lung and cause hemodynamic ...

Tianjin Medical University General Hospital

[Advance in the study of the role of macrophages in the pathogenesis of sepsis].

Diversity and plasticity are two hallmarks of macrophages. M1 macrophages (classically activated macrophages) are pro-inflammatory and have a central role in host defense against infection, while M2 macrophages (alternatively activated macrophages) are associated with responses to anti-inflammatory reactions and tissue remodeling, and they represent two terminals of the full spectrum of macrophage activation. Transformation of different phenotypes of macrophages regulates the initiation, development, and cessation of inflammatory diseases. Here we reviewed the characters and functions of macrophage polarization in infection, atherosclerosis, obesity, tumor, asthma, and sepsis, and proposed that targeting macrophage polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of inflammatory diseases. 

Macrophage polarization in inflammatory diseases.

This study aimed to observe the effect of hemoperfusion (HP) cartridge on different internal environment indicators at different time points in patients with acute blood poisoning and to find alternative indicators for the detection of blood poisoning.

Effect of hemoperfusion cartridge on different internal environmental indicators.

Although regulatory T cells (Tregs) are key to the maintenance of immunologic homeostasis and tolerance, little is known about Treg-mediated immunosuppression in the stage of sepsis. This article aimed to review the current literature on the role of Tregs in the pathophysiology of septic response, attempting to investigate the role of Tregs in immune dysfunction during sepsis.

The role of regulatory T cells in immune dysfunction during sepsis.

Xuebijing (XBJ) injection, a concoction of several Chinese herbs, has been widely used as an immunomodulator for the treatment of severe sepsis in China. However, the precise mechanisms responsible for its efficacy have not been fully elucidated. In our study, we determined the flow cytometry markers (F4/80, CD11c, and CD206), the levels of secreted cytokines (TNF-α, IL-6, and IL-10), and the expression of specific proteins of M2 (Ym1, Fizz1, and Arg1) to assess macrophage polarization. Treatment with XBJ lowered M1 associated cytokine levels and increased the level of M2 associated cytokine level. The percentage of M2 phenotype cells of XBJ group was much higher than that of the control group. Expressions of phosphorylated Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6) were markedly enhanced after the administration of XBJ; on the other hand, the M2 associated cytokines and proteins were decreased following treatment with JAK1 or STAT6 inhibitor. In addition, the treatment of XBJ significantly improved the survival rate of septic mice. These studies demonstrate that XBJ can markedly promote M2 polarization and improve the survival rate of septic mice, thereby contributing to therapeutic effect in the treatment of septic complications. 

Xuebijing Injection Promotes M2 Polarization of Macrophages and Improves Survival Rate in Septic Mice.

The primary mechanisms of sepsis induced cellular immunosuppression involve immune dysfunction of T lymphocytes and negative immunoregulation of regulatory T cells (Tregs). It has been found that tuftsin is an immune modulating peptide derived from IgG in spleen. T-peptide is one of tuftsin analogs. Herein, we examined the effect of T-peptide on cell-mediated immunity in the presence of lipopolysaccharide (LPS) and the survival rate in septic mice. T-peptide regulated the proliferative ability of CD4(+)CD25(-) T cells in dual responses. Meanwhile, 10 and 100 μg/ml T-peptides were able to enhance the apoptotic rate of CD4(+)CD25(-) T cells compared with 1 μg/ml T-peptide, but markedly lowered interleukin (IL)-2 levels. When CD4(+)CD25(+) Tregs were treated with T-peptide for 24 hours, and co-cultured with normal CD4(+)CD25(-) T cells, the suppressive ability of CD4(+)CD25(+) Tregs on CD4(+)CD25(-) T cells was significantly lowered, along with decreased expression in forkhead/winged helix transcription factor p-3 (Foxp-3) as well as cytotoxic T lymphocyte-associated antigen (CTLA)-4, and secretion of transforming growth factor (TGF)-β. Moreover, T-peptide has the ability to improve outcome of septic mice in a dose- and time- dependent manner, and associated with improvement in the microenvironment of cellular immunosuppression in septic mice.

Tuftsin-derived T-peptide prevents cellular immunosuppression and improves survival rate in septic mice.

Regulatory T cells (Tregs) appear to be involved in sepsis-induced immune dysfunction; neuropilin-1 (Nrp-1) was identified as a surface marker for CD4(+)CD25(+)Tregs. In the current study, we investigated the negative immunoregulation of Nrp-1(high)CD4(+)CD25(+)Tregs and the potential therapeutic value of Nrp-1 in sepsis. Splenic CD4(+)CD25(+)Tregs from cecal ligation and puncture (CLP) mouse models were further segregated into Nrp-1(high)Tregs and Nrp-1(low)Tregs; they were cocultured with CD4(+)CD25(-)  T cells. The expression of forkhead/winged helix transcription factor-3 (Foxp-3), cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), membrane associated transforming growth factor-β (TGF-β(m+)), apoptotic rate, and secretive ability [including TGF-β and interleukin-10 (IL-10)] for various types of Tregs, as well as the immunosuppressive ability of Tregs on CD4(+)CD25(-)  T cells, were determined. Meanwhile, the impact of recombinant Nrp-1 polyclonal antibody on the demethylation of Foxp-3-TSDR (Treg-specific demethylated region) was measured in in vitro study. Sepsis per se markedly promoted the expression of Nrp-1 of CD4(+)CD25(+)Tregs. Foxp-3/CTLA-4/TGF-β(m+) of Nrp-1(high)Tregs were upregulated by septic challenge. Nrp-1(high)Tregs showed strong resilience to apoptosis and secretive ability and the strongest immunosuppressive ability on CD4(+)CD25(-)  T cells. In the presence of lipopolysaccharide (LPS), the recombinant Nrp-1 polyclonal antibody reduced the demethylation of Foxp-3-TSDR. Nrp-1(high)Tregs might reveal primary negative immunoregulation in sepsis; Nrp-1 could represent a new potential therapeutic target for the study of immune regulation in sepsis. 

Neuropilin-1highCD4⁺CD25⁺ Regulatory T Cells Exhibit Primary Negative Immunoregulation in Sepsis.

Our previous research showed that neuropilin (Nrp) -1highCD4+CD25+Regulatory T cells (Tregs) exhibited primary negative immunoregulation in sepsis induced immune dysfunction. Tuftsin is the typical ligand of Nrp-1. Herein, we investigated the potential therapeutic value and mechanisms of tuftsin in sepsis. Sepsis per se markedly decreased the serum concentration of tuftsin, administration of tuftsin improved the survival rate of septic mice with cecal ligation and puncture (CLP). In vitro study, tuftsin prevented the negative immunoregulation of Nrp-1highCD4+CD25+Tregs, including weakening the expression of forkhead/winged helix transcription factor (Foxp)- 3/cytotoxic T lymphocyte associated antigen (CTLA)-4, inhibiting the secretion of transforming growth factor (TGF)-β, and weakening the immunosuppressive function of Nrp-1highCD4+CD25+Tregs to conventional CD4+CD25-T cells. Tuftsin markedly inhibited the demethylation of Foxp3-Tregs specific demethylated region (TSDR) of Nrp-1highCD4+CD25+Tregs. Tuftsin could represent a new potential therapeutic agentia to improve the outcome of septic mice, and associate with preventing the negative immunoregulation of Tregs via Nrp-1.

Tuftsin prevents the negative immunoregulation of neuropilin-1highCD4+CD25+Regulatory T cells and improves survival rate in septic mice.

Cellular immunosuppression appears to be involved in sepsis and sepsis-induced multiple organ dysfunction syndrome (MODS). Recent evidence showed that parenteral vitamin C (Vit C) had the ability to attenuate sepsis and sepsis-induced MODS. Herein, we investigated the impact of parenteral Vit C on cellular immunosuppression and the therapeutic value in sepsis. Using cecal ligation and puncture (CLP), sepsis was induced in WT and Gulo mice followed with 200 mg/Kg parenteral Vit C administration. The immunologic functions of CD4CD25 regulatory T cells (Tregs) and CD4CD25 T cells, as well as the organ functions, were determined. Administration of parenteral Vit C per se markedly improved the outcome of sepsis and sepsis-induced MODS of WT and Gulo mice. The negative immunoregulation of Tregs was inhibited, mainly including inhibiting the expression of forkhead helix transcription factor- (Foxp-) 3, cytotoxic T lymphocyte associated antigen- (CTLA-) 4, membrane associated transforming growth factor- (TGF-β), and the secretion of inhibitory cytokines [including TGF- and interleukin- (IL-) 10], as well as CD4 T cells-mediated cellular immunosuppression which was improved by parenteral Vit C in WT and Gulo septic mice. These results suggested that parenteral Vit C has the ability to improve the outcome of sepsis and sepsis-induced MODS and is associated with improvement in cellular immunosuppression.

The Parenteral Vitamin C Improves Sepsis and Sepsis-Induced Multiple Organ Dysfunction Syndrome via Preventing Cellular Immunosuppression.

[Chinese emergency medicine expert consensus on diagnosis and treatment of sepsis complicated with disseminated intravascular coagulation].

Sepsis is a lethal syndrome with a high incidence and a weighty economy burden. The pathophysiology of sepsis includes inflammation, immune dysfunction, and dysfunction of coagulation, while sepsis-induced cardiomyopathy (), defined as a global but reversible dysfunction of both sides of the heart induced by sepsis, plays a significant role in all of the aspects above in the pathogenesis of sepsis. The complex pathogenesis of  involves a combination of dysregulation of inflammatory mediators, mitochondrial dysfunction, oxidative stress, disorder of calcium regulation, autonomic nervous system dysregulation, and endothelial dysfunction. The treatments for  include the signal pathway intervention, Chinese traditional medicine, and other specific therapy. Here, we reviewed the latest literatures on the mechanisms and treatments of  and hope to provide further insights to researchers and create a new road for the therapy of sepsis.

Sepsis-Induced Cardiomyopathy: Mechanisms and Treatments.

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a group of cell surface transmembrane receptors expressed on immune cells, and regulate immune balance in inflammatory diseases. Sepsis is a life-threatened inflammatory syndrome induced by infection, and the pathogenesis of sepsis includes immune dysregulation, inflammation, and coagulation disorder. Here, we reviewed the various roles acted by Siglecs family in the pathogenesis of sepsis. Siglec-1, Siglec-5, and Siglec-14 play bidirectional roles through modulation of inflammation and immunity. Siglec-2 regulates the immune balance during infection by modulating B cell and T cell response. Siglec-9 helps endocytosis of toll-like receptor 4, regulates macrophages polarization, and inhibits the function of neutrophils during infection. Siglec-10 inhibits danger-associated molecular patterns induced inflammation, helps the initiation of antigen response by T cells, and decreases B-1a cell population to weaken inflammation. Regulating the Siglecs function in the different stages of sepsis holds great potential in the therapy of sepsis.

Sialic Acids in the Immune Response during Sepsis.

Sepsis is recognized as a life-threatening organ dysfunctional disease that is caused by dysregulated host responses to infection. Up to now, sepsis still remains a dominant cause of multiple organ dysfunction syndrome (MODS) and death among severe condition patients. Pyroptosis, originally named after the Greek words "" and "" in 2001, has been defined as a specific programmed cell death characterized by release of inflammatory cytokines. During sepsis, pyroptosis is required for defense against bacterial infection because appropriate pyroptosis can minimize tissue damage. Even so, pyroptosis when overactivated can result in septic shock, MODS, or increased risk of secondary infection. Proteolytic cleavage of gasdermin D (GSDMD) by caspase-1, caspase-4, caspase-5, and caspase-11 is an essential step for the execution of pyroptosis in activated innate immune cells and endothelial cells stimulated by cytosolic lipopolysaccharide (LPS). Cleaved GSDMD also triggers NACHT, LRR, and PYD domain-containing protein (NLRP) 3-mediated activation of caspase-1 via an intrinsic pathway, while the precise mechanism underlying GSDMD-induced NLRP 3 activation remains unclear. Hence, this study provides an overview of the recent advances in the molecular mechanisms underlying pyroptosis in sepsis.

Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis.

Quick Sequential Organ Failure Assessment (qSOFA) was proposed to replace SIRS as a new screening tool for the identification of septic patients at high mortality. However, researches from infected patients outside of ICU especially in Emergency Department (ED) drew contradictory conclusions on the prognostic value of qSOFA. This systematic review evaluated qSOFA as a prognostic marker of infected patients outside of ICU. The primary outcome was hospital mortality or 28- or 30-day mortality. Data were pooled based on sensitivity and specificity. Twenty-four trials with 121,237 participants were included. qSOFA had a poor sensitivity (0.58 [95% CI 0.47-0.67], 0.54 [95% CI 0.43-0.65]) and moderate specificity (0.69 [95% CI 0.48-0.84], 0.77 [95% CI 0.66-0.86]) for prediction of mortality in patients outside of ICU and ED patients only. Studies that used in-hospital mortality showed a higher sensitivity (0.61 [95% CI 0.50-0.71] vs 0.32 [95% CI 0.15-0.49]) and lower specificity (0.70 [95% CI 0.59-0.82] vs 0.92 [95% CI 0.85-0.99]) than studies that used 28 or 30-day mortality. Studies with overall mortality < 10% showed higher specificity (0.89 [95% CI 0.82-0.95] vs 0.62 [95% CI 0.48-0.76]) than studies with overall mortality ≥ 10%. There is no difference in the accuracy of diagnosis of sepsis between positive qSOFA scores and SIRS criteria. qSOFA was poor sensitivity and moderate specificity in predicting mortality of infected patients outside of ICU especially in ED. Combining qSOFA and SIRS may be helpful in predicting mortality.

Quick Sequential Organ Failure Assessment as a prognostic factor for infected patients outside the intensive care unit: a systematic review and meta-analysis.

Article	Year
[Advance in the study of the role of macrophages in the pathogenesis of sepsis]. Zhonghua wei zhong bing ji jiu yi xue\| PubMed ID: 23660103	2013
Macrophage polarization in inflammatory diseases. International journal of biological sciences\| PubMed ID: 24910531	2014
Effect of hemoperfusion cartridge on different internal environmental indicators. World journal of emergency medicine\| PubMed ID: 25215135	2013
The role of regulatory T cells in immune dysfunction during sepsis. World journal of emergency medicine\| PubMed ID: 25802559	2015
Xuebijing Injection Promotes M2 Polarization of Macrophages and Improves Survival Rate in Septic Mice. Evidence-based complementary and alternative medicine : eCAM\| PubMed ID: 26064161	2015
Tuftsin-derived T-peptide prevents cellular immunosuppression and improves survival rate in septic mice. Scientific reports\| PubMed ID: 26577833	2015
Neuropilin-1highCD4⁺CD25⁺ Regulatory T Cells Exhibit Primary Negative Immunoregulation in Sepsis. Mediators of inflammation\| PubMed ID: 27239104	2016
Tuftsin prevents the negative immunoregulation of neuropilin-1highCD4+CD25+Regulatory T cells and improves survival rate in septic mice. Oncotarget\| PubMed ID: 27835904	2016
The Parenteral Vitamin C Improves Sepsis and Sepsis-Induced Multiple Organ Dysfunction Syndrome via Preventing Cellular Immunosuppression. Mediators of inflammation\| PubMed ID: 28210072	2017
[Chinese emergency medicine expert consensus on diagnosis and treatment of sepsis complicated with disseminated intravascular coagulation]. Zhonghua wei zhong bing ji jiu yi xue\| PubMed ID: 28743331	2017
Sepsis-Induced Cardiomyopathy: Mechanisms and Treatments. Frontiers in immunology\| PubMed ID: 28970829	2017
Sialic Acids in the Immune Response during Sepsis. Frontiers in immunology\| PubMed ID: 29209331	2017
Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis. Mediators of inflammation\| PubMed ID: 29706799	2018
Quick Sequential Organ Failure Assessment as a prognostic factor for infected patients outside the intensive care unit: a systematic review and meta-analysis. Internal and emergency medicine\| PubMed ID: 30725323	2019

Yan-Fen Chai

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