The Janus kinase/signal transducer and activator of transcription (JAK/STAT) are a major signal transduction pathway in controlling and regulating a number of cytokine-mediated responses, including interferon-?, interleukin-1 (IL-1), IL-6, IL-10 and IL-4. The JAK/STAT pathway is particularly elegant because of its very rapid and simple cytoplasm-to-nucleus signaling. Recently, it has been found that JAK/STAT pathway might also be involved in the regulation of high mobility group box-1 protein (HMGB1), which plays an important role as a potential late mediator of sepsis. Inhibition of the activation of JAK/STAT pathway can down-regulate the gene expression of HMGB1 in vital organs, especially in the liver and lungs. In addition, treatment with JAK/STAT pathway inhibitors can effectively prevent the occurrence and development of multiple organ dysfunction syndrome following sepsis, and the probable underlying mechanism of which involves a reduction of direct or indirect harmful effect of HMGB1. Over the past few years, numerous investigations have contributed to our knowledge of the JAK/STAT pathway and its role in cytokine-mediated abnormality of immune function as well as inflammatory response during sepsis, and it might be helpful in further identifying a potential strategy of intervention for posttraumatic or postburn sepsis. This review summarizes the salient features of JAK/STAT pathway and focuses on the pathophysiological role of JAK/STAT in regulating proinflammatory cytokine activity and HMGB1 expression in vivo.

Sepsis and septic shock are common critical diseases in the ICU, which have a high mortality and seriously affect the patients'' quality of life.The pathogenesis of sepsis is very complicated and involves the changes in the functions of multiple systems and organs.Recently, the investigation into the potential mechanisms underlying the development of sepsis is becoming a hotspot all over the world.The author presents an overview on the advances in the studies of the pathogenesis of sepsis, relating to the imbalance of inflammatory response, immune dysfunction, abnormal blood coagulation, nerve-endocrine-immunity network, mitochondrial function damage, endoplasmic reticulum stress, autophagy, and genetic polymorphism, in order to provide some theoretical evidence for the prevention and treatment of sepsis in clinical practice.

Sepsis is essentially a result from immunological dissonance provoked by severe insults such as fulminant infection,severe trauma and extensive burns.It originates from excessive inflammatory responses and develops into immune paralysis or immunosupression.It has been demonstrated that cellular immune response plays a vital role in the pathogenesis of sepsis.In the stage of excessive inflammation,several kinds of immune cells are activated by pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) and subsequently produce a vast number of pro-inflammatory cytokines,while during the stage of immune paralysis,excessive apoptosis could result in decrease of immune cells with functional compromise.Inhibitory or regulatory immune cell subsets eventually dominate the direction of immune response and the production of inhibitory cytokines is enhanced.For clinical practice,surveillance of changes and shift in overall immune function is a basis for immunotherapy,especially to immunomodulation therapy.However,there is still a lack of adequate indexes or markers for integral evaluation of host immune state in the development of sepsis.

Janus kinase-signal transduction and transcription activator (JAK-STAT), mitogen- activated protein kinase (MAPK) and nuclear factor ?B (NF-?B) are three important cellular signalling pathways, which play pivotal roles in regulation of cellular physiologic as well as pathophysiologic functions. Based on the elucidation of the research progress of three signalling cascades, respectively, the current review focuses on the cross-talk of these signalling transduction, and the up-to-date details are also presented on their regulation in inflammatory response.

Sepsis is a severe complication which is usually caused by microbial infection,severe burns or trauma and major operations.Patients with sepsis were usually complicated with systemic inflammatory response and multi-organ dysfunction syndrome,which is the leading cause of death in the intensive care units.However,the main immunoregulatory mechanisms underlying severe sepsis remain unclear,and effective methods for monitoring immune status and immunomodulatory strategies need to be investigated.In recent years,the understanding of the mechanism of sepsis has been developed.Clinicians have learned that immune dysfunction took part in the pathophysiological process of sepsis.Therefore,rational monitoring of immune status in patients with severe sepsis after burns or major operation,seeking effective ways for diagnosis,treatment and intervention are of great significance in decreasing the mortality and improving the life quality.

ObjectiveTo observe the effects of high mobility group box-1 protein ( HMGB1 ) on function of murine spleen IL-10-producing dendritic cells (DCs) subset CD11clowCD45RBhighDCs.MethodsSplenic CD11clowCD45RBhighDCs and CD4 +T cells in Balb/c mice were purified by magnetic beads sorting.CD11clowCD45RBhighDCs were treated with various doses of HMGB1 (0,20,100,500ng/ml).Flow cytometry was used to determine expressions of CD11clowCD45RBhighDC surface molecules including CD40,CD80,CD86,Ⅰ-a/e and Toll-like receptor (TLR) 4.IL-10 level in CD11clow CD45RBhighDC culture supernatants was determined by ELISA method.The CD4+ T cells were divided into four groups: control group (without only treatment),untreated group (HMGB1-untreated CD11clow CD45RBhigh DCs plus CD4+T cells),high-dose HMGB1-treated group (500 ng/ml HMGB1-treated CD11clowCD45RBhigh DCs plus CD4 +T cells),high-dose HMGB1-treated + antibody 1 group (500 ng/ml HMGB1-treated CD11clowCD45RBhigh DCs plus IL-10 antibody and CD4+T cells),high-dose HMGB1-treated + antibody 2 group (500 ng/ml HMGB1-treated CD11clow CD45RBhigh DCs plus homotype IL-10 antibody and CD4 +T cells).IL-4 as well as interferon( IFN-γ) contents in CD4 + T cell culture supernatants were determined by flow cytometry.ResultsHMGB1 could markedly enhance the expressions of CD40,CD86 and TLR4 on CD11clowCD45RBhigh DC surface as well as level of IL-10 secreted by CD11clow CD45RBhigh DCs as compared with the non-HMGB1 treatment.Meantime,the secretion of IL-10 was HMGB1 concentration dependent.IFN-γ level in high-dose HMGB1-treated group was (279 ± 17) pg/ml,which was markedly lower than that in the untreated group [ (963 ± 11 ) pg/ml,P ＜ 0.05 \ ].IL-4 level in high-dose HMGB1-treated group was (372 ± 14) pg/ml,which was significantly higher than that in the untreated group [ (213 ± 10) pg/ml,P ＜0.05) \].ConclusionsHMGB1 promotes IL-10 production in CD11clowCD45RBhighDCs,induces the differentiation of CD4 +T cells to Th2 cells and downregulates the immune response via activating CD11clowCD45RBhigh DCs.

With rapid progress and dangerous prognosis, traumatic brain injury (TBI) brings great difficulties in the clinical treatment, which becomes a prominent problem for the modern emergency and critical care medicine. In addition to the necessary surgical intervention under special circumstances, there are new understandings about the clinical management measures, noninvasive and invasive monitoring mode of TBI in recent years. This review provides a summary of the monitoring and treatment on the TBI, with our deep understanding of regulatory mechanism underlying TBI, precise modulation might be of clinical significance in preventing secondary damage of tissues and organs, which would be associated with decreases in the disability and mortality of critically ill patients.

The present study was performed to investigate the significance and potential role of signal transducers and activators of transcription 3 (STAT3) activation in postburn Staphylococcus aureus sepsis. Seventy one male Wistar rats were randomly divided into five groups: normal controls, scald control group, postburn sepsis group, AG490 (JAK2 inhibitor) treatment group, and rapamycin (RPM, STAT3 inhibitor) treatment group. Tissue samples from the liver and lung were collected to determine activation of STAT3, and interferon ? (IFN ?) mRNA as well as protein expression. The results showed that activation of STAT3 was quickly up regulated at 0 5～1 hour following thermal injury combined with Staphylococcus aureus challenge in the liver and lung, and it gradually weakened after 2 hours. Treatment with AG490 or RPM could inhibit activation of STAT3 at 0 5 hour in the liver and lung. Meanwhile, IFN ? mRNA expression markedly declined at 2 hours after treatment with AG490 or RPM in the liver and RPM in the lung ( P

Objective To investigate the effects of inhibition of nuclear factor-kappa B (NF-?B) by pyrrolidine dithiocarbamate (PDTC) on tissue pro- and anti-inflammatory cytokine expression in rats with postburn Staphylococcus aureus sepsis and its potential regulating mechanism. Methods Thirty-four male Wistar rats were randomly divided into normal control group (n=6), scald control group (n=6), postburn sepsis group (n=12),and PDTC treatment group (n=10). Tissue samples from the liver, kidneys and lungs were collected to determine tumor necrosis factor-? (TNF-?) and interleukin-10 (IL-10) mRNA expression as well as their protein levels. Results Both TNF-? mRNA and protein expressions in the liver, kidneys and lungs of postburn septic animals were up-regulated rapidly at 0.5-2 hours (P

To investigate changes in Toll-like receptor 2 (TLR2) gene expression in postburn Staphylococcus aureus infection, and its potential signaling mechanism, 68 male Wistar rats were randomly divided into four groups as follows: normal control group (n=6), scald control group (n=6), postburn sepsis group (n=36),AG126 treatment group (n=10) and pyrrolidine dithiocarbamate (PDTC) treatment group (n=10). Tissue samples from the liver, kidney and lung were collected from every group to determine TLR2 and tumor necrosis factor-? (TNF-?) mRNA expression. The results showed that TLR2 mRNA expressions in the liver, kidney and lung from postburn septic animals were up-regulated rapidly, peaking at 0.5-2 hours (P