thymosin and Sepsis

Sepsis is the dysregulated host response to an infection resulting in life-threatening organ damage. Thymosin Beta 4 is an actin binding protein that inhibits the polymerization of G-actin into F-actin and improves mortality when administered intravenously to septic rats. Thymosin Beta 4 decreases inflammatory mediators, lowers reactive oxygen species, up-regulates anti-oxidative enzymes, anti-inflammatory genes, and anti-apoptotic enzymes making it an interesting protein to study in sepsis.. The authors summarize the current knowledge of actin and Thymosin Beta 4 as it relates to sepsis via a comprehensive literature search.. Sepsis results in measurable levels of F-actin in the circulation as well as a decreased concentration of Thymosin Beta 4. It is speculated that F-actinemia contributes to microcirculatory perturbations present in patients with sepsis by disturbing laminar flow. Given that Thymosin Beta 4 inhibits the polymerization of F-actin, it is possible that Thymosin Beta 4 decreases mortality in sepsis via the regulation of actin as well as its other anti-inflammatory properties and should be further pursued as a clinical trial in humans with sepsis.

Topics: Actins; Animals; Humans; Microcirculation; Oxidation-Reduction; Rats; Reactive Oxygen Species; Sepsis; Thymosin

Prothymosin alpha (proTα) is a ubiquitous polypeptide first isolated by Haritos in 1984, whose role still remains partly elusive. We know that proTα acts both, intracellularly, as an anti-apoptotic and proliferation mediator, and extracellularly, as a biologic response modifier mediating immune responses similarly to molecules termed as "alarmins". Our research team pioneered the elucidation of the mechanisms underlying the observed activities of proTα.. We were the first to demonstrate that proTα levels increase during normal and abnormal cell proliferation. We showed that proTα acts pleiotropically, inducing immunomodulatory effects on immune cell populations. We revealed that the immunoreactive region of proTα is the carboxyterminal decapeptide proTα(100-109) and both molecules stimulate innate immune responses, signaling through Toll-like receptors (TLRs), specifically TLR-4. We reported that proTα and proTα(100-109) bind on the surface of human neutrophils on sites involving TLR-4, and cell activation is complemented by cytoplasmic calcium ion influx. Further, we showed that proTα and proTα(100-109) act as adjuvants upstream of lymphocyte stimulation and, in the presence of antigen, promote the expansion of antigen-reactive effectors. Most recently, we reported that proTα(100-109) may accumulate in experimentally inflamed sites and can serve as a surrogate biomarker in severe bacterial infections, proposing that extracellular release of proTα or proTα(100- 109) alerts the immune system during conditions of danger.. We, therefore, suggest that proTα, and likely proTα(100-109), act as alarmins, being important immune mediators as well as biomarkers, and could eventually become targets for new therapeutic/diagnostic approaches in immune-related diseases like cancer, inflammation, and sepsis.

Topics: Alarmins; Autoimmune Diseases; Humans; Immunity, Innate; Killer Cells, Natural; Neoplasms; Protein Precursors; Sepsis; T-Lymphocytes; Thymosin; Toll-Like Receptors

To assess the effects of urinary trypsin inhibitor (UTI) ulinastatin combined with thymosin alpha1 (Tα1) on sepsis.. The meta-analysis included 8 randomized controlled trials (N=1112 patients) on UTI-based therapy for sepsis published before July 10, 2016. Two investigators independently extracted data and assessed the quality of each study. The short-term mortality rate, duration of mechanical ventilator and vasopressor use, length of intensive care unit stay, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and differences in inflammatory cytokines (interleukin [IL]-6, IL-10, and tumor necrosis factor α) were assessed using statistical software.. Treatment of UTI combined with Tα1 (UTI+Tα1) decreased the short-term mortality rate in septic patients by 36%, 35%, and 31% for 28, 60, 90 days, respectively. UTI+Tα1 decreased the duration of mechanical ventilation, APACHE II score, and levels of IL-6 and tumor necrosis factor α. Treatment of UTI+Tα1 did not reduce the duration of vasopressor use and length of intensive care unit stay, or increase IL-10 levels. Because of the high heterogeneity of the included trials, the results should be carefully assessed.. Treatment of UTI+Tα1 can suppress the production of proinflammatory cytokines, decrease the APACHE II score, shorten the duration of mechanical ventilation, and improve the 28-day survival rate.

Topics: Adult; China; Glycoproteins; Humans; India; Inflammation; Intensive Care Units; Interleukin-10; Interleukin-6; Length of Stay; Middle Aged; Randomized Controlled Trials as Topic; Research Design; Respiration, Artificial; Sepsis; Severity of Illness Index; Software; Survival Rate; Thymalfasin; Thymosin; Treatment Outcome; Tumor Necrosis Factor-alpha

Ulinastatin (UTI) and thymosin α1 (Tα1) have been investigated for their immunoregulatory properties in patients with severe sepsis. However, it is unclear whether immunomodulatory therapy using UTI combined with Tα1 (UCT), UTI alone (UA), or Tα1 alone (TA) improves the disease outcome. The objective of this study was to analyze the effectiveness of UCT, UA, and TA for the treatment of severe sepsis.. PubMed, EMBASE, and Cochrane Library databases were investigated from inception to September 2015. Randomized controlled trials (RCTs) examining the treatment of patients with severe sepsis by UCT, UA, and TA were defined as eligible. Data were analyzed using Review Manager 5.3, and the RCTs were evaluated by the Cochrane Handbook 5.1.0. The quality of the evidence was evaluated according to the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE).. Ten articles and 12 studies were included in this systematic review and meta-analysis. The primary outcome measures indicated that UCT was associated with significantly lower 28-day mortality (risk ratio [RR], 0.67; 95% confidence interval [CI], 0.57-0.80; p < 0.00001; n = 915; GRADE rating, moderate) and 90-day mortality (RR, 0.75; 95% CI, 0.61-0.93; p = 0.009; n = 547; GRADE rating, moderate); UA was associated with no significant difference in the 28-day mortality (RR, 0.60; 95% CI, 0.30-1.20; p = 0.15; n = 182; GRADE rating, low), and there was no report on 90-day mortality; TA was associated with significantly lower 28-day mortality (RR, 0.72; 95% CI, 0.55-0.93; p = 0.01; n = 494; GRADE rating, low), but there was no significant difference in the 90-day mortality (RR, 0.84; 95% CI, 0.54-1.31; p = 0.45; n = 91; GRADE rating, very low). In the secondary outcome measures, there was obvious heterogeneity in the length of the intensive care unit stay and that of the mechanical ventilation, length of the antibiotics and vasopressor use, and 28-day Acute Physiology and Chronic Health Evaluation II (APACHE II) scores.. Treatment of severe sepsis with UCT reduced both the 28-day and the 90-day mortality, whereas treatment with TA reduced only the 28-day mortality. The effects of UCT, UA, and TA on intensive care unit stay, mechanical ventilation, antibiotics and vasopressor use, and 28-day APACHE II scores of septic patients are still unclear. Additional high-quality RCTs are needed to define clearly the guidelines for the treatment of severe sepsis.. Systematic review, level IV.

Topics: Adjuvants, Immunologic; Drug Therapy, Combination; Glycoproteins; Humans; Sepsis; Thymalfasin; Thymosin; Trypsin Inhibitors

Objective. To systematically review the efficacy and potential immunomodulatory effect of ulinastatin combined with thymosin α1 (UTI) for sepsis. Design. A systematic review and meta-analysis of randomized controlled trials (RCTs). Data Sources. The following databases: PubMed, Embase, and Cochrane Central were searched to identify related clinical trials. The search terms were "ulinastatin", "thymosin", and "sepsis". Results. Six RCTs, 944 septic patients in total, were included in this meta-analysis. The result shows UTI increased the 28-day survival rate of septic patients, odds ratio (OR) = 2.01, 95% CI [1.53, 2.64]. After the treatment with UTI, the APACHE II score (four studies) dropped 4.72 further, mean = -4.72, 95% CI [-6.54, -2.91] (p < 0.00001). The mean time of ICU stay (four studies) in UTI group decreased 3.03 days further, mean = -3.03 [-6.99, 0.95] (p = 0.14), and mechanical ventilation time (four studies) decreased 2.05 days, mean = -1.81 [-2.96, -0.66] (p = 0.002). With the treatment of UTI, CD4+T cells raised 5.13%, mean = 5.13, 95% CI [2.75, 7.50] (p < 0.0001); there was no significant change in CD8+T cells, mean = -0.74 [-2.93, 1.45] (p = 0.51). Conclusion. According to this meta-analysis, with the treatment of UTI, the short-term survival rate of septic patients was increased and the illness severity was alleviated. ICU stay and mechanical ventilation time were effectively shortened. The beneficial effect of UTI might be due to the potential immunomodulatory effects of these two drugs.

Topics: Adult; Aged; Aged, 80 and over; Causality; Comorbidity; Female; Glycoproteins; Humans; Immunologic Factors; Male; Middle Aged; Prevalence; Randomized Controlled Trials as Topic; Respiration, Artificial; Respiratory Insufficiency; Risk Factors; Sepsis; Survival Rate; Thymalfasin; Thymosin; Treatment Outcome

Thymosin α1 (Tα1) as immunomodulatory treatment is supposed to be beneficial for the sepsis patients by regulating T cell subsets and inflammatory mediators. However, limited by the small sample size and the poor study design, the persuasive power of the single clinical studies is weak. This meta-analysis aimed to investigate the impact of Tα1 on the sepsis patients.. We searched for the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CBM, VIP, CNKI, WANFANG, Igaku Chuo Zasshi (ICHUSHI) and Korean literature databases reporting the effects of Tα1 on outcomes in sepsis patients.. Among 444 related articles, 19 randomized controlled trials (RCTs) met our inclusion criteria. Mortality events were reported in 10 RCTs included 530 patients, and the meta-analysis showed significant decrease in Tα1 group compared with control group (RR 0.59, 95 % CI 0.45 to 0.77, p = 0.0001). The subgroup analysis showed no difference between the two dosages (RR 0.59, 95 % CI 0.43 to 0.81; RR 0.59, 95 % CI 0.35 to 0.98, respectively). In 9 RCTs, with a total of 489 patients, Tα1 administered once per day decrease APACHE II score significantly (SMD -0.80, 95 % CI -1.14 to -0.47, p < 0.0001) while Tα1 twice per day showed no effect (SMD 0.30, 95 % CI-0.10 to 0.70, p = 0.14). However, the length of ICU stay, the incidence of multiple organ failure (MOF) and duration of mechanical ventilation were not significantly affected by Tα1 treatment (SMD -0.52, 95 % CI -1.06 to 0.11, p = 0.06; SMD -0.49, 95 % CI -1.09 to 0.11, p = 0.11; SMD -0.37, 95 % CI -0.90 to 0.17, p = 0.17, respectively). As to the immunological indicators, the level of HLA-DR were increased by Tα1 (SMD 1.23, 95 % CI 0.28 to 2.18, p = 0.01) according to the pooled analysis of 8 studies involving 721 patients. Lymphocyte subsets CD3, CD4 and cytokines IL-6, IL-10 and TNF-α were also beneficially affected by Tα1 treatment.. Tα1 may be beneficial to sepsis patients in reducing mortality and modulating inflammation reactions. However, the quality of evidence supporting the effectiveness is low considering the small sample sizes and inadequate adherence to standardized reporting guidelines for RCTs among the included studies.

Topics: APACHE; Cytokines; Humans; Immunologic Factors; Intensive Care Units; Interleukin-10; Interleukin-6; Length of Stay; Lymphocyte Subsets; Multiple Organ Failure; Randomized Controlled Trials as Topic; Respiration, Artificial; Sepsis; T-Lymphocyte Subsets; Thymalfasin; Thymosin; Treatment Outcome; Tumor Necrosis Factor-alpha

Thymosin alpha1 (Tα1) is considered a promising immunomodulatory drug. However, it is still unclear whether Tα1 should be recommended for the management of sepsis. Here we conducted a systematic review and meta-analysis to assess the efficacy of Tα1 based immunomodulatory therapy on the clinical outcomes of septic patients.. We searched for relevant clinical trials published before Dec. 12, 2014 through electronic databases. All articles about Tα1 based immunomodulatory therapy for sepsis were included regardless of language. Two authors independently selected studies, extracted data and assessed the quality of each included study. We polled the data related to all-cause mortality with Review Manager 5.1.. Twelve controlled trials were evaluated in all. Tα1 based immunomodulatory therapy had a significant trend toward lower all-cause mortality among patients with sepsis (pooled risk ratio 0.68, 95%CI 0.59-0.78, p<0.00001, 12 trials, n=1480).. Tα1 based immunomodulatory therapy was associated with a lower mortality in septic patients. Nevertheless, these findings should be interpreted cautiously because of the poor quality and small number of participants of the included trials. More well-designed worldwide multicenter clinical trials are needed to provide a conclusive guideline for clinical practice.

Topics: Humans; Immunologic Factors; Sepsis; Thymalfasin; Thymosin

Thymosin α 1 (Tα1) is a peptidic biological response modifier, which plays a significant role in activating and regulating various cells of the immune system. For the above-mentioned activities it is expected to exert a clinical benefit in the treatment of diseases where the immune system is altered.. Several clinical trials have been carried out with Tα1 for treatment or prevention of many different infectious diseases such as hepatitis B and C, sepsis and Aspergillosis in bone marrow-transplanted patients. Data available on the use of Tα1 in infectious disease as well as a vaccine enhancer will be reviewed to possibly generate new working hypothesis.. Tα1 has been widely used in thousands of patients. Nevertheless, there are some issues that have not yet been properly addressed (i.e., dose, schedule, combination treatments, end-points to be evaluated in clinical trials). In the most recent clinical trials Tα1 has been used at higher doses than those commonly used in the past showing a direct proportionality between the dose and the effect. The safety profile of Tα1 is excellent and it is virtually devoid of toxicity.

Topics: Amino Acid Sequence; Communicable Diseases; Hepatitis B, Chronic; Hepatitis C, Chronic; History, 20th Century; History, 21st Century; Humans; Molecular Sequence Data; Sepsis; Thymalfasin; Thymosin; Treatment Outcome

This meta-analysis was performed to evaluate the efficacy of ulinastatin (UTI) and thymosin α1 (Tα1) based immunomodulatory strategy in sepsis patients.. A systematic search was made of MEDLINE, Cochrane, ISI Web of Science and SCOPUS databases. Randomized clinical trials on treatment of sepsis with the combination of ulinastatin and Tα1, compared with placebo, were reviewed. Studies were pooled to relative risk (RR) and weighted mean differences (WMD), with 95% confidence interval (CI).. Six trials (enrolling 915 participants) met the inclusion criteria. Compared with placebo, the combination of ulinastatin and Tα1 presented significant effects on 28-day all-cause mortality (RR 0.67; 95% CI 0.57 to 0.80), 90-day all-cause mortality (RR 0.75; 95% CI 0.61 to 0.93), TNF-α (WMD -73.86ng/L; 95% CI -91.00 to -56.73ng/L), IL-6 (WMD -55.04ng/L; 95% CI -61.22 to -48.85ng/L), and duration of mechanical ventilation (WMD -2.26days; 95% CI -2.79 to -1.73days).. Immunomodulatory therapy that combines ulinastatin and Tα1 significantly improves all-cause mortality, inflammatory mediators and duration of mechanical ventilation in subjects with sepsis.

Topics: Glycoproteins; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunologic Factors; Sepsis; Thymalfasin; Thymosin

Despite advances in supportive care of critically ill patients, sepsis remains an important cause of death worldwide. More than 750,000 individuals develop severe sepsis in North America annually, with a mortality rate varying between 35 and 50%. Over recent years, numerous efforts have been committed to understanding the pathophysiology of septic syndrome, as well as attempts to intervene in the inflammatory cascade with the aim of altering the outcome of the syndrome and to improve survival. Not all of these attempts have been successful. Issued guidelines by the International Sepsis Forum have incorporated only the use of corticosteroids, tight glycemic control and the use of recombinant activated protein C as recommendations for the management of the septic patient along with the initial resuscitation and infection-site control measures. These strategies along, with novel attempts of immunomodulation, are thoroughly reviewed in this article.

Topics: Adrenal Cortex Hormones; Anti-Inflammatory Agents; Clinical Trials as Topic; Glycoproteins; Humans; Immunomodulation; Protein C; Recombinant Proteins; Sepsis; Thymosin

To assess the effects of thymosin alpha1 to enhance immunity and on the prognosis of sepsis.. The database from CNKI (1994-2008.10), CBM (1978-2008.10), VIP (1989-2008.10), Wanfang Database (1997-2008.10), PubMed (1966-2008.10), Cochrane Library (Issue 3, 2008), EMBASE(1974-2008.10) and SCI (1974-2008.10) were retrieved using the key words "sepsis OR septicemia OR blood poisoning OR systemic inflammatory response syndrome OR multiple organ failure OR multiple organ dysfunction syndrome" AND "thymosin * OR zadaxin OR thymalfasin". Also related journals were reviewed. Randomized and q-randomized trials of thymosin for sepsis were included. Two investigators were engaged to extract the data independently and evaluate the quality of the included studies with Handbook 4.2.6 recommended standard, and analyzed data with Cochrane Collaboration's RevMan 4.2.10.. Five randomized controlled trials (198 patients) were included. Meta-analysis showed that thymosin alpha1 may raise the level of CD4(+)T lymphocytes [WMD=6.24, 95% confidence interval (CI) 1.12 to 11.36] and the ratio of CD4(+)/CD8(+)(WMD=0.14, 95%CI 0.03 to 0.25, P=0.01), improve the immune state of the patients. Also, thymosin alpha1 therapy decreased the score of acute physiology and chronic health evaluation II (APACHE II), WMD=3.82, 95%CI 2.36 to 5.28 , P<0.001 ) and the mechanical ventilation days (WMD=-4.17, 95%CI-7.00 to -1.34, P=0.004 ). Furthermore, thymosin alpha1 therapy shortened the duration of intensive care unit (ICU) stay (WMD=-4.87, 95%CI -8.17 to -1.60, P=0.004).. The current evidence shows that thymosin alpha1 improves the immuno-suppression and helps recovery of the patient from disease. However not enough evidence is found in decreasing the mortality. Further randomized controlled trials should include the dosage, duration of the treatment and timing of using thymosin alpha1.

Topics: Humans; Prognosis; Randomized Controlled Trials as Topic; Sepsis; Thymalfasin; Thymosin; Treatment Outcome

Topics: CD4 Antigens; CD8 Antigens; Constipation; Delirium; Drug Therapy, Combination; Fibrin Fibrinogen Degradation Products; Glycoproteins; Humans; Oxygen; Sepsis; Thymosin; Treatment Outcome

To study the effect of acupuncture on the immune function of sepsis patients.. Ninety sepsis patients were assigned to the control group, the thymosin a1 group, and the acupuncture treatment group according to random digit table, 30 patients in each group. Patients in the control group were treated according to the guideline of Surviving Sepsis Campaign (SSC). Patients in the control group received routine treatment. Those in the thymosin alpha1 group additionally received subdermal injection of thymosin alpha1 (1.6 mg), once per day for 6 successive days. Needling at related points such as Zusanli (ST36), Yanglingquan (GB34), Neiguan (PC6), Guanyuan (RN4), and so on, was performed in patients of the acupuncture treatment group, once per day for 6 successive days. T cell subgroups (CD3+, CD4+, CD8+, CD4+ /CD8+) and immunoglobulin levels (IgG, IgA, IgM) were detected. The length of ICU hospital stay, hospital readmission rate, and 28-day mortality were compared among the three groups.. After six days of treatment, CD3+, CD4+, CD8+, IgG, IgA, IgM, and CD4+ /CD8+ ratio of three groups were all significantly increased (P < 0.01). Of them, CD3+, CD4+, CD8+, IgG, IgA, and IgM increased more significantly in the thymosin alpha1 group and the acupuncture treatment group (P < 0.01). Compared with the control group, the ICU hospitalization length was significantly shortened, the hospital readmission rate and the 28-day mortality were lower in the thymosin alpha1 group and the acupuncture treatment group (P < 0.05, P < 0.01). There was no statistical difference in each index between the thymosin alpha1 group and the acupuncture treatment group (P > 0.05).. Acupuncture could adjust the immune function of sepsis patients, improve their immunological indicators and prognoses.

Topics: Acupuncture Therapy; CD4-CD8 Ratio; Humans; Length of Stay; Prognosis; Sepsis; T-Lymphocyte Subsets; Thymalfasin; Thymosin

Severe sepsis is associated with a high mortality rate despite implementation of guideline recommendations. Adjunctive treatment may be efficient and require further investigation. In light of the crucial role of immunologic derangement in severe sepsis, thymosin alpha 1 (Tα1) is considered as a promising beneficial immunomodulatory drug. The trial is to evaluate whether Tα1 improves 28-day all-cause mortality rates and immunofunction in patients with severe sepsis.. We performed a multicenter randomized controlled trial in six tertiary, teaching hospitals in China between May 12, 2008 and Dec 22, 2010. Eligible patients admitted in ICU with severe sepsis were randomly allocated by a central randomization center to the control group or Tα1 group (1:1 ratio). The primary outcome was death from any cause and was assessed 28 days after enrollment. Secondary outcomes included dynamic changes of Sequential Organ Failure Assessment (SOFA) and monocyte human leukocyte antigen-DR (mHLA-DR) on day 0, 3, 7 in both groups. All analyses were done on an intention-to-treat basis.. A total of 361 patients were allocated to either the control group (n = 180) or Tα1 (n = 181) group. The mortalities from any cause within 28 days in the Tα1 group and control group were 26.0% and 35.0% respectively with a marginal P value (nonstratified analysis, P = 0.062; log rank, P = 0.049); the relative risk of death in the Tα1 group as compared to the control group was 0.74 (95% CI 0.54 to 1.02). Greater improvement of mHLA-DR was observed in the Tα1 group on day 3 (mean difference in mHLA-DR changes between the two groups was 3.9%, 95% CI 0.2 to 7.6%, P = 0.037) and day 7 (mean difference in mHLA-DR changes between the two groups was 5.8%, 95% CI 1.0 to 10.5%, P = 0.017) than in the control group. No serious drug-related adverse event was recorded.. The use of Tα1 therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis.. ClinicalTrials.gov NCT00711620.

Topics: Adjuvants, Immunologic; Aged; Aged, 80 and over; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Prospective Studies; Sepsis; Single-Blind Method; Survival Rate; Thymalfasin; Thymosin; Treatment Outcome

The aim of this prospective, double-blinded pilot trial study was to evaluate the effects of Thymosin alpha 1 use in the early phase on immunomodulation and clinical outcomes in patients with severe acute pancreatitis (SAP). A total of 24 patients with SAP were randomized to receive either conventional therapy for SAP or immunomodulatory therapy (TA1 group). The patients in the thymosin group were injected with Talpha1 3.2 mg twice per day for 7 days. The serum level of HLA-DR and CD4/CD8 ratio and other immune parameters were measured on admission, the 8th day and the 28th day. There was a low expression of monocyte HLA-DR in both groups on admission, and more rapid alterations in the HLA-DR were found in the TA1 group. The positive rates of blood and abdominal drainage culture were statistically significant during the 28th follow-up period. The duration of ICU stay was shorter after TA1 treatment. Improves cell-induced immunity and reduces infection rate in severe acute pancreatitis patients.

Topics: Adjuvants, Immunologic; Adult; CD4-CD8 Ratio; Double-Blind Method; Female; HLA-DR Antigens; Humans; Immunity, Cellular; Male; Middle Aged; Monocytes; Pancreatitis; Pneumonia; Sepsis; Thymalfasin; Thymosin; Treatment Outcome

To discuss the effect of continuous blood purification (CBP), thymosin alpha1 and combined therapy on cellular immunity in patients with severe sepsis.. Ninety-one patients, age over 18 years, suffering from severe sepsis with Marshall score over 5, admitted to the intensive care unit (ICU) from June, 2004 to October, 2007, were randomly divided into four groups. The patients in control group (24 cases) were treated with classical Surviving Sepsis Campaign (SSC) therapy, those in CBP group (22 cases) were treated with continuous renal replacement therapy (CRRT) or molecular adsorbent recirculating system (MARS) in the first 3 days. The group of thymosin alpha1 (23 cases) were treated with thymosin alpha1, in a dose of 1.6 mg subcutaneous injection per day for 7 days. The patients in the group of combined therapy (22 cases) were treated with CBP and thymosin alpha1. All three treatment groups were treated with classical SSC therapy at the same time. Acute physiology and chronic health evaluation II (APACHE II) score and Marshall score were evaluated. CD14(+) monocyte human leucocyte antigen DR (HLA-DR) levels and the count of T lymphocyte were measured before treatment and 3 days and 7 days after the treatment.. All 91 patients were included in the study. Compared with the control group, the 28-day mechanical ventilation (MV) time, length of ICU stay, 28-day mortality of three treatment groups were decreased. There was statistically significant difference in the length of ICU stay of the CBP group, and also the 28-day MV time, length of ICU stay of the group of combined therapy group (all P<0.05). Compared with the variables before treatment, Marshall scores were decreased significantly and levels of HLA-DR, CD3(+), CD4(+), CD8(+)T lymphocytes were increased significantly after 7-day treatment with thymosin alpha1 group (all P<0.05) . The above indexes and APACHE II scores were changed significantly as early as 3 days after treatment in CBP group and combined therapy group (P<0.05 or P<0.01). Compared with the variables at the same period in the control group, only CD3(+) T lymphocytes were increased significantly after 7-day treatment in thymosin alpha1 group (P<0.05), APACHE II scores and Marshall scores were decreased significantly , levels of HLA-DR and CD3(+), CD4(+), CD8(+) T lymphocytes were increased significantly after 7-day treatment in CBP group (all P<0.05). The above indexes were already changed significantly after 3-day treatment in the combined therapy group (P<0.05 or P<0.01). Compared with thymosin alpha1 group, all the indexes were improved but only level of CD3(+) T lymphocytes after 3-day treatment in the combined therapy group increased significantly (P<0.05).. CBP and thymosin alpha1 could increase cellular immunity in patients with severe sepsis, promote recovery of organ function and improve prognosis. The effect of CBP appears earlier and more pronounced. Combined treatment can be more effective.

Topics: Humans; Immunity, Cellular; Prognosis; Prospective Studies; Sepsis; Thymalfasin; Thymosin

To analyze clinical effect of immuno-modulatory therapy with ulinastatin and thymosin alpha1 on patients with sepsis.. Two hundred and forty-two septic patients admitted to Guangzhou General Hospital of Guangzhou Military Command intensive care unit (ICU) during 2004.10-2008.6 were included, and they were randomly divided into treatment group (128 cases) and control group (114 cases). The patients in control group were given regular conventional treatment according to Surviving Sepsis Campaign (SSC) in 2004, including early fluid resuscitation, antibiotic therapy, mechanical ventilation (MV) and blood purification. The treatment group received conventional treatment plus immuno-modulation therapy including ulinastatin (first 200 kU injection intravenous twice a day for 4 days and 100 kU for another 6 days) and thymosin alpha1 (1.6 mg subcutaneous twice a day for 4 days, followed by 1.6 mg per day subcutaneous for another 6 days). The total treatment course was 10 days. General demographics were observed, and acute physiology and chronic health evaluation II (APACHE II) scores were recorded. Serum interleukin-6 (IL-6), IL-10 levels of peripheral blood were detected by enzyme linked immunosorbent assay (ELISA). Peripheral blood CD14(+) monocyte human leucocyte antigen DR (HLA-DR) expression, and ratio of helper T lymphocyte 1 (Th1) cytokines interferon-gamma (CD4(+)IFN-gammaww(+)), and Th2 cytokines (CD4(+) IL-4(+)) were assessed with flow cytometer. Duration of infection and MV, length of ICU stay, rate of development of multiple organ dysfunction syndrome (MODS) and mortality rate on 28 days were observed as end-point.. Before treatment, there was no difference in all biomarkers between two groups (all P>0.05). After treatment, peripheral blood CD14ww+ monocyte HLA-DR expression and the ratio of CD4(+)IFN-gamma (+)/CD4(+) IL-4(+) increased significantly in the treatment group (both P<0.05), with serum IL-6, IL-10 levels and APACHE II scores all reduced remarkably (all P<0.05). The values showed significant differences compared with those of control group (all P<0.05). The MODS development rate in the treatment group was much lower than that of control group (21% vs. 47%, P<0.05), and the length of use of MV was significantly reduced [(6.08+/-2.46) days vs. (8.23+/-3.47) days, P<0.05]. There was no difference in the infection duration and length of ICU stay (both P>0.05). The mortality rate on 28 days in the treatment group was much lower than that in control group (20% vs. 33%, P<0.05).. The immuno-modulation therapy of ulinastatin and thymosin alpha1 can remarkably improve the duration of MV and the development rate of MODS and mortality rate on 28 days in the patients with sepsis, probably due to its effect in ameliorating the immuno-imbalance state of the patients. However, the duration of infection and length of ICU stay are not effected.

Topics: Adult; Aged; Female; Glycoproteins; HLA-DR Antigens; Humans; Interferon-gamma; Interleukin-10; Interleukin-4; Interleukin-6; Lipopolysaccharide Receptors; Male; Middle Aged; Sepsis; T-Lymphocytes, Helper-Inducer; Thymalfasin; Thymosin

Tradition treatment of sepsis and new therapies, including high dose corticosteroids and non-steroidal anti-inflammatory drugs, have proven unsuccessful in improving survival. This study aimed to evaluate the potential efficacy of immunomodulating therapy using Ulinastatin (UTI) plus Thymosin alpha1 (Talpha1) for improving organ function and reducing mortality in patients with severe sepsis.. A prospective study was carried out with randomized and controlled clinical analysis of 114 patients conforming to the enrollment standard. All patients had severe sepsis and received standard supportive care and antimicrobial therapy. Fifty-nine patients were also administered UTI plus Talpha1 (defined as Group A), 55 patients were given a placebo (defined as Group B). Clinical parameters were determined by evaluation with the Acute Physiology and Chronic Health Evaluation II (APACHE II), multiple organ failure (MOF) and the Glasgow Coma Scores (GCS) on entry and after therapy on the 3rd, 8th, and 28th day. By flow cytometery and ELISA lymphocyte subsets and cytokines were analyzed. Survival analysis was determined by the Kaplan-Meier method at 28, 60, and 90 days.. Based on comparison of the two groups, patients in Group A exhibited a better performance in organ failure scores which was noticeable soon after initiation of treatment. Patients in Group A also demonstrated a better resolution of pre-existing organ failures during the observation period. After initiation of treatment, significant improvements in the CD(4)(+)/CD(8)(+) ratio, a quicker balance between proinflammatory mediators such as tumor necrosis factor alpha, interleukin 6 and anti-inflammatory cytokines including interleukin 4 and interleukin 10 were found. This was followed by cumulative survival increases of 17.3% at 28 days, 28.9% at 60 days, and 31.4% at 90 days in Group A. The reduction in mortality was accompanied by a considerably shorter stay in the ICU and a shorter length of supportive ventilation, antimicrobial and dopamine therapy.. UTI plus Talpha(1) has a beneficial role in the treatment of severe sepsis.

Topics: Adjuvants, Immunologic; Adult; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Female; Glycoproteins; Humans; Interleukin-10; Interleukin-6; Lymphocyte Subsets; Male; Middle Aged; Sepsis; Survival Analysis; Thymalfasin; Thymosin; Treatment Outcome; Trypsin Inhibitors; Tumor Necrosis Factor-alpha

To investigate the immune and inflammation confusion state in severe sepsis and the effects of two way immunomodulation therapy with continuous blood purification (CBP), thymosin alpha1, and combined therapy of CBP and thymosin alpha(1).. 91 Patients with severe sepsis aged > 18, with Marshall score>5. were randomly divided into 4 groups: CBP Group (n = 22) undergoing continuous renal replacement therapy (CRRT) or molecular adsorbents recirculating system (MARS) therapy once a day for 3 days in addition to classical Surviving Sepsis Campaign (SSC) therapy, Thymosin alpha(1) Group (n = 23) undergoing subcutaneous injection of thymosin alpha(1) 1.6 mg once a day for 7 days in addition to SSC therapy, Combined Therapy Group (n = 22) undergoing CBP combined with thymosin alpha(1) treatment in addition to SSC therapy, and SSC Group (treatment control group, n = 24) undergoing SSC therapy only. Peripheral blood samples were collected before treatment, and 3 and 7 days after the beginning of treatment (days 4 and 8) to detect the serum interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha. The levels of CD(14)(+) monocyte human leucocyte antigen (HLA)-DR and T lymphocytes were monitored. The mechanical ventilation time, ICU stay length, and mortality within 28 d and mortality within 90 d were observed. Ten healthy persons were used as healthy control group.. Thirty-four of the 91 patients died within 28 d with a mortality of 77.4% (Death Group) and other 57 patients were put in Survival Group. The levels of serum IL-6, IL-10, and TNFalpha, and IL-6/IL-10 at different time points of both Death and Survival Groups were all significantly higher, and the HLA-DR level, and CD(3)(+), CD(4)(+), and CD(8)(+) T lymphocyte numbers at different time points of both Death and Survival Groups were all significantly lower than those of the healthy controls (P < 0.05 or < 0.01). The levels of serum IL-6, IL-6/IL-10, TNFalpha, HLA-DR, and CD(3)(+), CD(4)(+), and CD(8)(+) T lymphocyte at different time points of Death Group were all significantly higher than those of Survival Group (P < 0.05 or < 0.01). The CD(3)(+) T lymphocyte number on day 8 of Thymosin Group was significantly higher than that of SSC Group (all P < 0.05). The serum IL-6 and TNFalpha and IL-6/IL-10 were decreased, and HLA-DR, and CD(3)(+), CD(4)(+), and CD(8)(+) were increased significantly on day 8 in CBP and Combined Therapy Groups. The level of TNFalpha decreased, and the numbers of CD(3)(+) and CD(4)(+) T lymphocytes increased significantly on day 4 in Combined Therapy Group (P < 0.05 or P < 0.01). Compared with Thymosin Group, almost all the indexes of CBP and Combined Therapy Groups were improved, only the CD(3)(+) T lymphocyte level on day 4 increased and the IL-6/IL-10 ratio on day 8 was decreased significantly in Combined Therapy Group (both P < 0.05). Compared with those of SSC Group, the mechanical ventilation time, length of ICU stay within 28 days, and 28 days mortality and 90 days mortality of the 3 treatment groups were all decreased, and there were statistical differences in the length of ICU stay of CBP Group and in the mechanical ventilation time and length of ICU stay within 28 days of Combined Therapy Group (both P < 0.05).. Systemic inflammatory response and immunodepression exist simultaneously in severe sepsis. Thymosin alpha(1) increases the cellular immunity, and CBP bi-modulates the immune turbulence, reduces the inflammatory mediators, and ameliorates the immune homeostasis. These 2 therapies also improve the clinical prognosis and the combination of both would be more effective.

Topics: Adjuvants, Immunologic; Adult; Aged; Aged, 80 and over; Female; Hemofiltration; Humans; Immunity, Cellular; Inflammation; Male; Middle Aged; Prognosis; Prospective Studies; Sepsis; Thymalfasin; Thymosin

The aim of this study was to evaluate the potential efficacy of therapy with thymosin alpha(1) and ulinastatin for patients with sepsis due to carbapenem-resistant bacteria.. Prospective, randomized, parallel controlled clinical study.. A total of 120 patients received a diagnosis of sepsis caused by infection with carbapenem-resistant bacteria and satisfied the study enrollment criteria. Sixty patients received carbapenems combined with thymosin alpha(1) and ulinastatin (the CTU group), and the other 60 patients were treated with carbapenems and placebo (the CP group). For both groups, flow cytometry was used to enumerate lymphocyte subsets, and ELISA was used to determine cytokine concentrations.. When the 2 groups were compared, the CTU group exhibited a better performance with respect to organ failure scores such as the Acute Physiology and Chronic Health Evaluation II score, the Multiple Organ Failure Score, and the Glasgow Coma Scale. The CTU group also showed significant improvements in CD4(+)CD8(+) count after initiation of treatment. In addition, compared with the CP group, in the CTU group the balance between proinflammatory mediators (such as tumor necrosis factor-alpha, interleukin [IL]-1beta, IL-6, and IL-8) and anti-inflammatory cytokines (including IL-4 and IL-10) was better modulated, and the cumulative survival rate of the CTU group exceeded that of the CP group by 17.8% at day 28, 25.9% at day 60, and 27.4% at day 90.. Immunomodulatory therapy that combines thymosin alpha(1) and ulinastatin appears to improve the survival rate for patients infected with carbapenem-resistant bacteria. The number of patients in this study was relatively small, and although the same number of patients was initially enrolled in each study group, the groups were not the same size at the end of the study. Therefore, a larger clinical trial should be conducted to validate this conclusion.. The trial was registered with the Chinese State Food and Drug Administration (Peking Science and Technology Development Plan, 2002[641]), (registration number 2007Y0211).

Topics: Adult; Aged; Anti-Bacterial Agents; Bacteria; Carbapenems; Cholangitis; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Female; Glycoproteins; Humans; Immunologic Factors; Intestinal Obstruction; Liver Abscess; Male; Middle Aged; Pancreatitis; Peritonitis; Sepsis; Thymalfasin; Thymosin

To evaluate the efficacy of treatment of severe sepsis by combining anti-inflammatory and immune-enhancing agents.. Multiple-center, prospective, randomized, controlled designs. Cases were from surgical or general ICU of 26 university teaching hospitals. Totally, 433 adult patients developing severe sepsis with Marshall score 5-20 were enrolled. Patients received either standard treatment based on SSC direction (as group control), or additional Ulinastatin (urinary trypsin inhibitor) 300 K units per day+thymosin alpha1 (Maipuxin) 1.6 mg per day for 7 days (as treatment group 1, adopted in the first trial), or double dosage of the above agents (as treatment group 2, adopted in the second trial). The outcome of 28 and 90 days, APACHEII and Marshall score, monocyte HLA-DR/CD14+ at several points until 28 days, and the lengths of ICU stay, antibiotics usage and mechanical ventilation were determinated.. In the first trial (91 cases), there was no significant difference in variables between treatment group 1 and control at 28 days. In the second trial (342 cases), the mortality of treatment group 2 decreased from 38.32% to 25.14% (P=0.0088), compared with group control at 28 days, and from 52.10% to 37.14% (P=0.0054) on 90 days. APACHEIIalso decreased from 14.32 to 12.70 (P=0.0384) and monocyte HLA-DR/CD14+ increased from 40.13% to 51.65% (P=0.0092) on 28 days in treatment group 2. Other variables had no significant differences between two groups.. Treatment by the combining anti-inflammatory and immune enhancing agents can significantly improve the outcome of severe sepsis. The efficacy of this therapy seems to be dose dependent on.

Topics: Adjuvants, Immunologic; Adult; Aged; Drug Therapy, Combination; Drugs, Chinese Herbal; Female; Glycoproteins; Humans; Male; Middle Aged; Prospective Studies; Sepsis; Thymalfasin; Thymosin; Treatment Outcome; Trypsin Inhibitors

To study the clinical effect and long-term evaluation of immunomodulation therapy on trauma, severe sepsis and multiple organ dysfunction syndrome (MODS) patients.. Prospective, randomized, blind and controlled clinical analysis of 70 patients conforming to the enrolled standard was carried out. They were divided into two groups at random. One was control group (n=34) with regular therapy, and the treatment group (n=36) with ulinastatin plus thymosin-alpha1 on the base of regular therapy for 1 week. The immunological indexes were determined before and after therapy on the 1 st, 3 rd, 7 th, 14 th and 28 th day, including the changes in lymphocyte count, CD14(+) monocytes human leukocyte antigen (locus) DR (HLA-DR), clinical data and long-term follow-up.. During hospitalization, 20 patients died in the control group and 13 patients died in the treatment group. There was significant difference between two groups (P<0.05). After 7 up to 28 days of therapy, the counts of lymphocyte and CD14(+) monocytes HLA-DR were significantly higher than those in control group (all P<0.05). The duration of using mechanical ventilation and pressor agent in the treatment group were shorter than those in the control group (both P<0.01). The length of stay and the cost in the intensive care unit (ICU) were not significantly increased in the treatment group (both P>0.05). The long-term survival time in the treatment group was much longer than that in the control group (P<0.05).. Immunomodulation therapy can improve the prognosis of trauma, severe sepsis and MODS patients in a period of 28 days of observation, and lymphocyte counts and CD14(+) monocytes HLA-DR were increased significantly, showing that immunosuppression can be ameliorated. Immunomodulation therapy can shorten the time of mechanical ventilation and the use of pressor agent, and it does not increase the length of stay and the cost in ICU, and therefore the cost-effectiveness is high. It also can prolong the long-term survival time. The results show that immunomodulation therapy is one of successful therapeutic strategies in the care of critical illness.

Topics: Adjuvants, Immunologic; Adult; Aged; Female; Follow-Up Studies; Humans; Immunomodulation; Male; Middle Aged; Multiple Organ Failure; Prognosis; Prospective Studies; Protease Inhibitors; Sepsis; Single-Blind Method; Thymosin; Treatment Outcome; Wounds and Injuries

Thymosin alpha 1 (Tα1) is a highly conserved 28 amino-acid peptide naturally occurring in the thymus and plays critical roles in T cell maturity and differentiation. Its synthetic form, thymalfasin, has been approved by various regulatory agencies in the treatment of hepatitis B viral infection and as an enhancer of vaccine response in immune-compromised populations. In China, it has also widely utilized in patients with cancer and severe infections, as well as the emergency use during (Severe Acute Respiratory Syndrome)SARS and COVID-19 pandemic as an immune-regulator. Recent studies showed that Tα1 could significantly improve overall survival (OS) in patients with surgically resectable non-small cell lung cancer (NSCLC) and liver cancers in the adjuvant setting. For patients with locally advanced, unresectable NSCLC, Tα1 could significantly reduce chemoradiation-induced lymphopenia, pneumonia, and trending improvement of OS. Preclinical evidence are emerging to demonstrate that Tα1 may augment efficacy of cancer chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis and enhancing anti-tumor immunity by turning "cold-tumors" to "hot-tumors"; a protective role in reducing colitis caused by immune check-point inhibitors (ICIs). Potential enhancement of ICIs' clinical efficacies has also been indicated. ICIs have transformed ways treating patients with cancer but limitations such as relatively low response rates and certain safety issues remains. Given the roles of Tα1 in regulating cellular immunities and exceptional safety profiles demonstrated in decades clinical uses, we believe that it is plausible to explore implications of Tα1 the immune-oncology setting by combining with ICI-based therapeutic strategies. Background Activities of Tα1. Tα1 is a biological response modifier which activates various cells in the immune system [1-3]. Tα1 is therefore expected to have clinical benefits in disorders where immune responses are impaired or ineffective. These disorders include acute and chronic infections, cancers, and vaccine non-responsiveness. In severe sepsis, for example, sepsis-induced immunosuppression is increasingly recognized as the overriding immune dysfunction in these vulnerable patients [4] and there is now agreement that many patients with severe sepsis survive the first critical hours of the syndrome but eventually die later due to patients' immunosuppression which make the system diff

Topics: Carcinoma, Non-Small-Cell Lung; COVID-19; Humans; Lung Neoplasms; Pandemics; Sepsis; Thymalfasin; Thymosin

Thymosin beta 4 × (Tmsb4x) has been highlighted as an important regulator in immune and inflammation responses. Promoted differentiation of mononuclear cells into dendritic cells (DCs) exert a beneficial effect on septicemia. Herein, we investigated the effects of Tmsb4x on the mononuclear cells to affect immune responses during septicemia.. Initially, we isolated peripheral blood samples from healthy individuals and patients with septicemia for extraction of mononuclear cells, followed by Tmsb4x expression quantification. A cell model was constructed with mononuclear cells through lipopolysaccharide stimulation. The viability and apoptosis were evaluated in response to Tmsb4x silencing or re-expression. Additionally, the proportion of DCs was assessed by determining levels of inflammatory factors as well as by flow cytometric analysis. A mouse septicemia model was developed for in vivo validation.. Cell and animal models demonstrated decreased Tmsb4x expression in the setting of septicemia, which led to increased inflammatory response and reduced proportion of DCs, along with inhibited mononuclear cell viability and promoted apoptosis. However, restoration of Tmsb4x facilitated the differentiation of mononuclear cells into DCs.. To conclude, upregulated Tmsb4x promoted the generation of DCs from mononuclear cells, which contributed to deep understanding of underpinning mechanisms in the development of septicemia.

Topics: Animals; Cell Differentiation; Dendritic Cells; Leukocytes, Mononuclear; Mice; Sepsis; Thymosin

Sepsis is a systemic inflammatory response syndrome, associated with high risk of acute kidney injury (AKI) and in-hospital mortality. Thymosin beta-4 (Tβ4) is an actin-sequestering protein that can prevent inflammation in several tissues. Thus, we studied the role of Tβ4 in sepsis.. The Tβ4 concentrations were prospectively measured in 191 patients within 6 h of the intensive care units (ICU) admission with diagnosis of sepsis. The cohort was divided into Tβ4 concentration tertiles: 1.19-7.11 ng/ml (n = 64), 7.12-11.01 ng/ml (n = 64), and 11.02-28.10 ng/ml (n = 63).. Of 191 patients, 92 patients developed AKI, 24 of whom received continuous renal replacement therapy (CRRT), 29 patients died within 7 days, and 53 patients died within 28 days. Lower Tβ4 stages were correlated with poor prognosis, including AKI(odds ratio [OR], 2.102 per stage lower; 95% confidence interval [CI], 1.448 to 3.050; P < 0.001), CRRT(OR, 2.346 per stage lower; 95% CI, 1.287 to 4.276; P = 0.005), 7-day mortality(OR, 1.755 per stage lower; 95% CI, 1.050 to 2.935; P = 0.032), and 28-day mortality(OR, 1.821 per stage lower; 95% CI, 1.209 to 2.743; P = 0.004). Kaplan-Meier analysis also demonstrated that patients with lower Tβ4 stages had a high risk of AKI and death. In addition, the area under the curve (AUC) of Tβ4 for predicting AKI, CRRT, 7-day mortality, and 28-day mortality were, respectively, 0.702 (95% CI 0.628-0.776), 0.717 (95% CI 0.592-0.842), 0.694 (95% CI 0.579-0.808), and 0.682 (95% CI 0.598-0.767).. Lower Tβ4 stages are associated with higher odds of poor prognosis in ICU patients with sepsis.

Topics: Acute Kidney Injury; Aged; Biomarkers; Female; Hospital Mortality; Humans; Intensive Care Units; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Prospective Studies; Renal Replacement Therapy; Risk Assessment; Risk Factors; Sepsis; Thymosin

Thymosin beta-4 (Tβ4) is an actin-sequestering peptide that plays important roles in regeneration and remodeling of injured tissues. However, its function in a naturally occurring pathogenic bacterial infection model has remained elusive. We adopted Tβ4-overexpressing transgenic (Tg) mice to investigate the role of Tβ4 in acute pulmonary infection and systemic sepsis caused by

Topics: Animals; Cytokines; Disease Models, Animal; Disease Resistance; Ectopic Gene Expression; Host-Pathogen Interactions; Humans; Immunohistochemistry; Immunophenotyping; Legionella pneumophila; Legionnaires' Disease; Ligands; Male; Mice; Mice, Transgenic; Pneumonia, Bacterial; Sepsis; Thymosin; Toll-Like Receptors

Topics: Actins; Adult; Aged; Bacterial Infections; Biomarkers; Emergency Service, Hospital; Female; Hospitalization; Humans; Inflammation; Intensive Care Units; Male; Middle Aged; Noncommunicable Diseases; Organ Dysfunction Scores; Prognosis; Risk Factors; Sepsis; Shock, Septic; Thymosin

Sepsis is a life-threatening condition that requires urgent care. Thus, the identification of specific and sensitive biomarkers for its early diagnosis and management are of clinical importance. The alarmin prothymosin alpha (proTα) and its decapeptide proTα(100-109) are immunostimulatory peptides related to cell death. In this study, we generated bacterial models of sepsis in mice using two Klebsiella pneumoniae strains (L-78 and ATCC 43816) and monitored sepsis progression using proTα(100-109) as a biomarker. Serum concentration of proTα(100-109) gradually increased as sepsis progressed in mice infected with L-78, a strain which, unlike ATCC 43816, was phagocytosed by monocytes/macrophages. Analysis of splenocytes from L-78-infected animals revealed that post-infection spleen monocytes/macrophages were gradually driven to caspase-3-mediated apoptosis. These results were verified in vitro in L-78-infected human monocytes/macrophages. Efficient phagocytosis of L-78 by monocytes stimulated their apoptosis and the concentration of proTα(100-109) in culture supernatants increased. Human macrophages strongly phagocytosed L-78, but resisted cell death. This is the first report suggesting that high levels of proTα(100-109) correlate, both in vitro and in vivo, with increased percentages of cell apoptosis. Moreover, we showed that low levels of proTα(100-109) early post-infection likely correlate with sepsis resolution and thus, the decapeptide could eventually serve as an early surrogate biomarker for predicting bacteria-induced sepsis outcome.

Topics: Animals; Apoptosis; Biomarkers; Disease Models, Animal; Female; Klebsiella Infections; Klebsiella pneumoniae; Macrophages; Mice; Monocytes; Mortality; Phagocytosis; Protein Precursors; Sepsis; Thymosin

The actin polymerization regulator Thymosin β4 (Tβ4) has been shown to be involved in angiogenesis, wound healing, cell survival and anti-inflammatory responses. We have previously shown that Tβ4 is capable of recruiting pericytes, thus stabilizing the endothelial barrier function. Here, we analyzed whether treatment with Tβ4 is able to reduce the pericytes loss in lipopolysaccharides (LPS)-induced sepsis and to improve the hemodynamic function and survival in C57BL/6 mice.. Fourteen days before LPS injection, the mice were injected with an adeno-associated virus carrying the Tβ4 (rAAV.Tβ4) or LacZ gene (rAAV.LacZ). A sepsis-severity score was assessed, and non-invasive hemodynamic and permeability measurements were performed. Heart and muscle samples were analyzed for PECAM-1(+) capillaries and NG2(+)pericytes.. At 36 h, there was a decrease of sepsis severity score in rAAV.Tβ4-treated animals as compared to rAAV.LacZ-treated control. rAAV.Tβ4-treated animals displayed lower perivascular leakage and higher blood pressure compared to control. Of note, the rAAV.Tβ4 group showed a higher pericyte count in heart and peripheral muscle samples. Finally, Tβ4-treatment reduced mortality compared to control.. The data indicate a preventive role of Tβ4 in septic hypercirculation and highlight Tβ4 as a potential therapeutic target in severe sepsis.

Topics: Animals; Capillary Permeability; Cell Survival; Dependovirus; Genetic Therapy; HEK293 Cells; Hemodynamics; Humans; Mice; Mice, Inbred C57BL; Microcirculation; Pericytes; Sepsis; Thymosin; Transfection; Wound Healing

Recent understanding of the complex pathophysiology of melanoma and severe sepsis suggests that immune-modulating compounds such as thymosin alpha 1 (INN: thymalfasin; abbreviated Ta1) could be useful in the treatment of these two unrelated immune-suppressing indications.. Three nonclinical murine models were utilized, including: i) a lung metastasis B16 model; ii) a B16-based tumor growth model; and iii) a cecal-ligation and puncture (CLP) sepsis model.. In the lung metastasis model, Ta1 treatment alone led to a 32% decrease in metastases (p < 0.05). Additionally, combinations of Ta1 and an anti-PD-1 antibody led to significantly fewer metastases than vehicle. In the tumor growth model, significant decreases in tumor growth were seen: 34% (p = 0.015) to 46% (p = 0.001) depending on the Ta1 dose. In the CLP sepsis model, Ta1 treatment showed a positive trend towards increased survival and decreased bacterial load. In this CLP model, Ta1 also appeared to have an effect on the levels of some biomarkers.. All three models demonstrated a benefit after treatment with Ta1, with no evidence of toxicity. These initial pilot studies support the hypothesis that immune-suppressive indications, including sepsis and melanoma, may be treated with Ta1 alone or by Ta1 in combination with other immunotherapies.

Topics: Adjuvants, Immunologic; Animals; Antineoplastic Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Immunosuppressive Agents; Lung Neoplasms; Melanoma, Experimental; Mice; Sepsis; Skin Neoplasms; Thymalfasin; Thymosin

To explore the role of human immunoglobulin (Ig) and thymosin α1 therapy for severe sepsis through comparison between bundles combined with human immunoglobulin (Ig) and thymosin α1 therapy group (A group) and bundles group (B group).. A total of 526 subjects with severe sepsis in the ICU were divided into two groups: bundles combined with human immunoglobulin (Ig) and thymosin α1 therapy (A group) and bundles (B group). The two groups were then divided into two subgroups: one group had a history of underlying disease (A1 group and B1 group) and the other did not (A2 group and B2 group). Data on demographics, underlying diseases, infection site, organ involvement, duration of artificial ventilation, APACHE II and SOFA scores on day-1 and day-14 after ICU admission, and duration of ICU stay, were recorded. The study lasted 28 days. A total of 526 subjects with severe sepsis in the intensive care unit (ICU) of Beijing Chaoyang Hospital (affiliated with Capital Medical University; Beijing, China) from January 2008 to December 2011 were selected. Bundles combined with human immunoglobulin (Ig) and thymosin α1 therapy was administrated to 221 patients. 305 patients were treated with bundles.. Compared with the B group, the number of days of artificial ventilation was decreased (p < 0.005) and ICU stay shortened (p < 0.001) in the A group. After 14 days of treatment, APACHE II and SOFA scores were decreased (both p < 0.001). Mortality in the A group was decreased by 13.89% (p < 0.005). The survival period in the A group was longer than that of the B group (p < 0.001).. Bundles combined with human immunoglobulin (Ig) and thymosin α1 therapy may reduce APACHE II and SOFA scores, shorten the time of artificial ventilation and length of ICU stay, and improve the prognosis of subjects with severe sepsis.

Topics: Adjuvants, Immunologic; Aged; Aged, 80 and over; APACHE; China; Combined Modality Therapy; Drug Therapy, Combination; Female; Hospital Mortality; Humans; Immunoglobulins, Intravenous; Intensive Care Units; Length of Stay; Male; Middle Aged; Organ Dysfunction Scores; Patient Care Bundles; Respiration, Artificial; Retrospective Studies; Sepsis; Severity of Illness Index; Thymalfasin; Thymosin; Time Factors; Treatment Outcome

Immune dysfunction is a major cause of mortality in septic patients. Current evidence indicates an important role for dendritic cells (DCs) in the pathophysiology of immune dysfunction, and these cells are potential targets of immunomodulation therapies. In the present study, our aim was to enhance the resistance of endotoxemic mice to bacterial translocation and secondary infection and to improve the outcome of these infections using a combination therapy consisting of thymosin alpha1 and dexamethasone in a timely manner according to the changes of DCs' number. The effect of treatment with dexamethasone (DXM) and thymosin alpha1 (Tα1) on DCs was investigated by examining their number, MHCII and CD86 expression and their capacity to induce T cell activation. Endotoxemic mice were randomly divided into five treatment groups. The survival rates, the levels of TNF-α and IL-10, the occurrence of bacterial translocation, and the ability to clear secondary infections were determined. Additionally, the behavior of DCs over time was also evaluated. Tα1 induced significant increases in DC numbers in vivo, whereas DXM reduced cell numbers both in vitro and in vivo. However, neither drug induced significant changes in the capacity of DCs to induce T cell activation or their expression of MHCII or CD86. Among the five treatment groups, the mice treated with a combination of DXM and Tα1 had the highest survival rate; this increased survival was associated with a decrease in bacterial translocation to extra-intestinal organs and an enhanced ability to eradicate secondary infections by reversing the change in DC numbers during endotoxemia. Immunomodulatory therapy that combines Tα1 and DXM in a timely manner and was based on changes in DCs enhanced the resistance of endotoxemic mice to bacterial translocation and secondary infections, improving the outcome of the infection.

Topics: Animals; B7-2 Antigen; Bacterial Translocation; Cells, Cultured; Dendritic Cells; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Endotoxemia; Escherichia coli Infections; Female; Histocompatibility Antigens Class II; Immunologic Factors; Inflammation Mediators; Interleukin-10; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Sepsis; T-Lymphocytes; Thymalfasin; Thymosin; Time Factors; Tumor Necrosis Factor-alpha

A recent randomized controlled clinical trial of the immunostimulatory agent thymosin alpha-1 was conducted and showed a trend toward improved survival in patients receiving the drug (P = 0.06). Although this was a relatively small study and the exact mechanism of action of thymosin alpha-1 is not known, the present results further support the evolving concept that, as sepsis persists, a hypoinflammatory and immunosuppressive condition ensues and therapy that augments host immunity may be advantageous. Other immunomodulatory agents including granulocyte-macrophage colony-stimulating factor have shown promise in small trials in sepsis. In addition, there are a number of new immunoadjuvant agents such as IL-7 and anti-programmed cell death-1 that are showing remarkable abilities to enhance host immunity and improve outcomes in a variety of clinical disorders, including cancer and chronic viral infections. Animal studies show that these new immunoadjuvant agents improve survival in several clinically relevant models of sepsis. Given the relative safety of thymosin alpha-1 and these other new immunomodulatory agents as well as the persisting high mortality of sepsis, a strong case can be made for larger well-designed trials using immunoadjuvant therapy in patients who have documented immune suppression. Immunotherapy offers new hope in the treatment of sepsis and may dramatically change the face of the disease.

Topics: Adjuvants, Immunologic; Female; Humans; Male; Sepsis; Thymosin

To evaluate the therapeutic effect of ulinastatin combined with thymosin α1 in the treatment of severe sepsis in rats.. Normal Wistar rats were subject to cecal ligation and puncture (CLP) to establish models of severe sepsis. The rats were then randomized into 4 groups for treatment with saline (control), ulinastatin, thymosin α1, or the combination of the latter two injected through the caudal vein or subcutaneously at 6, 24, 48 and 72 h after modeling. The mortality rate was recorded daily and the rats were executed at 24, 48, 72 and 96 h after CLP to harvest the heart, liver, spleen, lung, kidney and small intestines for pathological examination. The spleen of the rats were taken for detection of apoptosis of the spleen cells.. The mortality rate of the septic rats in the combined treatment group was decreased significantly (P=0.0325). The control group showed the most severe organ damage, which was moderate in single drug treatment group and the mildest in combined treatment group. Obvious spleen cell apoptosis was found in the control group, and was significantly ameliorated in the combined treatment group[(47.4∓10.9)% vs (39.3∓11.4)%, P=0.0000].. Combined treatment with ulinastatin and thymosin α1 can significantly improve the prognosis and ameliorate organ damage and spleen cell apoptosis in rats with sever sepsis.

Topics: Animals; Apoptosis; Drug Therapy, Combination; Glycoproteins; Male; Rats; Rats, Wistar; Sepsis; Spleen; Thymalfasin; Thymosin

Tregs are involved in immune disorder during sepsis; they can lead to a Th2 immune reaction. Their inhibitory effects can help alleviate inflammatory injury, but may also cause secondary immune inhibition. Thymosin-alpha1 is a polypeptide with powerful immunomodulatory activities. Current reports have shown that Thymosin-alpha1 conferred beneficial effects to septic patients. To explore the relationship between Thymosin-alpha1 and Tregs, in this study, we investigated the changing trend in CD4(+)CD25(+)Foxp3(+) T lymphocytes in a CLP septic mouse model. We also investigated the variation of apoptotic rate of CD4(+)CD25(+) T lymphocytes, cytokine variation, and change of model survival rate when Thymosin-alpha1 intervening or not. We observed that the 72-h survival rate was improved, the percentage of CD4(+)CD25(+)Foxp3(+) T lymphocytes decreased and the apoptosis rate of CD4(+)CD25(+) T lymphocytes increased after intervention of Thymosin-alpha1. At same time the expression of pro-inflammation cytokines IL-2, TNF-alpha and anti-inflammatory cytokines IL-10 and TGF-beta were regulated. In conclusion, Thymosin-alpha1 can effectively control the inflammatory response intensity and improve the 72-h survival rate of septic mice. Regulating Tregs may be another important role of Thymosin-alpha1 conditioning the immune reaction in sepsis.

Topics: Animals; Apoptosis; Cytokines; Disease Models, Animal; Forkhead Transcription Factors; Ileum; Immunologic Factors; Mice; Sepsis; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Thymalfasin; Thymosin

To investigate the efficacy of immunotherapy on septic patients with Ulinastatin plus Thymosin-alpha(1).. Seventy postoperative septic patients were divided into two groups at random: the immunotherapy group (n equal to 36) and the conventional therapy group (n=34). Patients in the immunotherapy group received intravenous Ulinastatin of 200 000 U, 3 times per day for 3 days, Ulinastatin of 100 000 U, 3 times per day for 4 days, and subcutaneous injection of Thymosin-alpha(1) of 1.6 mg, twice per day for 3 days, then once per day for 4 days. While conventional therapies such as antibiotics and fluid resuscitation were undertaken in both groups. The expression levels of serum tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), IgG, C3, T lymphocyte subsets, CD14+ monocyte human leukocyte antigen (locus) DR (HLA-DR) and patients'28-day survival rate of the two groups were observed and evaluated.. The survival rate was significantly higher in the immunotherapy group (63.9%; 23/36) compared with the conventional therapy group (41.2%; 14/34). The serum TNF-alpha levels [(1.38+/-0.50) ng/ml in the immunotherapy group vs (1.88+/-0.53) ng/ml in the conventional group, P less than 0.05] and the serum IL-10 levels [(217.52+/-15.71) ng/ml vs (101.53+/-16.57) ng/ml, P less than 0.05] were significantly different between the two groups. The serum IgG levels in the immunotherapy group [(17.65+/-6.81) g/L] were significantly higher than in the conventional group [(11.94+/-5.32) g/L]. There were also significant differences in the expression levels of CD4+ T lymphocyte (35%+/-13% in the immunotherapy group vs 21%+/-7% in the conventional group, P less than 0.05) and CD14+ monocyte HLA-DR (50%+/-5% in the former vs 35%+/-4% in the latter, P less than 0.05).. Immunotherapy with Ulinastatin plus Thymosin-alpha(1) can enhance the inflammatory response, improve the immune homeostasis, and increase the survival rate of septic patients.

Topics: Adult; Aged; Female; Glycoproteins; Humans; Male; Middle Aged; Sepsis; Survival Rate; Thymalfasin; Thymosin

To investigate the effect of Thymosin and growth hormone(GH) on inflammatory response in burn rats or burn rats with sepsis.. Sixty-four SD rats were randomly divided into normal control group (NC, without treatment), sepsis group (S, with injection of LPS), sepsis + Thymosin group (ST, with successive injection of Thymosin and LPS), sepsis + GH group [SGH, with successive injection of recombinant human GH (rhGH) and LPS], burn group, burn + sepsis group (BS, with injection of LPS after burn), burn + sepsis + Thymosin group (BST, with successive injection of Thymosin and LPS after burn), burn + sepsis + GH (BSGH, with successive injection of rhGH and LPS after burn), with 8 rats in each group. Specimens of spleen tissues were harvested to determine HLA-DR in lymphocyte and evaluate inflammatory cell infiltration (score). Specimens of peripheral blood were collected to determine Toll-like receptor 4 (TLR4) level in monocyte and serum level of TNF-alpha, IL-4, IL-6, IL-10.. Compared with those in NC group, serum level of IL-10 in S group decreased obviously, while other indices increased obviously (P < 0.01). The levels of HLA-DR and TLR4 and serum level of TNF-alpha were similar between SGH and ST groups (P > 0.05). Compared with those in SGH group [(2.87 +/- 0.04) score, and IL-6 (0.0083 +/- 0.0018) microg/mg, IL-4 (0.0102 +/- 0.0021) microg/mg, IL-10 (0.0310 +/- 0.0027) microg/mg, respectively], degree of inflammatory cell infiltration (1.50 +/- 0.76) score and serum levels of IL-6, IL-4, IL-10 of rats in ST group decreased obviously (0.0064 +/- 0.0012, 0.0058 +/- 0.0024, 0.0230 +/- 0.0021 microg/mg, respectively, P < 0.01). The levels of HLA-DR, TLR4 and inflammatory cell infiltration degree of spleen in B group were respectively higher than those in NC group and lower than those in BS group. Compared with those in NC group, serum levels of TNF-alpha, IL-6 in B group increased significantly, while IL-4, IL-10 showed an opposite tendency. There was no obvious difference between BST and BSGH groups in serum levels of HLA-DR and IL-6 (P > 0.05). Compared with those in BST group, inflammatory cell infiltration degree in spleen and the levels of TLR, TNF-alpha obviously decreased (P < 0.01), while IL-4 and IL-10 levels increased in BSGH group (P < 0.01).. Inhibitive effects between Thymosin and GH on extensive inflammatory reaction were similar with or without trauma, and GH has better effect as compared with Thymosin when with trauma.

Topics: Animals; Anti-Inflammatory Agents; Burns; Human Growth Hormone; Inflammation; Male; Rats; Rats, Sprague-Dawley; Sepsis; Thymosin

Topics: Adjuvants, Immunologic; Apoptosis; Glycoproteins; Humans; Lymphocytes; Sepsis; Thymalfasin; Thymosin; Trypsin Inhibitors

To investigate the effect of thymosin alpha1 on immunological function and protein metabolism in peritoneal sepsis rats.. We observed the effect of thymosin alpha1 on T cell subclassification, TNFalpha, IL-6, IL-10, albumin, C-reactive protein (CRP) and mortality in cecal ligation and puncture (CLP) induced septic rats.. Concentration of TNFalpha and IL-6 in CLP induced septic rats increased significantly, and concentration of IL-10 decreased significantly compared to control group. Thymosin alpha1 significantly decreased TNFalpha, IL-6, and significantly raised concentration of plasma IL-10, percent of CD(3), CD(4), and CD(4)/CD(8) in septic group. Thymosin alpha1 reduced degressive degree of albumin. Concentration of CRP increased in both septic groups, but was less prominently in thymosin alpha1 treated group. Thymosin alpha1 reduced cumulate 7-day mortality.. Thymosin alpha1 can improve immunological function, inflammation condition and protein metabolism.

Topics: Adjuvants, Immunologic; Animals; C-Reactive Protein; Disease Models, Animal; Interleukin-10; Interleukin-6; Peritonitis; Rats; Rats, Sprague-Dawley; Sepsis; T-Lymphocyte Subsets; Thymalfasin; Thymosin; Tumor Necrosis Factor-alpha

Topics: BCG Vaccine; Bone Marrow Transplantation; Female; Humans; Immunologic Deficiency Syndromes; Infant; Sepsis; Staphylococcal Infections; Thymosin; Thymus Gland; Tuberculosis

In preparation for the use of bovine thymosin, a thymic hormone, as a specific T cell stimulator in immunodepressed patients, we studied its effect on E rosette formation of peripheral lymphocytes from patients with (1) advanced malignancies, (2) extensive burns, and (3) septicemia. E rosette formation in vitro with and without thymosin was evaluated in 52 patients with carcinoma of the breast (25) or lung (27) in relation to adjuvant therapy and/or surgery. The depression of E rosettes in cancer patients was most striking when adjuvant therapy, irradiation, and/or chemotherapy were used; in 20 patients this was elevated by incubation with thymosin. There was a delay in recovery of depressed E rosette levels after radical mastectomies in four patients, recovery being accelerated by thymosin. In ten burn patients (40 to 80 percent of body surface area, second and third degree burns), the depression in E rosette levels occurred in the first week and was most marked in 3 to 4 weeks. In eight patients this was elevated by thymosin in vitro. In four septic patients, all undergoing operation, serial studies suggested that recovery from sepsis was accompanied by spontaneous rise in E rosette levels. This process was accelerated by thymosin in vitro. This study as well as previous experiments with animals suggest that thymosin may influence depressed host resistance favorably by increasing T-cell-mediated immunity.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Burns; Child; Child, Preschool; Female; Humans; Immune Adherence Reaction; Immunologic Deficiency Syndromes; In Vitro Techniques; Lung Neoplasms; Male; Middle Aged; Sepsis; T-Lymphocytes; Thymosin; Thymus Extracts