thymosin-beta(4) 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

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

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