Elevated High Mobility Group Box 1 Research Articles

High Mobility Group Box 1 Induces a Negative Inotropic Effect on the Left Ventricle in an Isolated Rat Heart Model of Septic Shock A Pilot Study

Sepsis can be exacerbated by an inappropriate immune response and the severe impact of this disease on the cardiovascular system is well documented. High mobility group box 1 (HMGB1) protein is an important mediator in the pathogenesis of sepsis and its role in cardiovascular system dysfunction was investigated in an lipopolysaccharide (LPS)-induced rat model of sepsis. Twelve hours after intravenous bolus injections of LPS (5 mg/kg), rats were killed and heart samples were harvested. Immunoblot analysis was performed to assess expression levels of HMGB1 in cardiac myocytes. Left ventricular developed pressure (LVDP) served as a measure of systolic function. LPS administration was associated with an increase in the expression of HMGB1 in cardiac myocytes and a decrease in cardiac function. Hearts from the LPS-treated rats were also perfused with recombinant HMGB1 and cardiac function measured. The dose-dependent effects observed with elevated HMGB1 included decreased LVDP, decreased left ventricular (LV) + dP/dt(max), decreased absolute value of LV- dP/dt(min), and increased LV end-diastolic pressure. HMGB1 stimulation produces a negative inotropic effect during septic shock, suggesting an important role for this molecule in cardiovascular system dysfunction during sepsis.

Systemic and local high mobility group box 1 concentrations during severe infection

Objective: High mobility group box 1 (HMGB1) has been implicated as a late mediator in sepsis. We here sought to determine the extent of HMGB1 release in patients with sepsis stratified to the three most common infectious sources and to determine HMGB1 concentrations at the site of infection during peritonitis or pneumonia. Design: Observational studies in patients and healthy humans challenged with lipopolysaccharide. Setting: Three intensive care units and one clinical research unit. Patients and Subjects: Three patient populations were studied: 1) 51 patients with sepsis due to pneumonia (n = 29), peritonitis (n = 12), or urinary tract infection (n = 10); 2) 17 patients with peritonitis; and 3) four patients with community-acquired pneumonia. In addition, eight healthy subjects were studied after intravenous injection of lipopolysaccharide (4 ng/kg). Interventions: One population of healthy volunteers received lipopolysaccharide intravenously. Measurements and Main Results: Patients with severe sepsis due to pneumonia displayed elevated circulating HMGB1 concentrations at both days 0 and 3 after inclusion. Patients with sepsis due to peritonitis had elevated HMGB1 levels at day 0 but not at day 3, whereas urinary tract infection was associated with a delayed HMGB1 response, with elevated levels only at day 3. HMGB1 concentrations did not differ between survivors and nonsurvivors and were not correlated to either disease severity or concurrently measured cytokine levels. In line with these observations, although intravenous lipopolysaccharide injection clearly elevated plasma cytokine levels, HMGB1 remained undetectable. In patients with peritonitis, HMGB1 concentrations in abdominal fluid were more than ten-fold higher than in concurrently obtained plasma. In pneumonia patients, HMGB1 levels were higher in bronchoalveolar lavage fluid obtained from the site of infection than in lavage fluid from healthy controls. Conclusions: In severe sepsis, the kinetics of HMGB1 release may differ depending on the primary source of infection. In patients with severe infection, HMGB1 release may predominantly occur at the site of infection.

Systemic and local high mobility group box 1 concentrations during severe infection

High mobility group box 1 (HMGB1) has been implicated as a late mediator in sepsis. We here sought to determine the extent of HMGB1 release in patients with sepsis stratified to the three most common infectious sources and to determine HMGB1 concentrations at the site of infection during peritonitis or pneumonia. Observational studies in patients and healthy humans challenged with lipopolysaccharide. Three intensive care units and one clinical research unit. Three patient populations were studied: 1) 51 patients with sepsis due to pneumonia (n = 29), peritonitis (n = 12), or urinary tract infection (n = 10); 2) 17 patients with peritonitis; and 3) four patients with community-acquired pneumonia. In addition, eight healthy subjects were studied after intravenous injection of lipopolysaccharide (4 ng/kg). One population of healthy volunteers received lipopolysaccharide intravenously. Patients with severe sepsis due to pneumonia displayed elevated circulating HMGB1 concentrations at both days 0 and 3 after inclusion. Patients with sepsis due to peritonitis had elevated HMGB1 levels at day 0 but not at day 3, whereas urinary tract infection was associated with a delayed HMGB1 response, with elevated levels only at day 3. HMGB1 concentrations did not differ between survivors and nonsurvivors and were not correlated to either disease severity or concurrently measured cytokine levels. In line with these observations, although intravenous lipopolysaccharide injection clearly elevated plasma cytokine levels, HMGB1 remained undetectable. In patients with peritonitis, HMGB1 concentrations in abdominal fluid were more than ten-fold higher than in concurrently obtained plasma. In pneumonia patients, HMGB1 levels were higher in bronchoalveolar lavage fluid obtained from the site of infection than in lavage fluid from healthy controls. In severe sepsis, the kinetics of HMGB1 release may differ depending on the primary source of infection. In patients with severe infection, HMGB1 release may predominantly occur at the site of infection.

Elevation of serum high‐mobility group box 1 protein during granulocyte colony‐stimulating factor‐induced peripheral blood stem cell mobilisation

High mobility group box 1 (HMGB1) is a non-histone protein involved in maintaining the architecture of chromatin. HMGB1 also acts extracellularly as a cytokine, in processes such as inflammation, cell migration and stem cell recruitment. The involvement of HMGB1 in granulocyte colony-stimulating factor (G-CSF)-induced mobilisation of haematopoietic stem cells was investigated in 21 healthy donors. G-CSF treatment significantly elevated serum HMGB1 levels, which increased from 1.16 +/- 0.86 ng/ml, before treatment, to 31.1 +/- 5.99 ng/ml, after treatment. These findings suggest HMGB1 may play a role during the mobilisation of stem cells from the bone marrow into the systemic circulation.