Despite significant advances in intensive care therapy and antibiotics, severe sepsis accounts for 9% of all deaths in the United States annually. The pathological sequelae of sepsis are characterized by a systemic inflammatory response, but experimental therapeutics that target specific early inflammatory mediators [tumor necrosis factor (TNF) and IL-1β] have not proven efficacious in the clinic. We recently identified high mobility group box 1 (HMGB1) as a late mediator of endotoxin-induced lethality that exhibits significantly delayed kinetics relative to TNF and IL-1β. Here, we report that serum HMGB1 levels are increased significantly in a standardized model of murine sepsis, beginning 18 h after surgical induction of peritonitis. Specific inhibition of HMGB1 activity [with either anti-HMGB1 antibody (600 μg per mouse) or the DNA-binding A box (600 μg per mouse)] beginning as late as 24 h after surgical induction of peritonitis significantly increased survival (nonimmune IgG-treated controls = 28% vs. anti-HMGB1 antibody group = 72%, P < 0.03; GST control protein = 28% vs. A box = 68%, P < 0.03). Animals treated with either HMGB1 antagonist were protected against the development of organ injury, as evidenced by improved levels of serum creatinine and blood urea nitrogen. These observations demonstrate that specific inhibition of endogenous HMGB1 therapeutically reverses lethality of established sepsis indicating that HMGB1 inhibitors can be administered in a clinically relevant time frame.

The purposes of this study were to establish normative data for airway size and shape and to evaluate differences associated with age and sex using 3-dimensional (3-D) imaging. Patients being evaluated by computed tomography (CT) for pathologic conditions not related to the airway were included. Using 3-D Slicer (Harvard Surgical Planning Laboratory, Brigham and Women's Hospital, Boston, MA), a software program, digital 3-D CT reconstructions were made and parameters of airway size analyzed: volume (VOL), surface area (SA), length (L), mean cross-sectional area (mean CSA), minimum retropalatal (RP), minimum retroglossal (RG), minimum cross-sectional area (min CSA), and lateral (LAT) and anteroposterior (AP) retroglossal airway dimensions. Evaluation of airway shape included LAT/AP and RP/RG ratios, uniformity (U), and sphericity, a measure of compactness (Ψ). Children were stratified by stage of dentition: primary, 0 to 5 years; mixed, 6 to 11 years; permanent, 12 to 16 years; and adults, older than 16 years. Differences in airway parameters by age and sex were analyzed. Forty-six CT scans (31 males) were evaluated. Adults had larger (VOL, SA, L, mean CSA, and LAT), more elliptical (increased LAT/AP, P = 0.01), less uniform (U, P = 0.02), and less compact (decreased Ψ, P = 0.001) airways than children. Among children, those in the permanent dentition demonstrated greater VOL (P < 0.01), SA (P < 0.01), L (P < 0.01), and mean CSA (P < 0.01) than those in the primary dentition. There were no gender differences in airway parameters. Understanding differences in 3-D airway size and morphology by age may serve as a basis for evaluation of patients with obstructive sleep apnea and may help to predict and to evaluate outcomes of treatment.