Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.
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-1] 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-1. 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 g per mouse) or the DNAbinding A box (600 g 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.
We recently discovered that a ubiquitous protein, high mobility group box 1 protein (HMGB1), is released by activated macrophages, and functions as a late mediator of lethal systemic inflammation. To elucidate mechanisms underlying the regulation of HMGB1 release, we examined the roles of other cytokines in induction of HMGB1 release in macrophage cell cultures. Macrophage migration inhibitory factor, macrophage-inflammatory protein 1β, and IL-6 each failed to significantly induce the release of HMGB1 even at supraphysiological levels (up to 200 ng/ml). IFN-γ, an immunoregulatory cytokine known to mediate the innate immune response, dose-dependently induced the release of HMGB1, TNF, and NO, but not other cytokines such as IL-1α, IL-1β, or IL-6. Pharmacological suppression of TNF activity with neutralizing Abs, or genetic disruption of TNF expression (TNF knockout) partially (50–60%) inhibited IFN-γ-mediated HMGB1 release. AG490, a specific inhibitor for Janus kinase 2 of the IFN-γ signaling pathway, dose-dependently attenuated IFN-γ-induced HMGB1 release. These data suggest that IFN-γ plays an important role in the regulation of HMGB1 release through a TNF- and Janus kinase 2-dependent mechanism.
VNS significantly attenuates TNF synthesis and shock during reperfusion injury in a standard model of aortic occlusion. Clinical evaluation of VNS for this condition may be warranted.
Bacterial endotoxin [lipopolysaccharide (LPS)] stimulates macrophages to sequentially release early [tumor necrosis factor (TNF)] and late [high mobility group box 1 (HMGB1)] proinflammatory cytokines. The requirement of CD14 and mitogen-activated protein kinases [MAPK; e.g., p38 and extracellular signal-regulated kinase (ERK)1/2] for endotoxin-induced TNF production has been demonstrated previously, but little is known about their involvement in endotoxin-mediated HMGB1 release. Here, we demonstrated that genetic disruption of CD14 expression abrogated LPS-induced TNF production but only partially attenuated LPS-induced HMGB1 release in cultures of primary murine peritoneal macrophages. Pharmacological suppression of p38 or ERK1/2 MAPK with specific inhibitors (SB203580, SB202190, U0126, or PD98059) significantly attenuated LPS-induced TNF production but failed to inhibit LPS-induced HMGB1 release. Consistently, an endogenous, immunosuppressive molecule, spermine, failed to inhibit LPS-induced activation of p38 MAPK and yet, still significantly attenuated LPS-mediated HMGB1 release. Direct suppression of TNF activity with neutralizing antibodies or genetic disruption of TNF expression partially attenuated HMGB1 release from macrophages induced by LPS at lower concentrations (e.g., 10 ng/ml). Taken together, these data suggest that LPS stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms.
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 (Psi). 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 Psi, 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.
While counselling patients on what to expect during the recovery process after facial paralysis is an important part of any clinical visit, FaCE score correlations suggest that female patients with chronic facial palsy and increased age constitute a patient category that may require additional time and attention to prevent or mitigate psychosocial dysfunction.
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