Targeting HMGB1 in the treatment of sepsis.

INTRODUCTION: Sepsis refers to the host's deleterious and non-resolving systemic inflammatory response to microbial infections and represents the leading cause of death in the intensive care unit. The pathogenesis of sepsis is complex, but partly mediated by a newly identified alarmin molecule, the high mobility group box 1 (HMGB1). AREAS COVERED: Here we review the evidence that support extracellular HMGB1 as a late mediator of experimental sepsis with a wider therapeutic window and discuss the therapeutic potential of HMGB1-neutralizing antibodies and small molecule inhibitors (herbal components) in experimental sepsis. EXPERT OPINION: It will be important to evaluate the efficacy of HMGB1-targeting strategies for the clinical management of human sepsis in the future.

Delphi consensus on the feasibility of translating the ACEP clinical policies into computerized clinical decision support.

Clinical practice guidelines are developed to reduce variations in clinical practice, with the goal of improving health care quality and cost. However, evidence-based practice guidelines face barriers to dissemination, implementation, usability, integration into practice, and use. The American College of Emergency Physicians (ACEP) clinical policies have been shown to be safe and effective and are even cited by other specialties. In spite of the benefits of the ACEP clinical policies, implementation of these clinical practice guidelines into physician practice continues to be a challenge. Translation of the ACEP clinical policies into real-time computerized clinical decision support systems could help address these barriers and improve clinician decision making at the point of care. The investigators convened an emergency medicine informatics expert panel and used a Delphi consensus process to assess the feasibility of translating the current ACEP clinical policies into clinical decision support content. This resulting consensus document will serve to identify limitations to implementation of the existing ACEP Clinical Policies so that future clinical practice guideline development will consider implementation into clinical decision support at all stages of guideline development.

Peripheral administration of fetuin-A attenuates early cerebral ischemic injury in rats.

Cerebral ischemia-elicited inflammatory responses are driven by inflammatory mediators produced both by central (e.g., neurons and microglia) and infiltrating peripheral immune cells (e.g., macrophage/monocyte), and contribute to the evolution of tissue injury. A ubiquitous molecule, spermine, is released from injured cells, and counter-regulates release of various proinflammatory cytokines. However, the spermine-mediated anti-inflammatory activities are dependent on the availability of fetuin-A, a liver-derived negative acute-phase protein. Using an animal model of focal cerebral ischemia (i.e., permanent middle cerebral artery occlusion, MCAo), we found that levels of fetuin-A in the ischemic brain tissue were elevated in a time-dependent manner, starting between 2 and 6 h, peaking around 24 to 48 h, and returning to baseline 72 h after MCAo. When administered peripherally, exogenous fetuin-A gained entry across the BBB into the ischemic brain tissue, and dose dependently reduced brain infarct volume at 24 h after MCAo. Meanwhile, fetuin-A effectively attenuated (i) ischemia-induced HMGB1 depletion from the ischemic core; (ii) activation of centrally (e.g., microglia) and peripherally derived immune cells (e.g., macrophage/monocytes); and (iii) TNF production in ischemic brain tissue. Taken together, these experimental data suggest that fetuin-A protects against early cerebral ischemic injury partly by attenuating the brain inflammatory response.

High mobility group box 1 protein as a potential drug target for infection- and injury-elicited inflammation.

In response to infection or injury, a ubiquitous nucleosomal protein, HMGB1 is secreted actively by innate immune cells, and / or released passively by injured/damaged cells. Subsequently, extracellular HMGB1 alerts, recruits, and activates various innate immune cells to sustain a rigorous inflammatory response. A growing number of HMGB1 inhibitors ranging from neutralizing antibodies, endogenous hormones, to medicinal herb-derived small molecule HMGB1 inhibitors (such as nicotine, glycyrrhizin, tanshinones, and EGCG) are proven protective against lethal infection and ischemic injury. Here we review emerging evidence that support extracellular HMGB1 as a proinflammatory alarmin(g) danger signal, and discuss a wide array of HMGB1 inhibitors as potential therapeutic agents for sepsis and ischemic injury.

Novel HMGB1-inhibiting therapeutic agents for experimental sepsis.

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection. The inflammatory response is partly mediated by innate immune cells (such as macrophages, monocytes, and neutrophils), which not only ingest and eliminate invading pathogens but also initiate an inflammatory response by producing early (e.g., TNF and IFN-gamma) and late (e.g., high-mobility group box [HMGB1]) proinflammatory cytokines. Here, we briefly review emerging evidence that support extracellular HMGB1 as a late mediator of experimental sepsis and discuss therapeutic potential of several HMGB1-inhibiting agents (including neutralizing antibodies and steroid-like tanshinones) in experimental sepsis.

Potential role of high mobility group box 1 in viral infectious diseases.

A nuclear protein, high mobility group box 1 (HMGB1), is released passively by necrotic cells and actively by macrophages/monocytes in response to exogenous and endogenous inflammatory stimuli. After binding to the receptor for advanced glycation end products (RAGE), or Toll-like receptor 4 (TLR4), HMGB1 activates macrophages/monocytes to express proinflammatory cytokines, chemokines, and adhesion molecules. Pharmacological suppression of its activities or release is protective against lethal endotoxemia and sepsis, establishing HMGB1 as a critical mediator of lethal systemic inflammation. In light of observations that many viruses (e.g., West Nile virus, Salmon anemia virus) can induce passive HMGB1 release, we propose a potential pathogenic role of HMGB1 in viral infectious diseases.

Bench to bedside: HMGB1-a novel proinflammatory cytokine and potential therapeutic target for septic patients in the emergency department.

Overwhelming gram-negative bacterial infection and life-threatening systemic inflammation are widespread problems in critically ill emergency department patients. Currently, the treatment of these patients is largely supportive, focusing on antibiotics, fluids, hemodynamic and ventilatory support, and intensive monitoring. The only Food and Drug Administration-approved pharmaceutical agent for the treatment of sepsis is activated protein C, with its use largely relegated to the intensive care unit. The subject thus remains an active area of exploration for emergency medicine research. During sepsis and inflammation, innate immune cells release excessive amounts of proinflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1beta. If delivered early enough, anti-TNF antibodies can be an effective therapy in experimental models of septic shock. Anti-TNF antibodies have been developed for clinical use in rheumatoid arthritis and Crohn's disease. However, anti-TNF treatment for sepsis has been difficult to achieve in the clinical setting, perhaps because TNF's early release and transient appearance in the serum create a narrow therapeutic window. An alternative strategy would be to identify "late" mediators that may be clinically more accessible. High mobility group box 1 (HMGB1), a protein previously known only as a nuclear transcription factor, is now implicated as a late mediator of sepsis. Targeting late mediators of lethal systemic inflammation represents a novel approach that may widen the therapeutic window and lead to new strategies for inhibiting the deleterious effects of the inflammatory cascade. Here the authors review the studies that led to the discovery of HMGB1 as a late mediator of systemic inflammation and discuss the possibility of HMGB1 as a therapeutic target for septic patients in the emergency department.

Extracellular HMGB1 as a proinflammatory cytokine.

High mobility group box-1 protein (HMGB1, formerly known as HMG-1), a highly conserved ubiquitous protein, has been for a long time described as a nuclear DNA-binding protein involved in nucleosome stabilization and gene transcription. Recent discoveries indicate that HMGB1 is released from activated innate immune cells or necrotic cells and functions as an important mediator of endotoxemia, sepsis, arthritis, and local inflammation. Therapeutic agents that inhibit HMGB1 release or action confer significant protection against endotoxemia, sepsis, and arthritis in animal models and thus hold potential for the clinical management of various inflammatory diseases.

A survey of the emergency department population and their interest in preventive health education.

OBJECTIVE: To determine which preventive health information the emergency department (ED) population (patients and visitors) would be most interested in having available to them while they spend time in the waiting area. METHODS: This was a prospective survey of consecutive adults seated in the ED waiting area during a representative week on predetermined shifts. The survey asked them to indicate whether they would be interested in obtaining information about the following preventive health issues: breast cancer, prostate cancer, smoking, obesity, stress reduction, exercise programs, alcohol/drugs, HIV, blood pressure screening, immunizations, referrals to primary care physicians, Pap smears, car safety, smoke detectors, domestic and youth violence, depression, gun safety, and safe sex. RESULTS: Of the 1284 subjects approached, 878 (68%) made up the study group (56% female, mean age = 44 years, 60% white); 406 refused. The information people were most interested in obtaining was the following: 52% of the respondents were interested in referral to stress reduction programs, 51% in information about exercise programs, 42% in blood pressure screening, 40% in information about breast cancer screening, 33% in depression information/screening, 33% in prostate cancer screening, 26% in immunization against pneumococcus, 24% in immunization against tetanus, 26% in smoking cessation programs, and 26% in safe driving information. Women were most interested in breast cancer screening (64%); and men, in prostate cancer screening (55%). CONCLUSIONS: Of the 878 subjects in the study group, 96% were interested in obtaining information about one or more preventive health issues. An opportunity exists to respond to this interest by providing material for public health education in the waiting area of EDs.