Methicillin-resistant Staphylococcus Aureus and Vancomycin-resistant Enterococci: Prevalence and Predictors of Colonization in Patients Presenting to the Emergency Department from Nursing Homes

Journal of the American Geriatrics Society. Aug, 2002  |  Pubmed ID: 12165014

IFN-gamma Induces High Mobility Group Box 1 Protein Release Partly Through a TNF-dependent Mechanism

Journal of Immunology (Baltimore, Md. : 1950). Apr, 2003  |  Pubmed ID: 12646658

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 1beta, and IL-6 each failed to significantly induce the release of HMGB1 even at supraphysiological levels (up to 200 ng/ml). IFN-gamma, 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-1alpha, IL-1beta, or IL-6. Pharmacological suppression of TNF activity with neutralizing Abs, or genetic disruption of TNF expression (TNF knockout) partially (50-60%) inhibited IFN-gamma-mediated HMGB1 release. AG490, a specific inhibitor for Janus kinase 2 of the IFN-gamma signaling pathway, dose-dependently attenuated IFN-gamma-induced HMGB1 release. These data suggest that IFN-gamma plays an important role in the regulation of HMGB1 release through a TNF- and Janus kinase 2-dependent mechanism.

Extracellular HMGB1 As a Proinflammatory Cytokine

Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research. Jun, 2004  |  Pubmed ID: 15212706

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.

Bench to Bedside: HMGB1-a Novel Proinflammatory Cytokine and Potential Therapeutic Target for Septic Patients in the Emergency Department

Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. Aug, 2004  |  Pubmed ID: 15289194

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.

Pathogenic Role of HMGB1 in SARS?

Medical Hypotheses. 2004  |  Pubmed ID: 15325019

High mobility group box 1 protein (HMGB1) is released by necrotic cells or activated macrophages/monocytes, and functions as a late mediator of lethal systemic and local pulmonary inflammation. Passive immunization with anti-HMGB1 antibodies confers significant protection against lethal endotoxemia, sepsis, and acute lung injury, even when antibodies are administered after the onset of these diseases. In light of observations that three Chinese herbal formulations recommended for treatment of severe acute respiratory syndrome (SARS) specifically inhibited the release of HMGB1 from innate immune cells, we hypothesize that HMGB1 might occupy a pathogenic role in SARS by mediating an injurious pulmonary inflammatory response.

Bacterial Endotoxin Stimulates Macrophages to Release HMGB1 Partly Through CD14- and TNF-dependent Mechanisms

Journal of Leukocyte Biology. Nov, 2004  |  Pubmed ID: 15331624

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.

Bilateral Nursemaid's Elbow

The American Journal of Emergency Medicine. Oct, 2004  |  Pubmed ID: 15520958

Age-associated Time Delays in the Treatment of Acute Myocardial Infarction with Primary Percutaneous Transluminal Coronary Angioplasty

The American Journal of Emergency Medicine. Jan, 2005  |  Pubmed ID: 15672332

Multiple studies have shown that age is a significant factor associated with suboptimal treatment for acute myocardial infarction (AMI). We performed a retrospective pilot study using a chart review of patients who presented with AMI who were subsequently treated with percutaneous transluminal coronary angioplasty (PTCA) from November 1995 to January 1997 at our institution. Ninety-four patients met inclusion criteria, with 5 excluded for insufficient data. Mean time for "door-to-balloon" in all patients was 118 +/- 48 minutes. The mean patient age was 60 years. Mean times (minutes) for patients grouped by decades of life are as follows: 143 +/- 59 (30-39 years), 114 +/- 51 (40-49 years), 99 +/- 41 (50-59 years), 116 +/- 44 (60-69 years), 135 +/- 47 (70-79 years), and 133 +/- 133 (80 years and older). Statistical analysis was performed using analysis of variance ( P = 0.04). In this study, age was associated with treatment delays. There was a parabolic relationship of age with time, with a greater time delay occurring in "younger" and "older" patients.

Suppression of HMGB1 Release by Stearoyl Lysophosphatidylcholine:an Additional Mechanism for Its Therapeutic Effects in Experimental Sepsis

Journal of Lipid Research. Apr, 2005  |  Pubmed ID: 15687351

Stearoyl lysophosphatidylcholine (LPC) has recently been proven protective against lethal sepsis by stimulating neutrophils to eliminate invading pathogens through an H2O2-dependent mechanism. Here, we demonstrate that stearoyl LPC, but not caproyl LPC, significantly attenuates circulating high-mobility group box 1 (HMGB1) levels in endotoxemia and sepsis by suppressing endotoxin-induced HMGB1 release from macrophages/monocytes. Neutralizing antibodies against G2A, a potential cell surface receptor for LPC, partially abrogated stearoyl LPC-mediated suppression of HMGB1 release. Thus, stearoyl LPC confers protection against lethal experimental sepsis partly by facilitating the elimination of the invading pathogens and partly by inhibiting endotoxin-induced release of a late proinflammatory cytokine, HMGB1.

The Aqueous Extract of a Popular Herbal Nutrient Supplement, Angelica Sinensis, Protects Mice Against Lethal Endotoxemia and Sepsis

The Journal of Nutrition. Feb, 2006  |  Pubmed ID: 16424112

Despite recent advances in antibiotic therapy and intensive care, sepsis remains a widespread problem in critically ill patients. The high mortality from sepsis is in part mediated by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., tumor necrosis factor, interleukin-1, and interferon-gamma) and late [e.g., high mobility group box 1 protein (HMGB1)] proinflammatory cytokines. Our discovery of HMGB1 as a late mediator of lethal systemic inflammation has initiated a new field of investigation for the development of experimental therapeutics. A popular Chinese herb, Angelica sinensis (also known as Dang Gui or Dong Quai) has been used traditionally for treating women with gynecological disorders (such as dysmenorrheal and hot flashes). Here we examined the effect of Angelica sinensis extract on endotoxin-induced HMGB1 release in vitro, and explored its therapeutic potential in animal models of lethal endotoxemia and sepsis [induced by cecal ligation and puncture (CLP)] in vivo. We demonstrated that a low-molecular-weight (<10 kDa) fraction of A. sinensis extract significantly attenuated endotoxin-induced HMGB1 release in part through interfering with its cytoplasmic translocation in macrophage cultures. Prophylactic administration of an aqueous extract of A. sinensis significantly attenuated systemic HMGB1 accumulation in vivo, and conferred a dose-dependent protection against lethal endotoxemia. Furthermore, delayed administration of A. sinensis extract beginning 24 h after CLP attenuated systemic HMGB1 accumulation, and significantly rescued mice from lethal sepsis. Taken together, these data suggest that A. sinensis contains water-soluble components that exert protective effects against lethal endotoxemia and experimental sepsis in part by attenuating systemic accumulation of a late proinflammatory cytokine, HMGB1.

Role of HMGB1 in Cardiovascular Diseases

Current Opinion in Pharmacology. Apr, 2006  |  Pubmed ID: 16487750

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 vascular endothelial cells and 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 the pathogenic role of inflammation in cardiovascular diseases, we propose that HMGB1, a proinflammatory cytokine derived from both injured endothelium and activated macrophages/monocytes, could contribute to the progression of atherosclerosis and other cardiovascular diseases.

Potential Role of High Mobility Group Box 1 in Viral Infectious Diseases

Viral Immunology. 2006  |  Pubmed ID: 16553546

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.

Elevated High-mobility Group Box 1 Levels in Patients with Cerebral and Myocardial Ischemia

Shock (Augusta, Ga.). Jun, 2006  |  Pubmed ID: 16721263

Cerebral and myocardial ischemia, two of the leading causes of morbidity and mortality worldwide, are associated with inflammation that can lead to multiple organ failure and death. High-mobility group box 1(HMGB1), a recently described mediator of lethal systemic inflammation, has been detected in individuals with severe sepsis and hemorrhagic shock, but its role during ischemic injury in humans is unknown. To determine whether systemic HMGB1 levels are elevated after ischemic injury, a prospective observational study was performed in subjects with a diagnosis of either Acute Coronary Syndrome (ACS) or cerebral vascular ischemia (transient ischemic attack or cerebral vascular accident). Subjects (n, 16; age [mean], 67+/-16.3 years) were enrolled in the North Shore-LIJ emergency department within 24 h of symptom onset. Blood samples were collected, and HMGB1 levels analyzed by Western blot analysis using previously described methods (Wang et al. Science. 1999). Control samples were obtained from healthy age- and sex-matched volunteers (n, 16; age [mean], 68+/-15.8 years). Here, we report that serum HMGB1 levels were significantly elevated in both myocardial ischemia subjects (myocardial control serum HMGB1, 1.94+/-2.05 ng/mL, vs. myocardial ischemia serum HMGB1, 159+/-54.3 ng/mL; P<0.001); and in cerebral ischemia subjects (cerebral control serum HMGB1, 16.8+/-10.9 ng/mL, vs. cerebral ischemia serum HMGB1, 218+/-18.8 ng/mL; P<0.001). These results suggest that systemic HMGB1 levels are elevated in human ischemic disease.

A Cardiovascular Drug Rescues Mice from Lethal Sepsis by Selectively Attenuating a Late-acting Proinflammatory Mediator, High Mobility Group Box 1

Journal of Immunology (Baltimore, Md. : 1950). Mar, 2007  |  Pubmed ID: 17339485

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal anti-inflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10-25 microM). However, several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone IIA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis.

HMGB1 As a Potential Therapeutic Target

Novartis Foundation Symposium. 2007  |  Pubmed ID: 17380789

Despite recent advances in antibiotic therapy and intensive care, sepsis remains the most common cause of death in the intensive care units, claiming approximately 225000 victims annually in the USA alone. The pathogenesis of sepsis is attributable, at least in part, to dysregulated systemic inflammatory responses characterized by excessive accumulation of various proinflammatory cytokines. A ubiquitous nuclear protein, high mobility group box 1 (HMGB1), is released by activated macrophages/monocytes, and functions as a late mediator of lethal endotoxaemia and sepsis. First, circulating HMGB1 levels are elevated in a delayed fashion (after 16-32h) in endotoxaemic and septic animals. Second, administration of recombinant HMGB1 to mice recapitulates many clinical signs of sepsis, including fever, derangement of intestinal barrier function, lung injury and lethal multiple organ failure. Third, administration of anti-HMGB1 antibodies or inhibitors (e.g. ethyl pyruvate, nicotine, stearoyl lysophosphatidylcholine and Chinese herbs such as Angelica sinensis) protects mice against lethal endotoxaemia, and rescues mice from lethal experimental sepsis even when the first doses are given 24 hours after onset of sepsis. Taken together, these experimental data establish HMGB1 as a late mediator of lethal endotoxaemia and sepsis with a wider therapeutic window for the clinical management of lethal systemic inflammatory diseases.

Cholinergic Anti-inflammatory Pathway Activity and High Mobility Group Box-1 (HMGB1) Serum Levels in Patients with Rheumatoid Arthritis

Molecular Medicine (Cambridge, Mass.). Mar-Apr, 2007  |  Pubmed ID: 17597834

High Mobility Group Box-1 (HMGB1) is a cytokine implicated in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. The cholinergic anti-inflammatory pathway, a vagus nerve-dependent mechanism, inhibits HMGB1 release in experimental disease models. Here, we examine the relationship between vagus nerve activity and HMGB1 in patients with RA. We compared RR interval variability, an index of cardiac vagal modulation, HMGB1 and hsCRP serum levels, and disease activity scores in thirteen RA patients and eleven age- and sex-matched controls. In RA patients, serum levels of HMGB1 and hsCRP were elevated as compared with controls (HMGB1=71 ng/mL [45-99] vs. 18 ng/mL [0-40], P<0.0001; hsCRP=14.5 mg/L [0.7-59] vs. 1 mg/L [0.4-2.9], P<0.001). RR interval variability in RA patients was significantly decreased as compared with controls (HF=38 msec2 [14-80] vs. 288 msec2 [38-364], P<0.0001; rMSSD=20.9+/-9.79 msec, 52.6+/-35.3 msec, P<0.01). HMGB1 levels and RR interval variability were significantly related (rho=-0.49, P<0.01). HMGB1 serum levels significantly correlated with disease activity scores (DAS-28) in patients with RA (P=0.004). The study design does not enable a determination of causality, but the results are consistent with the hypothesis that decreased cholinergic anti-inflammatory pathway activity is associated with increased HMGB1 levels in patients with RA.

A Major Ingredient of Green Tea Rescues Mice from Lethal Sepsis Partly by Inhibiting HMGB1

PloS One. 2007  |  Pubmed ID: 17987129

The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., HMGB1) pro-inflammatory cytokines. Our recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We previously reported that green tea brewed from the leaves of the plant Camellia sinensis is effective in inhibiting endotoxin-induced HMGB1 release.

Hyperglycemia Aggravates Endotoxin-induced High Mobility Group Box 1 Protein Release: Yet Another Reason Not to Be Too Sweet

Critical Care Medicine. Aug, 2008  |  Pubmed ID: 18664811

Therapeutic Potential of HMGB1-targeting Agents in Sepsis

Expert Reviews in Molecular Medicine. 2008  |  Pubmed ID: 18980707

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 upon recognition of pathogen-associated molecular patterns (PAMPs). The prevailing theories of sepsis as a dysregulated inflammatory response, as manifested by excessive release of inflammatory mediators such as tumour necrosis factor and high-mobility group box 1 protein (HMGB1), are supported by extensive studies employing animal models of sepsis. Here we review emerging evidence that support extracellular HMGB1 as a late mediator of experimental sepsis, and discuss the therapeutic potential of several HMGB1-targeting agents (including neutralising antibodies and steroid-like tanshinones) in experimental sepsis.

Caging a Beast in the Inflammation Arena: Use of Chinese Medicinal Herbs to Inhibit a Late Mediator of Lethal Sepsis, HMGB1

International Journal of Clinical and Experimental Medicine. 2008  |  Pubmed ID: 19079688

Sepsis refers to a systemic inflammatory response syndrome resulting from a microbial infection, which kills > 225,000 people annually in the U.S. alone. The high mortality of sepsis is partly mediated by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF) and late (e.g., HMGB1) pro-inflammatory cytokines. Although early proinflammatory cytokines may be protective against infection, excessive accumulation of late-acting proinflammatory mediators (such as HMGB1) may sustain a potentially injurious inflammatory response. Agents capable of inhibiting HMGB1 activities (e.g., neutralizing antibodies) or release [e.g., Chinese herbs, Danggui (Angelica sinensis), Danshen (Salvia miltiorrhiza) and Green tea (Camellia sinensis)] rescue mice from lethal sepsis even when given 24 hours after onset of the disease. Here we review emerging evidence that support a critical role for extracellular HMGB1 as a late mediator of lethal sepsis, and several commonly used Chinese herbs (Danggui, Danshen and Green tea) as potential HMGB1- targeting therapeutic agents in experimental sepsis.

Novel HMGB1-inhibiting Therapeutic Agents for Experimental Sepsis

Shock (Augusta, Ga.). Oct, 2009  |  Pubmed ID: 19333143

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.

Spermine Protects Mice Against Lethal Sepsis Partly by Attenuating Surrogate Inflammatory Markers

Molecular Medicine (Cambridge, Mass.). Jul-Aug, 2009  |  Pubmed ID: 19593412

The pathogenesis of sepsis is partly attributable to dysregulated inflammatory response mediated by pathogen-associated molecular patterns (PAMPs) (for example, endotoxin) and damage-associated molecular patterns (DAMPs) (for example, high-mobility group box 1 [HMGB1]). An endogenous ubiquitous polyamine, spermine, inhibits endotoxin-induced cytokine release in vitro, but its capacities to attenuate sepsis- and HMGB1-induced inflammatory responses was previously unknown. We thus tested the hypothesis that spermine protects mice against lethal sepsis by attenuating sepsis-induced local and systemic inflammatory responses. Intraperitoneal (i.p.) administration of spermine (10 mg/kg, twice daily, for 3 d) conferred a significant protection against lethal sepsis. The protective effects were associated with a significant reduction in peritoneal and serum levels of several surrogate markers of sepsis (for example, Interleukin-6 [IL-6], keratinocyte-derived chemokine [KC], monocytes chemoattractant protein-1 [MCP-1], macrophage inflammatory protein-2 [MIP-2], tissue inhibitor of metalloproteinase-1 [TIMP-1], soluble tumor necrosis factor-alpha receptor I [sTNFRI], and soluble tumor necrosis factor-alpha receptor II [sTNFRII]) during a late stage of sepsis. In vitro, spermine effectively inhibited HMGB1-induced release of the above surrogate markers in peritoneal macrophages. Thus, spermine confers protection against lethal sepsis partly by attenuating sepsis- and HMGB1-induced inflammatory responses.

High Mobility Group Box 1 Protein As a Potential Drug Target for Infection- and Injury-elicited Inflammation

Inflammation & Allergy Drug Targets. Mar, 2010  |  Pubmed ID: 19906009

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.

Peripheral Administration of Fetuin-A Attenuates Early Cerebral Ischemic Injury in Rats

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism. Mar, 2010  |  Pubmed ID: 19953099

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.

Immediate Cardiac Arrest and Subsequent Development of Cardiogenic Shock Caused by Lightning Strike

The Journal of Trauma. Jan, 2010  |  Pubmed ID: 20065746

A Hepatic Protein, Fetuin-A, Occupies a Protective Role in Lethal Systemic Inflammation

PloS One. 2011  |  Pubmed ID: 21347455

A liver-derived protein, fetuin-A, was first purified from calf fetal serum in 1944, but its potential role in lethal systemic inflammation was previously unknown. This study aims to delineate the molecular mechanisms underlying the regulation of hepatic fetuin-A expression during lethal systemic inflammation (LSI), and investigated whether alterations of fetuin-A levels affect animal survival, and influence systemic accumulation of a late mediator, HMGB1.

EGCG Stimulates Autophagy and Reduces Cytoplasmic HMGB1 Levels in Endotoxin-stimulated Macrophages

Biochemical Pharmacology. May, 2011  |  Pubmed ID: 21371444

Historically, consumption of Green tea (Camellia sinensis) has been associated with health benefits against multiple diseases including cancer, atherosclerosis and cardiovascular disorders. Emerging evidence has suggested a pathogenic role for HMGB1, a newly identified "late" mediator of lethal systemic inflammation, in the aforementioned diseases. Here we demonstrated that a major ingredient of Green tea, EGCG, was internalized into HMGB1-containing LC3-positive cytoplasmic vesicles (likely autophagosomes) in macrophages, and induced HMGB1 aggregation in a time-dependent manner. Furthermore, EGCG stimulated LC3-II production and autophagosome formation, and inhibited LPS-induced HMGB1 up-regulation and extracellular release. The EGCG-mediated HMGB1 inhibitory effects were diminished by inhibition of class III phosphatidylinositol-3 kinase (with 3-methyladenine) or knockdown of an essential autophagy-regulating protein, beclin-1. Moreover, the EGCG-mediated protection against lethal sepsis was partly impaired by co-administration of an autophagy inhibitor, chloroquine. Taken together, the present study has suggested a possibility that EGCG inhibits HMGB1 release by stimulating its autophagic degradation.

Anti-Inflammatory Role of Fetuin-A in Injury and Infection

Current Molecular Medicine. Jan, 2012  |  Pubmed ID: 22292896

Infection and injury are two seemingly unrelated processes that often converge on common innate inflammatory responses mediated by pathogen- or damage-associated molecular patterns (PAMPs or DAMPs). If dysregulated, an excessive inflammation menifested by the overproduction and release of proinflammatory mediators (e.g., TNF, IFN-γ, and HMGB1) may adversely lead to many pathogenic consequences. As a counter-regulatory mechanism, the liver strategically re-prioritizes the synthesis and systemic release of acute phase proteins (APP) including the fetuin-A (also termed alpha-2-HS-glycoprotein for the human homologue). Fetuin-A is divergently regulated by different proinflammatory mediators, and functions as a positive or negative APP in injury and infection. It not only facilitates anti-inflammatory actions of cationic polyamines (e.g., spermine), but also directly inhibits PAMP-induced HMGB1 release by innate immune cells. Peripheral administration of fetuin-A promotes a short-term reduction of cerebral ischemic injury, but confers a long-lasting protection against lethal endotoxemia. Furthermore, delayed administration of fetuin-A rescues mice from lethal sepsis even when the first dose is given 24 hours post the onset of disease. Collectively, these findings have reinforced an essential role for fetuin-A in counter-regulating injury- or infection-elicited inflammatory responses.