Pub Date : 2006-06-01DOI: 10.1177/09680519060120030501
P. Aspichueta, B. Pérez-Agote, S. Pérez, B. Ochoa, O. Fresnedo
Bacterial infection elicits hypertriglyceridemia attributed to increased hepatic production of very low-density lipoprotein (VLDL) particles and decreased peripheral metabolism. The mechanisms underlying VLDL overproduction in sepsis are as yet unclear, but seem to be fed/fasted state-dependent. To learn more about this, we investigated hepatocytes isolated from fasted rats, made endotoxic by 1 mg/kg lipopolysaccharide (LPS) injection, for their ability to secrete the VLDL protein and lipid components. The results were then related to lipogenesis markers and expression of genes critical to VLDL biogenesis. Endotoxic rats showed increased levels of serum VLDL-apoB (10-fold), -triglyceride (2-fold), and -cholesterol (2-fold), whereby circulating VLDL were lipid-poor particles. Similarly, VLDL-apoB secretion by isolated endotoxic hepatocytes was ~85% above control, whereas marginal changes in the output of VLDL-lipid classes occurred. This was accompanied by a substantial rise in apoB and a moderate rise in MTP mRNA levels, but with basal de novo formation and efficiency of secretion of triglycerides, cholesterol and cholesteryl esters. These results indicate that during periods of food restriction, endotoxin does not enhance lipid provision to accomplish normal lipidation of overproduced apoB molecules, though this does occur to a sufficient extent to pass the proteasome checkpoint and secretion of lipid-poor, type 2 VLDL takes place.
{"title":"Impaired response of VLDL lipid and apoB secretion to endotoxin in the fasted rat liver","authors":"P. Aspichueta, B. Pérez-Agote, S. Pérez, B. Ochoa, O. Fresnedo","doi":"10.1177/09680519060120030501","DOIUrl":"https://doi.org/10.1177/09680519060120030501","url":null,"abstract":"Bacterial infection elicits hypertriglyceridemia attributed to increased hepatic production of very low-density lipoprotein (VLDL) particles and decreased peripheral metabolism. The mechanisms underlying VLDL overproduction in sepsis are as yet unclear, but seem to be fed/fasted state-dependent. To learn more about this, we investigated hepatocytes isolated from fasted rats, made endotoxic by 1 mg/kg lipopolysaccharide (LPS) injection, for their ability to secrete the VLDL protein and lipid components. The results were then related to lipogenesis markers and expression of genes critical to VLDL biogenesis. Endotoxic rats showed increased levels of serum VLDL-apoB (10-fold), -triglyceride (2-fold), and -cholesterol (2-fold), whereby circulating VLDL were lipid-poor particles. Similarly, VLDL-apoB secretion by isolated endotoxic hepatocytes was ~85% above control, whereas marginal changes in the output of VLDL-lipid classes occurred. This was accompanied by a substantial rise in apoB and a moderate rise in MTP mRNA levels, but with basal de novo formation and efficiency of secretion of triglycerides, cholesterol and cholesteryl esters. These results indicate that during periods of food restriction, endotoxin does not enhance lipid provision to accomplish normal lipidation of overproduced apoB molecules, though this does occur to a sufficient extent to pass the proteasome checkpoint and secretion of lipid-poor, type 2 VLDL takes place.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"181 - 191"},"PeriodicalIF":0.0,"publicationDate":"2006-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120030501","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-01DOI: 10.1177/09680519060120030201
A. Medvedev, I. Sabroe, J. Hasday, S. Vogel
Many host cell types, including endothelial and epithelial cells, neutrophils, monocytes, natural killer cells, dendritic cells and macrophages, initiate the first line of defense against infection by sensing conserved microbial structures through Toll-like receptors (TLRs). Recognition of microbial ligands by TLRs induces their oligomerization and triggers intracellular signaling pathways, leading to production of pro- and anti-inflammatory cytokines. Dysregulation of the fine molecular mechanisms that tightly control TLR signaling may lead to hyperactivation of host cells by microbial products and septic shock. A prior exposure to bacterial products such as lipopolysaccharide (LPS) may result in a transient state of refractoriness to subsequent challenge that has been referred to as `tolerance'. Tolerance has been postulated as a protective mechanism limiting excessive inflammation and preventing septic shock. However, tolerance may compromise the host's ability to counteract subsequent bacterial challenge since many septic patients exhibit an increased incidence of recurrent bacterial infection and suppressed monocyte responsiveness to LPS, closely resembling the tolerant phenotype. Thus, by studying mechanisms of microbial tolerance, we may gain insights into how normal regulatory mechanisms are dysregulated, leading ultimately to microbial hyporesponsivess and life-threatening disease. In this review, we present current theories of the molecular mechanisms that underlie induction and maintenance of `microbial tolerance', and discuss the possible relevance of tolerance to several infectious and non-infectious diseases.
{"title":"Invited review: Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease","authors":"A. Medvedev, I. Sabroe, J. Hasday, S. Vogel","doi":"10.1177/09680519060120030201","DOIUrl":"https://doi.org/10.1177/09680519060120030201","url":null,"abstract":"Many host cell types, including endothelial and epithelial cells, neutrophils, monocytes, natural killer cells, dendritic cells and macrophages, initiate the first line of defense against infection by sensing conserved microbial structures through Toll-like receptors (TLRs). Recognition of microbial ligands by TLRs induces their oligomerization and triggers intracellular signaling pathways, leading to production of pro- and anti-inflammatory cytokines. Dysregulation of the fine molecular mechanisms that tightly control TLR signaling may lead to hyperactivation of host cells by microbial products and septic shock. A prior exposure to bacterial products such as lipopolysaccharide (LPS) may result in a transient state of refractoriness to subsequent challenge that has been referred to as `tolerance'. Tolerance has been postulated as a protective mechanism limiting excessive inflammation and preventing septic shock. However, tolerance may compromise the host's ability to counteract subsequent bacterial challenge since many septic patients exhibit an increased incidence of recurrent bacterial infection and suppressed monocyte responsiveness to LPS, closely resembling the tolerant phenotype. Thus, by studying mechanisms of microbial tolerance, we may gain insights into how normal regulatory mechanisms are dysregulated, leading ultimately to microbial hyporesponsivess and life-threatening disease. In this review, we present current theories of the molecular mechanisms that underlie induction and maintenance of `microbial tolerance', and discuss the possible relevance of tolerance to several infectious and non-infectious diseases.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"133 - 150"},"PeriodicalIF":0.0,"publicationDate":"2006-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120030201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208742","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-01DOI: 10.1177/09680519060120030301
J. Cavaillon, D. Annane
Sepsis and systemic inflammatory response syndrome (SIRS) are associated with an exacerbated production of both pro- and anti-inflammatory mediators that are mainly produced within tissues. Although a systemic process, the pathophysiological events differ from organ to organ, and from organ to peripheral blood, leading to the concept of compartmentalization. The nature of the insult (e.g. burn, hemorrhage, trauma, peritonitis), the cellular composition of each compartment (e.g . nature of phagocytes, nature of endothelial cells), and its micro-environment (e.g. local presence of granulocyte-macrophage colony stimulating factor [GM-CSF] in the lungs, low levels of arginine in the liver, release of endotoxin from the gut), and leukocyte recruitment, have a great influence on local inflammation and on tissue injury. High levels of pro-inflammatory mediators (e.g. interleukin-1 [IL-1], tumor necrosis factor [TNF], gamma interferon [IFN-γ], high mobility group protein-1 [HMGB1], macrophage migration inhibitory factor [MIF]) produced locally and released into the blood stream initiate remote organ injury as a consequence of an organ cross-talk. The inflammatory response within the tissues is greatly influenced by the local delivery of neuromediators by the cholinergic and sympathetic neurons. Acetylcholine and epinephrine contribute with IL-10 and other mediators to the anti-inflammatory compensatory response initiated to dampen the inflammatory process. Unfortunately, this regulatory response leads to an altered immune status of leukocytes that can increase the susceptibility to further infection. Again, the nature of the insult, the nature of the leukocytes, the presence of circulating microbial components, and the nature of the triggering agent employed to trigger cells, greatly influence the immune status of the leukocytes that may differ from one compartment to another. While anti-inflammatory mediators predominate within the blood stream to avoid igniting new inflammatory foci, their presence within tissues may not always be sufficient to prevent the initiation of a deleterious inflammatory response in the different compartments.
{"title":"Invited review: Compartmentalization of the inflammatory response in sepsis and SIRS","authors":"J. Cavaillon, D. Annane","doi":"10.1177/09680519060120030301","DOIUrl":"https://doi.org/10.1177/09680519060120030301","url":null,"abstract":"Sepsis and systemic inflammatory response syndrome (SIRS) are associated with an exacerbated production of both pro- and anti-inflammatory mediators that are mainly produced within tissues. Although a systemic process, the pathophysiological events differ from organ to organ, and from organ to peripheral blood, leading to the concept of compartmentalization. The nature of the insult (e.g. burn, hemorrhage, trauma, peritonitis), the cellular composition of each compartment (e.g . nature of phagocytes, nature of endothelial cells), and its micro-environment (e.g. local presence of granulocyte-macrophage colony stimulating factor [GM-CSF] in the lungs, low levels of arginine in the liver, release of endotoxin from the gut), and leukocyte recruitment, have a great influence on local inflammation and on tissue injury. High levels of pro-inflammatory mediators (e.g. interleukin-1 [IL-1], tumor necrosis factor [TNF], gamma interferon [IFN-γ], high mobility group protein-1 [HMGB1], macrophage migration inhibitory factor [MIF]) produced locally and released into the blood stream initiate remote organ injury as a consequence of an organ cross-talk. The inflammatory response within the tissues is greatly influenced by the local delivery of neuromediators by the cholinergic and sympathetic neurons. Acetylcholine and epinephrine contribute with IL-10 and other mediators to the anti-inflammatory compensatory response initiated to dampen the inflammatory process. Unfortunately, this regulatory response leads to an altered immune status of leukocytes that can increase the susceptibility to further infection. Again, the nature of the insult, the nature of the leukocytes, the presence of circulating microbial components, and the nature of the triggering agent employed to trigger cells, greatly influence the immune status of the leukocytes that may differ from one compartment to another. While anti-inflammatory mediators predominate within the blood stream to avoid igniting new inflammatory foci, their presence within tissues may not always be sufficient to prevent the initiation of a deleterious inflammatory response in the different compartments.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"151 - 170"},"PeriodicalIF":0.0,"publicationDate":"2006-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120030301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208753","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-06-01DOI: 10.1177/09680519060120030401
O. Dehus, T. Hartung, C. Hermann
Lipopolysaccharide (LPS), which makes up about 75% of the surface of Gram-negative bacteria, is known to be their major immune stimulatory principle (for review, see Rietschel and Brade1). It is released from the bacterial surface when bacteria multiply, or when they die and lyse, leading to the activation of immune cells as well as epithelial, endothelial or smooth muscle cells.2 The recognition of LPS by host cells is an important step for the induction of inflammatory processes and antibacterial defense mechanisms, but might also lead to multiorgan failure and shock upon excessive systemic LPS exposure.3–5 Chemical characterization and structural analysis of LPSs from numerous enterobacteriaceae have revealed common structural features. The basic structure of LPS consists of a repetitive polysaccharide (O-antigen), which forms the outer part, the core oligosaccharide and the lipid A moiety, which is embedded in the outer membrane.6–8 The O-antigen carbohydrate chain is a polymer of repeating oligosaccharides, which differ between species and determine the serological specificity of bacteria. In contrast, the structure of the lipid A, which consists of a phosphorylated disaccharide backbone, substituted with fatty acid, is highly conserved and exerts the endotoxic activity.9–11 It is recognized by host immune cells via specific pattern recognition receptors, which immediately activate the host cells and stimulate cytokine release and complement activation leading to inflammatory responses.12 The C3H/HeJ mouse has long been known to be hyporesponsive to LPS
{"title":"Endotoxin evaluation of eleven lipopolysaccharides by whole blood assay does not always correlate with Limulus amebocyte lysate assay","authors":"O. Dehus, T. Hartung, C. Hermann","doi":"10.1177/09680519060120030401","DOIUrl":"https://doi.org/10.1177/09680519060120030401","url":null,"abstract":"Lipopolysaccharide (LPS), which makes up about 75% of the surface of Gram-negative bacteria, is known to be their major immune stimulatory principle (for review, see Rietschel and Brade1). It is released from the bacterial surface when bacteria multiply, or when they die and lyse, leading to the activation of immune cells as well as epithelial, endothelial or smooth muscle cells.2 The recognition of LPS by host cells is an important step for the induction of inflammatory processes and antibacterial defense mechanisms, but might also lead to multiorgan failure and shock upon excessive systemic LPS exposure.3–5 Chemical characterization and structural analysis of LPSs from numerous enterobacteriaceae have revealed common structural features. The basic structure of LPS consists of a repetitive polysaccharide (O-antigen), which forms the outer part, the core oligosaccharide and the lipid A moiety, which is embedded in the outer membrane.6–8 The O-antigen carbohydrate chain is a polymer of repeating oligosaccharides, which differ between species and determine the serological specificity of bacteria. In contrast, the structure of the lipid A, which consists of a phosphorylated disaccharide backbone, substituted with fatty acid, is highly conserved and exerts the endotoxic activity.9–11 It is recognized by host immune cells via specific pattern recognition receptors, which immediately activate the host cells and stimulate cytokine release and complement activation leading to inflammatory responses.12 The C3H/HeJ mouse has long been known to be hyporesponsive to LPS","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"13 1","pages":"171 - 180"},"PeriodicalIF":0.0,"publicationDate":"2006-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120030401","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-04-01DOI: 10.1177/09680519060120020101
U. Seydel
We all know that future cannot be planned. Things tend to develop their own momentum. This is true also for my planning of my engagement for the Journal of Endotoxin Research as Editor-inChief. When I agreed to undertake this task (starting in May 2004), I was thinking of a longer lasting engagement beyond my retirement in 2 months (end of April 2006). Now, the burden of this task along with increasing burdens of my main job as scientist and chief of a relatively large research group – in particular in connection with the approaching date of my retirement – caused too much stress, which finally had a severe impact on my health status. Thus, I have to ask for your understanding that for reasons of stress reduction and health improvement I had to decide to resign as Editor-in-Chief.
{"title":"Thank you and good-bye from the former Editor","authors":"U. Seydel","doi":"10.1177/09680519060120020101","DOIUrl":"https://doi.org/10.1177/09680519060120020101","url":null,"abstract":"We all know that future cannot be planned. Things tend to develop their own momentum. This is true also for my planning of my engagement for the Journal of Endotoxin Research as Editor-inChief. When I agreed to undertake this task (starting in May 2004), I was thinking of a longer lasting engagement beyond my retirement in 2 months (end of April 2006). Now, the burden of this task along with increasing burdens of my main job as scientist and chief of a relatively large research group – in particular in connection with the approaching date of my retirement – caused too much stress, which finally had a severe impact on my health status. Thus, I have to ask for your understanding that for reasons of stress reduction and health improvement I had to decide to resign as Editor-in-Chief.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"67 - 67"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120020101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-04-01DOI: 10.1177/09680519060120020601
M. Lipcsey, A. Larsson, M. Eriksson, J. Sjölin
Although porcine intravenous endotoxin shock models are widely employed in experimental sepsis, endotoxin dose-effect studies are scarce. Our primary aim was to establish the dose response to increasing endotoxin doses in inflammatory, coagulatory and haemodynamic effect variables, as well as to determine the optimal time point for assessment in a pig model. A secondary aim was to study pathophysiological covariations between the different responses. Twenty anaesthetised piglets received endotoxin intravenously in doses of 0.063 (n = 3), 0.25 (n = 3), 1.0 ( n = 3), 4.0 (n = 3), 8 (n = 3) and 16 µg/kg/h (n = 2). In addition, non-endotoxin piglets constituted a control group (n = 3). Physiological variables were registered and blood samples analysed for TNF-α, IL-6, leukocyte, platelet and haemoglobin concentrations hourly for 6 h. Increases in the endotoxin dose induced significant log—log cytokine responses as well as log—linear leukocyte and platelet responses. Significant log—linear responses were observed for circulatory parameters, plasma leakage, hypoperfusion and pulmonary compliance. Significant covariations in the responses were noted. In conclusion, there were log—log or log—linear responses to endotoxin suggesting a greater effect of a given dose at lower pre-existing endotoxin concentrations and lower doses of ≤ 1 µg/kg/h may be of advantage in experiments designed to study potential anti-endotoxin effects of experimental drugs or measures.
{"title":"Inflammatory, coagulatory and circulatory responses to logarithmic increases in the endotoxin dose in the anaesthetised pig","authors":"M. Lipcsey, A. Larsson, M. Eriksson, J. Sjölin","doi":"10.1177/09680519060120020601","DOIUrl":"https://doi.org/10.1177/09680519060120020601","url":null,"abstract":"Although porcine intravenous endotoxin shock models are widely employed in experimental sepsis, endotoxin dose-effect studies are scarce. Our primary aim was to establish the dose response to increasing endotoxin doses in inflammatory, coagulatory and haemodynamic effect variables, as well as to determine the optimal time point for assessment in a pig model. A secondary aim was to study pathophysiological covariations between the different responses. Twenty anaesthetised piglets received endotoxin intravenously in doses of 0.063 (n = 3), 0.25 (n = 3), 1.0 ( n = 3), 4.0 (n = 3), 8 (n = 3) and 16 µg/kg/h (n = 2). In addition, non-endotoxin piglets constituted a control group (n = 3). Physiological variables were registered and blood samples analysed for TNF-α, IL-6, leukocyte, platelet and haemoglobin concentrations hourly for 6 h. Increases in the endotoxin dose induced significant log—log cytokine responses as well as log—linear leukocyte and platelet responses. Significant log—linear responses were observed for circulatory parameters, plasma leakage, hypoperfusion and pulmonary compliance. Significant covariations in the responses were noted. In conclusion, there were log—log or log—linear responses to endotoxin suggesting a greater effect of a given dose at lower pre-existing endotoxin concentrations and lower doses of ≤ 1 µg/kg/h may be of advantage in experiments designed to study potential anti-endotoxin effects of experimental drugs or measures.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"112 - 99"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120020601","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-04-01DOI: 10.1177/09680519060120020901
David C. Morrison
to the endotoxin community the death of our colleague, Elizabeth Ziegler, Professor of Medicine Emeritus at the University of California, San Diego School of Medicine. Elizabeth died on January 2, 2006 of complications from diabetes, a disease that posed a continuing challenge to her for many of her adult years. This did not, of course, keep her from being a dedicated teacher, scholar and friend, and the many of us who have had the extraordinary opportunity to interact with this remarkable woman will sorely miss her. Elizabeth was the ultimate optimist, not only in her perspectives of her own life, but also in the goodness of others and in mankind overall. Elizabeth received her Bachelor of Arts degree from Mount Holyoke College and her Doctor of Medicine degree from the John’s Hopkins University School of Medicine where she also served as a resident in internal medicine. She was then recruited to the University of California, San Diego School of Medicine as a research fellow in infectious disease where, under the tutelage of Dr Abraham Braude, she developed her life-long interest in the mechanisms of pathogenesis of septic shock. More particularly, she joined Dr Braude in developing one of the very first therapeutic intervention strategies for the treatment of patients with septic shock. By immunizing volunteer firemen with a Gram-negative vaccine from the galactose-epimerase deficient strain of Escherichia coli (the so-called J-5 mutant), she, Dr Braude and their colleagues developed a heterologous human immune serum that, when administered to patients with septic shock, provided significant protection in comparison to control pre-immune serum. The results of these studies, reported in the New England Journal of Medicine, stimulated great interest in the potential promise of rough, Oantigen-deficient Gram-negative organisms as potential in the antigens in the preparation of vaccines to improve therapeutic outcomes in septic shock. The advent of monoclonal antibodies in the early 1980s further stimulated interest in this field and Drs Ziegler and Braude and their colleagues were among the first to capitalize upon this technology to create monoclonal antibodies against common LPS antigens, and more specifically lipid A and core polysaccharide determinants. Considerable efforts by these investigators and others were directed towards establishing the therapeutic efficacy of one such monoclonal antibody in both experimental animal models of LPS toxicity and experimental infection, and ultimately in a comprehensive placebo-controlled, double-blinded clinical study of patients with sepsis. Although the results of this study appeared, at least in some aspects, to duplicate the results of the earlier polyclonal antibody studies, sufficient methodological questions were raised concerning both the antigenic specificity of the therapeutic monoclonal antibody and its therapeutic efficacy that its acceptance by the overall medical and scientific community wa
我们的同事，加州大学圣地亚哥分校医学院名誉医学教授Elizabeth Ziegler的去世向内毒素界表示哀悼。伊丽莎白于2006年1月2日死于糖尿病并发症，这种疾病在她成年后的许多年里一直困扰着她。当然，这并没有妨碍她成为一位敬业的老师、学者和朋友，我们中许多有机会与这位杰出的女性互动的人都会非常想念她。伊丽莎白是一个极端的乐观主义者，这不仅体现在她对自己生活的看法上，也体现在她对他人和整个人类的善良上。她在Mount Holyoke College获得文学学士学位，在John 's Hopkins University School of Medicine获得医学博士学位，在那里她还担任内科住院医师。随后，她被加州大学圣地亚哥分校医学院招募为传染病研究员，在Abraham Braude博士的指导下，她对感染性休克的发病机制产生了毕生的兴趣。更具体地说，她与Braude博士一起开发了治疗感染性休克患者的首批治疗干预策略之一。她、布劳德博士和他们的同事们用一种革兰氏阴性疫苗对志愿消防员进行免疫，这种疫苗来自于大肠杆菌的半乳糖- epimase缺陷菌株(即所谓的J-5突变株)，他们开发了一种异源人类免疫血清，当给感染性休克患者使用时，与对照免疫前血清相比，这种血清提供了显著的保护作用。这些研究结果发表在《新英格兰医学杂志》(New England Journal of Medicine)上，激发了人们对粗糙的、缺乏抗原的革兰氏阴性菌作为制备疫苗的潜在抗原的极大兴趣，以改善感染性休克的治疗效果。20世纪80年代早期单克隆抗体的出现进一步激发了人们对这一领域的兴趣，Ziegler博士和Braude博士及其同事是第一批利用这项技术制造针对常见LPS抗原的单克隆抗体的人，更具体地说是针对脂质A和核心多糖决定因子的单克隆抗体。这些研究者和其他人的大量努力都是为了在LPS毒性和实验性感染的实验动物模型中建立一种这样的单克隆抗体的治疗效果，并最终在脓毒症患者的全面安慰剂对照双盲临床研究中进行。尽管这项研究的结果似乎，至少在某些方面，重复了早期多克隆抗体研究的结果，但对治疗性单克隆抗体的抗原特异性及其治疗效果提出了足够多的方法学问题，使其被整个医学界和科学界接受不断受到挑战。虽然后来的体外研究，其中一些是由本备忘录的作者进行的，明确地确立了Elizabeth和她的同事所研究的抗体与脂质A结合的能力，但在脓毒症患者中，治疗效果的最终证据从未得到明确证实。顺便说一下，其他通过抗脂质A抗体产生保护性免疫的实验策略，以及免疫介质细胞响应内毒素LPS特异性靶向炎症介质的相关策略也出现了类似的情况。虽然这些多次的失败使包括Elizabeth Ziegler在内的许多研究人员在进一步追求免疫干预治疗败血症的概念方面受到了共同的阻碍，但他们仍然永远地向医学界和公众证明了败血症和休克作为人类疾病的关键重要性，在医学研究人员改善人类健康的努力中不容忽视。
{"title":"Elizabeth Ziegler MD 1942—2006","authors":"David C. Morrison","doi":"10.1177/09680519060120020901","DOIUrl":"https://doi.org/10.1177/09680519060120020901","url":null,"abstract":"to the endotoxin community the death of our colleague, Elizabeth Ziegler, Professor of Medicine Emeritus at the University of California, San Diego School of Medicine. Elizabeth died on January 2, 2006 of complications from diabetes, a disease that posed a continuing challenge to her for many of her adult years. This did not, of course, keep her from being a dedicated teacher, scholar and friend, and the many of us who have had the extraordinary opportunity to interact with this remarkable woman will sorely miss her. Elizabeth was the ultimate optimist, not only in her perspectives of her own life, but also in the goodness of others and in mankind overall. Elizabeth received her Bachelor of Arts degree from Mount Holyoke College and her Doctor of Medicine degree from the John’s Hopkins University School of Medicine where she also served as a resident in internal medicine. She was then recruited to the University of California, San Diego School of Medicine as a research fellow in infectious disease where, under the tutelage of Dr Abraham Braude, she developed her life-long interest in the mechanisms of pathogenesis of septic shock. More particularly, she joined Dr Braude in developing one of the very first therapeutic intervention strategies for the treatment of patients with septic shock. By immunizing volunteer firemen with a Gram-negative vaccine from the galactose-epimerase deficient strain of Escherichia coli (the so-called J-5 mutant), she, Dr Braude and their colleagues developed a heterologous human immune serum that, when administered to patients with septic shock, provided significant protection in comparison to control pre-immune serum. The results of these studies, reported in the New England Journal of Medicine, stimulated great interest in the potential promise of rough, Oantigen-deficient Gram-negative organisms as potential in the antigens in the preparation of vaccines to improve therapeutic outcomes in septic shock. The advent of monoclonal antibodies in the early 1980s further stimulated interest in this field and Drs Ziegler and Braude and their colleagues were among the first to capitalize upon this technology to create monoclonal antibodies against common LPS antigens, and more specifically lipid A and core polysaccharide determinants. Considerable efforts by these investigators and others were directed towards establishing the therapeutic efficacy of one such monoclonal antibody in both experimental animal models of LPS toxicity and experimental infection, and ultimately in a comprehensive placebo-controlled, double-blinded clinical study of patients with sepsis. Although the results of this study appeared, at least in some aspects, to duplicate the results of the earlier polyclonal antibody studies, sufficient methodological questions were raised concerning both the antigenic specificity of the therapeutic monoclonal antibody and its therapeutic efficacy that its acceptance by the overall medical and scientific community wa","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"127 - 128"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120020901","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-04-01DOI: 10.1177/09680519060120020301
S. Traub, S. von Aulock, T. Hartung, C. Hermann
Muropeptides are breakdown products of peptidoglycan (PGN) of Gram-negative and Gram-positive bacteria. They are released during bacterial growth and division, as part of the host response by lysozyme and amidases, or upon antibiotic treatment. After phagocytosis of bacteria or bacterial breakdown products by host immune cells, the muropeptides trigger intracellular signaling cascades, leading to altered gene expression and activation of the immune response. Numerous muropeptides and derivatives have been synthesized chemically to characterize their immunostimulatory effects and adjuvant activity. Muramyl dipeptide, a natural partial structure of PGN, is the minimal structure with adjuvant activity. This review discusses the structure and occurrence of muropeptides and gives a broad overview of their inflammatory and adjuvant activity and the possible involvement of receptors in these responses.
{"title":"Invited review: MDP and other muropeptides — direct and synergistic effects on the immune system","authors":"S. Traub, S. von Aulock, T. Hartung, C. Hermann","doi":"10.1177/09680519060120020301","DOIUrl":"https://doi.org/10.1177/09680519060120020301","url":null,"abstract":"Muropeptides are breakdown products of peptidoglycan (PGN) of Gram-negative and Gram-positive bacteria. They are released during bacterial growth and division, as part of the host response by lysozyme and amidases, or upon antibiotic treatment. After phagocytosis of bacteria or bacterial breakdown products by host immune cells, the muropeptides trigger intracellular signaling cascades, leading to altered gene expression and activation of the immune response. Numerous muropeptides and derivatives have been synthesized chemically to characterize their immunostimulatory effects and adjuvant activity. Muramyl dipeptide, a natural partial structure of PGN, is the minimal structure with adjuvant activity. This review discusses the structure and occurrence of muropeptides and gives a broad overview of their inflammatory and adjuvant activity and the possible involvement of receptors in these responses.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"69 - 85"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120020301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-04-01DOI: 10.1177/09680519060120020401
S. Garekar, S. Heidemann, M. Glibetić
Pretreatment with heat confers cardiopulmonary protection in endotoxemic animals. This mechanism may be through suppression of pro-inflammatory mediator production. The objectives of this study were to determine the effect of heat stress on tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-2 (MIP-2) in a lipopolysaccharide-exposed macrophage cell line and to study the relationship between TNF-α and MIP-2 production. Heat pretreatment resulted in decreased TNF-α transcription and translation by lipopolysaccharide-exposed macrophages; and increased MIP-2 concentration without additional effect in transcription. Administration of TNF-α antibody prior to exposure to lipopolysaccharide resulted in increased MIP-2 concentration suggesting that TNF-α acts to down-regulate MIP-2 production. The mechanism by which heat stress causes an increase in MIP-2 concentration may be secondary to its suppressing effect on TNF-α production.
{"title":"Heat stress response results in increased macrophage inflammatory protein-2 concentration in a lipopolysaccharide-exposed macrophage cell line","authors":"S. Garekar, S. Heidemann, M. Glibetić","doi":"10.1177/09680519060120020401","DOIUrl":"https://doi.org/10.1177/09680519060120020401","url":null,"abstract":"Pretreatment with heat confers cardiopulmonary protection in endotoxemic animals. This mechanism may be through suppression of pro-inflammatory mediator production. The objectives of this study were to determine the effect of heat stress on tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-2 (MIP-2) in a lipopolysaccharide-exposed macrophage cell line and to study the relationship between TNF-α and MIP-2 production. Heat pretreatment resulted in decreased TNF-α transcription and translation by lipopolysaccharide-exposed macrophages; and increased MIP-2 concentration without additional effect in transcription. Administration of TNF-α antibody prior to exposure to lipopolysaccharide resulted in increased MIP-2 concentration suggesting that TNF-α acts to down-regulate MIP-2 production. The mechanism by which heat stress causes an increase in MIP-2 concentration may be secondary to its suppressing effect on TNF-α production.","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"87 - 92"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120020401","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2006-04-01DOI: 10.1177/09680519060120020201
Otto Holst
{"title":"Welcome from the new Editor","authors":"Otto Holst","doi":"10.1177/09680519060120020201","DOIUrl":"https://doi.org/10.1177/09680519060120020201","url":null,"abstract":"","PeriodicalId":80292,"journal":{"name":"Journal of endotoxin research","volume":"12 1","pages":"68 - 68"},"PeriodicalIF":0.0,"publicationDate":"2006-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1177/09680519060120020201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"65208201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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