Sepsis and septic shock: a history.

Infectious disease has been a leading cause of death in humans since the first recorded tabulations. From Hippocrates and Galen, to Lister, Fleming and Semmelweiss, this article reviews the notable historical figures of sepsis research. The early descriptions and theories about the etiology (microbial pathogens), pathogenesis (toxins and mediators), and treatment of sepsis-associated disease are also discussed.

Methods of endotoxin removal from biological preparations: a review.

PURPOSE: Endotoxins, also called lipopolysaccharides (LPS), are major contaminants found in commercially available proteins or biologically active substances, which often complicate study of the biological effects of the main ingredient. The presence of small amounts of endotoxin in recombinant protein preparations can cause side effects in host organism such as endotoxin shock, tissue injury, and even death. Due to these reactions, it is essential to remove endotoxins from drugs, injectables, and other biological and pharmaceutical products. An overview of this subject is provided by this article. METHODS: An extensive review of literature with regard to methods for removal of endotoxin from biotechnological preparations was carried out. RESULTS: A short history of endotoxin is presented first. This is followed by a review of chemical and physical properties of endotoxin and its pathophysiological effects when the body is exposed to LPS excessively or systemically. The techniques of endotoxin determination and interaction of endotoxin with proteins is also presented, taking into consideration the established techniques as well as the state of the art technology in this field. A review of techniques of endotoxin removal from biotechnological preparations is described, emphasizing how endotoxin removal can be carried out in an economical way based on a number of processes discussed in the literature (e.g., adsorption, two-phase partitioning, ultrafiltration and chromatography). Different methods are mentioned with relatively high protein recoveries; however, special attention is given to two-phase aqueous micellar systems, which are valuable tools for endotoxin removal from pharmaceutical proteins on a small scale because they provide a mild environment for biological materials. CONCLUSIONS: Efficient and cost-effective removal of endotoxins from pharmaceutical and biotechnology preparations is challenging. Despite development of novel methods, such as the two-phase aqueous micellar systems, in recent years, more research is needed in this field.

Panum's studies on "putrid poison" 1856. An early description of endotoxin.

In 1855-1856 the Danish physiologist, Peter Ludvig Panum (1820-1885) performed a series of remarkable experiments on "putrid poison", a hypothetical substance claimed to be responsible for the symptoms and signs seen in patients with sepsis. Dogs were given intravenous infusions of putrefying solutions, and symptoms and signs were recorded. Infusion of a suitable amount resulted in characteristic sepsis symptoms and signs, which only started after a delay of half an hour. By modifying his test solutions Panum could show that the toxic principle was a solid substance, soluble in water, but insoluble in alcohol, and with preserved activity after long-term boiling. "Putrid poison" has striking similarities with endotoxin, a cell wall product of Gram-negative bacteria and a powerful inducer of inflammation and septic shock. Thanks to Panum's carefully arranged experiments and meticulous recording of observations it is fair to conclude that "putrid poison" was endotoxin, and as such he deserves credit for being the first to have described endotoxin. Panum published his observations twice, in Danish in 1856, and in German in 1874. At first he rejected the possibility that bacteria could play a causative role in the development of symptoms and signs seen after infusion of "putrid poison". However, in his last publication he hypothesized that "putrid poison" could be a bacterial product, and he envisaged future antibacterial chemotherapy of sepsis and treatment with anti-endotoxin agents.

Richard Pfeiffer and Alexandre Besredka: creators of the concept of endotoxin and anti-endotoxin.

Richard Pfeiffer, working with Robert Koch in Berlin, intellectually and experimentally conceived the concept of endotoxin as a heat-stable bacterial poison responsible for the pathophysiological consequences of certain infectious diseases. Pfeiffer's definition of endotoxin included the inability to evoke neutralizing antibodies against this bacterial toxin. Alexandre Besredka, Ilya (Elie) Metchnikoff's successor at the Institut Pasteur in Paris, was the first to demonstrate that, in fact, antibodies could be engendered which were capable of suppressing the poisonous effects of endotoxin. Endotoxin and anti-endotoxin antibodies have since then fascinated researchers of many disciplines and continue to do so, particularly in the fields of diagnosis, prevention, and therapy of severe Gram-negative infections.

Innate immune sensing and its roots: the story of endotoxin.

How does the host sense pathogens? Our present concepts grew directly from longstanding efforts to understand infectious disease: how microbes harm the host, what molecules are sensed and, ultimately, the nature of the receptors that the host uses. The discovery of the host sensors--the Toll-like receptors--was rooted in chemical, biological and genetic analyses that centred on a bacterial poison, termed endotoxin.

[Endotoxins in gastroenterology--a medico-historical sketch]. / Endotoxine in der Gastroenterologie--Ein medizinhistorischer Abriss.

First descriptions of effects of intestinal bacterial endotoxins date from the middle of the 19th century (P. L. Panum et al.). The antitoxic function of the liver has been investigated by I. P. Pawlow in 1893. At the turn of the last century the theory of "auto-intoxication" (C. Bouchard, I. I. Metschnikoff et al.) was well known, but there were also first systematic studies of the facultatively pathogenic intestinal bacteria (T. Escherich, H. Tissier, J. Strasburger). In the twenties of our century V. van der Reis and L. Bogendoerfer worked out important fundamentals of human gastrointestinal microecology. Endotoxins as component of cellular wall of gram-negative bacteria are found by A. Boivin et al., J. W. Walker et al. First applicable proof for the detection of endotoxins was the pyrogen test with rabbits. The Limulus amoebocyte lysate test (J. Levin and F. B. Bang) has been employed as a more simple, rapid and sensitive method and was introduced in gastroenterology in a larger extent. Connections between endotoxinaemia and liver diseases, effects of endotoxins on gastrointestinal mucosa and on the course of shock are subjects of actual investigations.