(Chest 1993; 104: 1572-81) ARDS = adult respiratory distress syndrome; BSA = visible form [i]or[/i] frame surface area; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; EDR = endothelium-derived relaxation factor; FHF = fulminant hepatic failure; IBD = inflammatory bowel disease; IL = lipopolysaccharide-binding proteins; LP = lipopolysaccharides; MSOF = multiple a whole s organ failure; PAF = platelet activating factor; SIRS = systemic inflammatory reply syndrome; TNF = tumor necrosis factor.

(Chest 1993; 104: 1572-81)

ARDS = adult respiratory distress syndrome; BSA = visible form [i]or[/i] frame surface area; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; EDR = endothelium-derived relaxation factor; FHF = fulminant hepatic failure; IBD = inflammatory bowel disease; IL = lipopolysaccharide-binding proteins; LP = lipopolysaccharides; MSOF = multiple a whole s organ failure; PAF = platelet activating factor; SIRS = systemic inflammatory reply syndrome; TNF = tumor necrosis factor.

Serious infections fall out in as many as 500000 hospitalized patients each year in the United States.[1] Of these, individual third to one half exhibit shock related to their infection,[2,3] and these have a posterior mortality rate of 40 to 50 percent[4] When a source of infection is identified, the responsible organisms are gram-negative bacteria in about half the cases.[5] In these gram-negative infections, bacterial endotoxins (lipopolysaccharides, LPS) appear to play a central pathogenetic role

Bacterial endotoxins are compound compounds located in the small cavity walls of gram-negative bacteria. While diverse in detail, their edifices share a common design conserv across bacterial species - antigenic sugar moieties are leap to the hydrophobic lipid A (Fig 1) Their for the use of all structure and location on bacterial small cavity walls render endotoxins suitable for recognition according to host defenses. Mammals have evolv sensitive means to ascertain endotoxin as a sign of gram-negative bacterial growth; hence, endotoxin triggers powerful defensive answers which mediate its toxic consequences Miyamoto et al[6] and Staub[7] have allude toed that there may be significant variations between species in macrophage processing of foreign antigens, potentially explaining differences observ between various archetypes of endotoxemic shock.

Understanding the pathophysiologic forces of endotoxin in human disease requires an understanding of the physiology of army responses. We begin with a brief overview of the biochemistry and pharmacology of endotoxin, and then discuss evidence that it plays a part in several human disease states: sepsis, liver failure, bakes bowel diseases, and pancreatitis. We then review the protean physiologic abnormalities in these diverse conditions that may originate from the initiation of armed force defenses by endotoxin. Finally, we discuss therapeutic interventions intended to attenuate the exaggerated and sometimes lethal chain of cause and effects of the endotoxin-triggered cascade.

Biochemistry and Pharmacology of

Endotoxins

Endotoxin (Fig 1) is a lipopolysaccharide compos of a variably antigenic series of sugars" attached to a lipid A moiety The polysaccharide portion of the monad consists of an O-specific chain and a core oligosaccharide. The O-specific chain consists of up to 70 repeating oligosaccharide units. Each unit contains up to seven sugar residucs and is characteristic for each different bacterial species. The core is an heterooligosaccharide consisting of couple components. The inner core sugars are similar between species while the exterior core differs between and within species. Lipid A is a structurally manifold molecule with a hydrophilic compage sugar and lipophilic fatty acid moieties nevertheless is very similar between species.[9] When injected into mammals, neither the core nor the O-specific chains themselves elicit physiologic replys characteristic of sepsis. Wild stamp (smooth) microbes may lose their O-antigen, becoming jagged mutants.[8] Loss of the O-antigen assigns the bacteria more sensitive to opsonization and clearance.[8] In contrast to the core and O-specific chain, lipid A does initiate the landlord responses associated with sepsis, and these answers can be reproduced with injection of synthetic lipid A.[10]

When injected into animals, endotoxin binds to a number of different proteins, including albumin, lipoproteins, fulfilment and globulins,[11] as well as to a specific binding factor, lipopolysaccharide binding protein.[12] Endotoxin clearance and physiologic answers may be related to the order of protein binding. When radioactively-labeled endotoxin is injected into rats, 80 percent appears in the liver within 5 hours of injection, if it were not that significant concentrations also appear in the grudge and adrenal glands. While one degradation occurs in the macrophages of the liver, the majority of injected endotoxin is eliminated in the bile.[13] In rats, the biologic activity of excret endotoxin is essentially unchanged[13] while in humans there may be a certain detoxification.[14]

Detection of Endotoxin

Endotoxin is measured utilizing the hemolymph of amoebocytes from the Limulus horseshoe crab.[15,16] This substance contains a proenzyme which is directly activated by way of endotoxin. The activated enzyme cleaves peptide cords in a second protein, also quick in emergencies in the hemolymph, leading to coagulation and visible gelling of the mixture. This Limulus amoebocyte lysate (LAL) assay can ascertain nanogram per deciliter concentrations of endotoxin. The gelatin means has been modified by the use of enzyme substrate that can be measured spectrophotometrically.[15,16] This semiquantitative chromogenic assay discovers endotoxin to less than 10 pg/dl

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