Endotoxin- Production and Function

Endotoxin and Gram Negative BacteriaThe lipid portion of lipopolysaccharides, called Lipid A, found in the outer portion of the cell wall of gram-negative bacteria is called endotoxin.

Endotoxins are released when gram-negative bacteria die and their cell walls undergo lysis, thus liberating the endotoxin. Endotoxins are also released during bacterial multiplication. Antibiotics used to treat diseases caused by gram-negative bacteria can lyse the bacterial cells; this reaction releases endotoxin and may lead to an immediate worsening of the symptoms, but the condition usually improves as the endotoxin breaks down. Endotoxins exert their effects by stimulating macrophages to release cytokines in very high concentrations. At these levels, cytokines are toxic. All endotoxins produce the same signs and symptoms, regardless of the species of microorganism, although not to the same degree. These include chills, fever, weakness, generalized aches, and, in some cases, shock and even death. Endotoxins can also induce miscarriage.

Another consequence of endotoxins is the activation of blood -clotting proteins, causing the formation of small blood clots. These blood clots obstruct capillaries, and the resulting decreased blood supply induces the death of tissues. This condition is referred to as disseminated intravascular coagulation (DIC). Bacterial cell death caused by lysis or antibiotics can also produce fever by this mechanism. Both aspirin and acetaminophen reduce fever by inhibiting the synthesis of prostaglandins.

Shock refers to any life-threatening decrease in blood pressure. Shock caused by bacteria is called septic shock. Gram-negative bacteria cause endotoxic shock. Like fever, the shock produced by endotoxins is related to the secretion of a cytokine by macrophages. Phagocytosis of gram-negative bacteria causes the phagocytes to secrete tumor necrosis factor (TNF), sometimes called cachectin. TNF binds to many tissues in the body and alters their metabolism in a number of ways. One effect of TNF is damage to blood capillaries; their permeability is increased, and they lose large amounts of fluid. The result is a drop in blood pressure that results in shock. Low blood pressure has serious effects on the kidneys, lungs, and gastrointestinal tract. In addition, the presence of gram-negative bacteria such as Haemophilus influenzae type b in cerebrospinal fluid causes the release of IL- J and TNE. These, in turn, cause a weakening of the blood- brain barrier that normally protects the central nervous system from infection. The weakened barrier lets phagocytes in, but this also lets more bacteria enter from the bloodstream.

Endotoxins do not promote the formation of effective antitoxins against the carbohydrate component of an endotoxin. Antibodies are produced, but they tend not to counter the effect of the toxin; sometimes, in fact, they actually enhance its effect.

Representative microorganisms that produce endotoxins are Salmonella typhi (the causative agent of typhoid fever), Proteus spp. (frequently the causative agents of urinary tract infections), and Neisseria meningitidis (the causative agent of meningococcal meningitis),

It is important to have a sensitive test to identify the presence of endotoxins in drugs, medical devices, and body fluids. Materials that have been sterilized may contain endotoxins, even though no bacteria can be cultured from them. One such laboratory test is called the Umulus amoebocyte lysate (LAL) assay, which can detect even minute amounts of endotoxin.

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