ABSTRACT
From an early date, investigators realized that there was more to the febrile (fever) response than a simple reaction of the body to bacterial infection. Burdon-Sanderson in 1896 (1) described an additional fever mechanism commonly observed (other than that caused by infection). In cases of sever trauma or fractures in which the skin was not broken and, therefore, in which no bacterial infection could have occurred, fever was commonly observed. Albert Charrin claimed that cells contained “thermogenic substances” (1) and substances from which thermogenic substances could be generated. These concepts were forerunners of today’s modern understanding of a complex host response (of which fever is a component) to a variety of exogenous triggers (of which endotoxin is considered the most potent) via endogenous mediators known as cytokines. Lewis Thomas, in Lives of a Cell (2) vividly described the host response to endotoxin as follows:
The gram-negative bacteria . . . display lipopolysaccharide (LPS) endotoxin in their walls, and these macromolocules are read by our tissues as the very worst of bad news. When we sense lipopolysaccharide, we are likely to turn on every defense at our disposal; we will bomb, defoliate, blockade, seal off, and destroy all the tissues in the area. Leukocytes become more actively phagocytic, release lysosomal enzymes, turn sticky, and aggregate together in dense masses, occluding capillaries and shutting off the blood supply. Complement is switched on at the right point in its sequence to release chemotactic signals, calling in leukocytes from everywhere. Vessels become hyper-reactive to epinephrine so that physiologic concentrations suddenly possess necrotizing properties. Pyrogen is released from leukocytes, adding fever to hemorrhage, necrosis, and shock. It is a shambles. All of this seems unnecessary, panic-driven. There is nothing intrinsically poisonous about endotoxin, but it must look awful, or feel awful, when sensed by cells. Cells believe that it signifies the presence of gram-negative bacteria, and they will stop at nothing to avoid this threat. . . It is, basically, a response to propaganda. . . .
