From inflammation to sickness: historical perspective.

The concept of the four cardinal signs of acute inflammation comes from antiquity as rubor et tumor cum calore et dolore, (redness and swelling with heat and pain) extended later by functio laesa (loss of function). The contemporary understanding of this process we owe to 19th-century milestone discoveries by Rudolph Virchow, Julius Cohnheim and Elie Metchnikoff. In the 20th century, the development of potent technological tools allowed the rapid expansion of knowledge of the cells and mediators of inflammatory processes, as well as the molecular mechanisms of their interactions. It turned out that some mediators of inflammation have both local and distant targets, among them the liver (responding by the production of several acute phase reactants) and neurohormonal centers. In the last decades it has become clear that the immune system shares mediators and their receptors with the neurohormonal system of the body; thus, they form a common homeostatic entity. Such an integrative view, introduced by J. Edwin Blalock, when combined with Hans Selye's concept of stress, led to the contemporary understanding of sickness behavior, defined by Robert Dantzer as a highly organized strategy of the organism to fight infections and to respond to other environmental stressors.