The mechanism (pathogenesis) of the development of fever
Increasing the temperature of the “set point” of the preoptic region of the hypothalamus. An increase in the temperature of the “set point” of the preoptic region of the hypothalamus almost always occurs under the influence of the endogenous pyrogen – a substance secreted by phagocytic leukocytes and macrophages. Endogenous pyrogen is the final common link in the vast majority of febrile diseases. An exception is the action of irradiation of the central nervous system, scorpion venom and DDT, which directly increase the temperature of the “set point”. It has been suggested that epinephrine and norepinephrine in overdose can directly increase the temperature of the “set point” of the preoptic region of the hypothalamus.
Some types of tumors secrete endogenous pyrogens or endogenous pyrogen-like substances. Brain damage can affect the “set point”, as well as other areas of the preoptic region of the hypothalamus.
Endogenous pyrogen during the development of fever
Intravenous bacterial endotoxin causes fever only after a latent period of about 90 minutes. Endogenous pyrogen under the same route of administration causes fever for several minutes. Human blood after incubation with bacterial endotoxin when administered to volunteers also quickly causes fever, which confirms the view that the endogenous pyrogenic substance is released by leukocytes. Most studies have shown that the administration of endotoxin directly in the preoptic region of the hypothalamus is ineffective, while the injection of even the smallest dose of endogenous pyrogen into the same region immediately causes fever.
However, one of the papers described fever with direct administration of endotoxin into the ventricles or the anterior part of the hypothalamus of the rat brain.
Initially it was assumed that only circulating polymorphonuclear leukocytes can release endogenous pyrogen. Therefore, the development of fever in patients with granulocytopenia seemed a mystery. However, it was subsequently proved that most, if not all, phagocytic cells developing from bone marrow progenitors emit endogenous pyrogen. Some cells that do not originate from the bone marrow, such as fibroblasts, phagocytic latex particles in tissue culture, but they do not release endogenous pyrogen.
Alveolar and peritoneal macrophages, as well as reticuloendothelial cells of the liver and spleen, can produce endogenous pyrogen. Endotoxin, which quickly binds to circulating granulocytes, causes fever primarily by stimulating the production of endogenous pyrogen by these cells. On the other hand, live bacteria and viruses are eliminated from the blood mainly by the reticuloendothelial system and cause fever by stimulating the formation and release of endogenous pyrogen by the cells of this system in the liver and spleen. Although lymphocytes do not form endogenous pyrogen, they secrete lymphokine, which stimulates the production and secretion of endogenous pyrogen by granulocytes and monocytes. It is not yet clear whether eosinophils are involved in the production of endogenous pyrogen. The release of endogenous pyrogen is noted not only in infectious diseases.
The main trigger for the formation and release of endogenous pyrogen is the phagocytosis of microorganisms, antigen – antibody complexes, dead or damaged cells, cellular fragments. For example, with the introduction of group D erythrocytes to patients with antibodies against antigen D, chills and fever are observed after a latent period of 90 minutes, which confirms the presence of an intermediate stage in the production of endogenous pyrogen. Endogenous pyrogen is formed in allergic diseases, connective tissue diseases and inflammatory reactions in response to tumors. Apparently, there is a special mechanism for the development of fever with injury and tissue destruction.
Endogenous pyrogen is a low molecular weight protein. After it has been isolated by phagocytic cells, it leaves the bloodstream and quickly penetrates the preoptic region of the hypothalamus. Endogenous pyrogen is an extremely potent substance and can cause fever in laboratory animals when administered intravenously in nanogram quantities. At present, it is believed that endogenous pyrogen is not contained as such in phagocytic cells, but is formed in them under the influence of appropriate stimuli. This stage requires a certain time, as it includes the synthesis of new informational RNA. The secretion of endogenous pyrogen does not lead to the lysis or death of phagocytes.