FeverMechanism of Fever and the Body ThermoregulationHippocrates maintained that “heat is the immortal substance of life endowedwith intelligence.... However, heat must also be refrigerated by respirationand kept within bounds if the source or principle of life is to persist; for ifrefrigeration is not provided, the heat will consume itself.”Fadel Muhammad Garishah
Thermoregulation• Thermoregulation is a process that involves acontinuum of neural structures andconnections extending to and from thehypothalamus and limbic system through thelower brain stem and reticular formation tothe spinal cord and sympathetic ganglia.
Hypothalamus as Thermoreg?Many, although notall, thermophysiologists believethat the tem- perature-sensitivepreoptic area regulates bodytemperature by inte- gratingthermal input signals fromthermosensors in the skin andcore areas, including the centralnervous system.
• Heat is derived from biochemical reactions occurring in all living cells.• At the mitochondrial level, energy derived from the catabolism of metabolitessuch as glucose is used in oxidative phosphorylation to convert ADP to ATP.• Heat generated primarily in vital organs lying deep within the body core isdistributed throughout the body via the circulatory system.
Shivering• In adult humans and most other large mammals, shivering isthe primary means whereby heat production is enhanced.• Nonshivering thermogenesis is more important in smallermammals, newborns (including humans), and cold-acclimatedmammals• Brown adipose tissue has been most closely associated withnonshivering thermogenesis.
Fever?an elevation of bodytemperature above thenormal range of 36.5–37.5 °C due to an increase inthe temperature regulatoryset point.Karakitsos D, Karabinis A (September 2008). "Hypothermiatherapy after traumatic brain injury in children". N. Engl. J. Med.359 (11): 1179–80.
What is the point?• Various endogenous substances and drugsappear to affect temperature regulation byaltering the activity of hypothalamic neurons(Pyrogens)• Whether they cross the blood-brain barrier to doso or act by evoking the release of othermediators (e.g., prostaglandin E2 [PGE2]) incircumventricular organs, such as the organumvasculosum of the lamina terminalis (OVLT), isuncertain.
PyrogensEndogenousPyrogensExogenousPyrogensThe list of currently recognizedpyrogenic cytokines includes inter-leukin-1 (IL-1 [IL-1α and IL-β]), tumornecrosis factor-α (TNF-α), IL-6, ciliaryneurotropic factor (CNF), and interferon(IFN)bacterial lipopolysaccharide (LPS) induces fever directly(rather than indirectly through the induction of pyrogeniccytokines) by interacting with Kupffer’s cells, therebyinitiating pyrogenic signals that are transmitted to thepreoptic area of the hypothalamus via the hepatic branch ofthe vagus nerve.
Mechanism (1)• It has long been suspected that interactionsbetween pyrogenic cytokines and theirreceptors in the preoptic region of theanterior hypothalamus activate phospholipaseA2,• liberating plasma membrane arachidonic acidas a substrate for the cyclooxygenase (COX)pathway.• Resulted in prostaglandin secretion.
Mechanism (2)• Cytokines which are secreted by Leukocytesinto the bloodstream in response toexogenous pyrogens find their way to theOVLT, where they induce synthesis ofprostaglandins mediating the febrile response.
Figure 2. A Proposed Mechanism for the Actions of Cytokines on the Brain That Induce Fever.• Circulating cytokines: TNF-alpha, IL-1β, IFNs, can enter the circumventricular organs through fenestrated capillaries.• Cytokines may act on different cell types, including neurons, microglia, and astrocytes (and possibly perivascularcells), to induce the production of prostaglandins such as E2 (PGE2).• These may diffuse through the glial barrier surrounding the circumventricular organs and enter the brain. Analternative and perhaps parallel pathway involves the production of cytokines and possibly other neurotransmittersby neurons whose cell bodies are in or near the circumventricular organs.• These neurons may project into the brain and contact other nerve cells (some of which may also contain cytokines)that activate the coordinated endocrine, autonomic, and behavioral responses involved in fever.
Endogenous Antipyretics• α–Melanocyte-stimulating hormone (α-MSH)• Glucocorticoids and their inducers(e.g., corticotropin-releasing hormone [CRH]and corticotropin) inhibit the synthesis ofpyrogenic cytokines such as IL-6 and TNF-α.
Benefits?• Further evidence of fever’s beneficial effectscan be found in numerous investigationsdemonstrating enhanced resistance of animalsto infection with increases in bodytemperature within the physiologic range.• In such studies, all the principal pyrogeniccytokines have been shown to have immune-potentiating capabilities, which mighttheoretically enhance resistance to infection.
Disadvantages?• The febrile response’s potential for harm wasreflected in a flurry of reports suggesting thatIL-1, TNF-α, IL-6, and IFN mediate thephysiologic abnormalities of certain infections.• Purified LPS induces a spectrum of physiologicabnormalities similar to those occurring inpatients with gram-negative bacterial sepsis.
Therapy?• Antipyretic drugs can be grouped into three generalcategories on the basis of their mechanisms of action.• These include corticosteroids, aspirin and the othernonsteroidal anti-inflammatory drugs (NSAIDs), andacetaminophen.• CS: They block the transcription of pyrogenic cytokinesand inducible COX via interactions involving theglucocorticoid receptor.• Acetaminophen and aspirin and the other NSAIDs allinhibit COX- mediated synthesis of inflammatorythromboxanes and prostaglandins from arachidonicacid.