FeverMechanism of Fever and the Body Thermoregulation

Hippocrates maintained that “heat is the immortal substance of life endowed with

intelligence.... However, heat must also be refrigerated by respiration and kept within

bounds if the source or principle of life is to persist; for if refrigeration is not provided,

the heat will consume itself.”

Fadel Muhammad Garishah

Thermoregulation

• Thermoregulation is a process that involves a continuum of neural structures and connections extending to and from the hypothalamus and limbic system through the lower brain stem and reticular formation to the spinal cord and sympathetic ganglia.

Hypothalamus as Thermoreg?

Many, although not all, thermophysiologists believe that the tem- perature-sensitive preoptic area regulates body temperature by inte- grating thermal input signals from thermosensors in the skin and core areas, including the central nervous system.

• Heat is derived from biochemical reactions occurring in all living cells. • At the mitochondrial level, energy derived from the catabolism of metabolites

such as glucose is used in oxidative phosphorylation to convert ADP to ATP.• Heat generated primarily in vital organs lying deep within the body core is

distributed throughout the body via the circulatory system.

Shivering

• In adult humans and most other large mammals, shivering is the primary means whereby heat production is enhanced.

• Nonshivering thermogenesis is more important in smaller mammals, newborns (including humans), and cold-acclimated mammals

• Brown adipose tissue has been most closely associated with nonshivering thermogenesis.

Fever?

an elevation of body temperature above the normal range of 36.5–37.5 °C due to an increase in the temperature regulatory set point.

Karakitsos D, Karabinis A (September 2008). "Hypothermia therapy after traumatic brain injury in children". N. Engl. J. Med. 359 (11): 1179–80.

What is the point?

• Various endogenous substances and drugs appear to affect temperature regulation by altering the activity of hypothalamic neurons (Pyrogens)

• Whether they cross the blood-brain barrier to do so or act by evoking the release of other mediators (e.g., prostaglandin E2 [PGE2]) in circumventricular organs, such as the organum vasculosum of the lamina terminalis (OVLT), is uncertain.

Pyrogens

Endogenous Pyrogens

ExogenousPyrogens

The list of currently recognized pyrogenic

cytokines includes inter- leukin-1 (IL-1 [IL-1α

and IL-β]), tumor necrosis factor-α (TNF-α), IL-

6, ciliary neurotropic factor (CNF), and

interferon (IFN)

bacterial lipopolysaccharide (LPS) induces fever directly (rather than

indirectly through the induction of pyrogenic cytokines) by interacting

with Kupffer’s cells, thereby initiating pyrogenic signals that are

transmitted to the preoptic area of the hypothalamus via the hepatic

branch of the vagus nerve.

Mechanism (1)

• It has long been suspected that interactions between pyrogenic cytokines and their receptors in the preoptic region of the anterior hypothalamus activate phospholipase A2,

• liberating plasma membrane arachidonic acid as a substrate for the cyclooxygenase (COX) pathway.

• Resulted in prostaglandin secretion.

Mechanism (2)

• Cytokines which are secreted by Leukocytes into the bloodstream in response to exogenous pyrogens find their way to the OVLT, where they induce synthesis of prostaglandins 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 perivascular

cells), 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. An

alternative and perhaps parallel pathway involves the production of cytokines and possibly other neurotransmitters by 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 of pyrogenic cytokines such as IL-6 and TNF-α.

Benefits?

• Further evidence of fever’s beneficial effects can be found in numerous investigations demonstrating enhanced resistance of animals to infection with increases in body temperature within the physiologic range.

• In such studies, all the principal pyrogenic cytokines have been shown to have immune-potentiating capabilities, which might theoretically enhance resistance to infection.

Disadvantages?

• The febrile response’s potential for harm was reflected in a flurry of reports suggesting that IL-1, TNF-α, IL-6, and IFN mediate the physiologic abnormalities of certain infections.

• Purified LPS induces a spectrum of physiologic abnormalities similar to those occurring in patients with gram-negative bacterial sepsis.

Therapy?

• Antipyretic drugs can be grouped into three general categories on the basis of their mechanisms of action.

• These include corticosteroids, aspirin and the other nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen.

• CS: They block the transcription of pyrogenic cytokines and inducible COX via interactions involving the glucocorticoid receptor.

• Acetaminophen and aspirin and the other NSAIDs all inhibit COX- mediated synthesis of inflammatory thromboxanes and prostaglandins from arachidonic acid.