Fever is regulated by the hypothalamus, which integrates signals from the skin and core body areas. Pyrogens such as cytokines and bacterial lipopolysaccharide can cross the blood-brain barrier and act on the preoptic region of the hypothalamus to elevate the temperature set point. This activates the synthesis of prostaglandins like PGE2, which signal fever through thermoregulatory pathways and induce physiological changes. While fever has benefits in fighting infection, excessive fever can also cause harm. Antipyretic drugs like corticosteroids, NSAIDs, and acetaminophen work to reduce fever by blocking cytokine production or inhibiting prostaglandin synthesis.

1. 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

10. 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.

11. 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.

14. • 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.

15. 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.

16. 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.

17. 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.

18. Pyrogens
Endogenous
Pyrogens
Exogenous
Pyrogens
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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.