During fever induced by bacterial lipopolysaccharide (LPS), the central mechanism of temperature resetting involves:

• A Direct action of LPS on the anterior hypothalamus to stimulate prostaglandin E2 synthesis
• B LPS activating the posterior hypothalamic heat retention center directly through vagal afferents
• C Cytokines blocking cold-sensitive neurons in the preoptic area, preventing heat dissipation
• D LPS stimulating peripheral macrophages to release IL-1β, IL-6, TNF-α; these cytokines (or their signal) reaching the organum vasculosum of the lamina terminalis (OVLT) to induce COX-2-derived PGE2, which resets the anterior hypothalamic thermostat ✓

Explanation

LPS induces fever through a well-defined cascade: LPS activates peripheral immune cells (monocytes/macrophages) to release pyrogenic cytokines (IL-1β, IL-6, TNF-α). These large-molecule cytokines cannot cross the intact blood-brain barrier but act on the circumventricular organ OVLT (organum vasculosum of the lamina terminalis), which lacks a complete BBB. OVLT cells express COX-2 and produce prostaglandin E2 (PGE2) locally. PGE2 then diffuses to the preoptic area of the anterior hypothalamus, binding EP3 receptors on GABAergic neurons and reducing inhibitory tone on heat-production pathways, thereby raising the thermoregulatory set point. Aspirin/NSAIDs work by inhibiting COX-2.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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