Molecular hydrogen potentiates hypothermia and prevents hypotension and fever in LPS-induced systemic inflammation

Molecular hydrogen (H₂) exerts anti-oxidative, anti-apoptotic, and anti-inflammatory effects. Here we tested the hypothesis that H₂ modulates cardiovascular, inflammatory, and thermoregulatory changes in systemic inflammation (SI) induced by lipopolysaccharide (LPS) at different doses (0.1 or 1.5 mg/kg, intravenously, to induce mild or severe SI) in male Wistar rats (250-300 g). LPS or saline was injected immediately before the beginning of 360-minute inhalation of H₂ (2% H₂, 21% O₂, balanced with nitrogen) or room air (21% O₂, balanced with nitrogen). Deep body temperature (Tb) was measured by dataloggers pre-implanted in the peritoneal cavity. H₂ caused no change in cardiovascular, inflammatory parameters, and Tb of control rats (treated with saline). During mild SI, H₂ reduced plasma surges of proinflammatory cytokines (TNF-α and IL-6) while caused an increase in plasma IL-10 (anti-inflammatory cytokine) and prevented fever. During severe SI, H₂ potentiated hypothermia, and prevented fever and hypotension, which coincided with reduced plasma nitric oxide (NO) production. Moreover, H₂ caused a reduction in surges of proinflammatory cytokines (plasma TNF-α and IL-1β) and prostaglandin E₂ [(PGE₂), in plasma and hypothalamus], and an increase in plasma IL-10. These data are consistent with the notion that H₂ blunts fever in mild SI, and during severe SI potentiates hypothermia, prevents hypotension reducing plasma NO production, and exerts anti-inflammatory effects strong enough to prevent fever by altering febrigenic signaling and ultimately down-modulating hypothalamic PGE₂ production.