Spontaneous and pharmacologically induced hypothermia protect mice against endotoxic shock

• DOI: 10.1111/bph.70000
• Publication Date: 2025-02-23T23:40:41Z
• Authors: Arely Tinajero; Warda Merchant; Adan Khan; Surbhi; Alexandre Caron; Ryan Reynolds; Lin Jia; Laurent Gautron
• Keywords: Hypoxia

Background and Purpose Despite the well‐known occurrence of hypothermia during sepsis, its underlying biological nature adaptive value remain debated. Experimental Approach Using indirect calorimetry, telemetry, thermal gradient studies pharmacological studies, we examined metabolic responses mice treated with a shock‐inducing lethal dose lipopolysaccharide (LPS). Key Results We report that LPS‐treated undergo spontaneous hypothermia, driven by hypometabolism cold‐seeking behaviours, even when animals approach end life. Conversely, rewarming at 30°C delayed but worsened mortality, thus highlighting importance hypothermia. Additionally, show LPS‐induced was partly mediated peripheral neurotensin expressed in response to vascular toll‐like receptor 4 (TLR4) signalling. The administration analogue (JMV449) induced significantly ameliorated clinical presentation lethality rates mice. Moreover, therapeutic benefits were prevented switched 30°C. Lastly, these beneficial outcomes attributed reduction oxygen consumption, stress cytopathic hypoxia, rather than modulation cytokine storm. Conclusion Implications Collectively, our findings indicate pharmacologically‐induced protect against endotoxic shock.