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Conversely, rewarming LPS\u2010treated mice at 30\u00b0C delayed hypothermia but worsened mortality, thus highlighting the adaptive importance of hypothermia. Additionally, we show that LPS\u2010induced hypothermia was partly mediated by peripheral neurotensin expressed in response to vascular toll\u2010like receptor 4 (TLR4) signalling. The administration of a neurotensin analogue (JMV449) induced pharmacological hypothermia and significantly ameliorated the clinical presentation and lethality rates in LPS\u2010treated mice. Moreover, the therapeutic benefits of pharmacological hypothermia were prevented when LPS\u2010treated mice were switched to 30\u00b0C. Lastly, these beneficial outcomes were attributed to a reduction in oxygen consumption, metabolic stress and cytopathic hypoxia, rather than the modulation of the cytokine storm.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>Collectively, our findings indicate that spontaneous and pharmacologically\u2010induced hypothermia protect against endotoxic shock.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70000","type":"journal-article","created":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T23:40:41Z","timestamp":1740354041000},"page":"2621-2641","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Spontaneous and pharmacologically induced hypothermia protect mice against endotoxic shock"],"prefix":"10.1111","volume":"182","author":[{"given":"Arely","family":"Tinajero","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Center for Hypothalamic Research UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warda","family":"Merchant","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Center for Hypothalamic Research UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adan","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Center for Hypothalamic Research UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Surbhi","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Center for Hypothalamic Research UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Caron","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Center for Hypothalamic Research UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Center for Hypothalamic Research UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences The University of Texas at Dallas  Richardson Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3609-7441","authenticated-orcid":false,"given":"Laurent","family":"Gautron","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Center for Hypothalamic Research UT Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,23]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15538"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2006.04854.x"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000001"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2012.11.015"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2102-21.2022"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1177\/0885066620942154"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-020-01946-3"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M076844"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-59430-4_7"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.12.005"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/35013070"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1213\/ANE.0000000000006343"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)43429-7"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-022516-034133"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.277277"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2021.129917"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00028.2015"},{"issue":"5","key":"e_1_2_12_19_1","first-page":"176","article-title":"Post\u2010shock metabolic response","volume":"16","author":"Cuthbertson D. 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