{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:04:54Z","timestamp":1788959094532,"version":"build-2803163510"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":539,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["201610PJT"],"award-info":[{"award-number":["201610PJT"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012856","name":"Alberta Children\u2019s Hospital Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012856","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["201610PJT"],"award-info":[{"award-number":["201610PJT"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Alberta Children\u2019s Hospital Research Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.atsjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Extreme heat caused by climate change is increasing the transmission of infectious diseases, resulting in a sharp rise in heat-related illness and mortality. Understanding the mechanistic link between heat, inflammation, and disease is thus important for public health. Thermal hyperpnea, and consequent respiratory alkalosis, is crucial in febrile seizures and convulsions induced by heat stress in humans. Here, we address what causes thermal hyperpnea in neonates and how it is affected by inflammation. Transient receptor potential cation channel subfamily V member 1 (TRPV1), a heat-activated channel, is sensitized by inflammation and modulates breathing and thus may play a key role. To investigate whether inflammatory sensitization of TRPV1 modifies neonatal ventilatory responses to heat stress, leading to respiratory alkalosis and an increased susceptibility to hyperthermic seizures, we treated neonatal rats with bacterial LPS, and breathing, arterial pH, in vitro vagus nerve activity, and seizure susceptibility were assessed during heat stress in the presence or absence of a TRPV1 antagonist (AMG-9810) or shRNA-mediated TRPV1 suppression. LPS-induced inflammatory preconditioning lowered the threshold temperature and latency of hyperthermic seizures. This was accompanied by increased tidal volume, minute ventilation, expired CO2, and arterial pH (alkalosis). LPS exposure also elevated vagal spiking and intracellular calcium concentrations in response to hyperthermia. TRPV1 inhibition with AMG-9810 or shRNA reduced the LPS-induced susceptibility to hyperthermic seizures and altered the breathing pattern to fast shallow breaths (tachypnea), making each breath less efficient and restoring arterial pH. These results indicate that inflammation exacerbates thermal hyperpnea-induced respiratory alkalosis associated with increased susceptibility to hyperthermic seizures, primarily mediated by TRPV1 localized to vagus neurons.<\/jats:p>","DOI":"10.1165\/rcmb.2023-0451oc","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T09:29:15Z","timestamp":1712741355000},"page":"195-206","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":11,"title":["The Impact of Inflammation on Thermal Hyperpnea: Relevance for Heat Stress and Febrile Seizures"],"prefix":"10.1093","volume":"71","author":[{"given":"Karlene T.","family":"Barrett","sequence":"first","affiliation":[{"name":"Alberta Children\u2019s Hospital Research Institute"},{"name":"Hotchkiss Brain Institute"},{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arijit","family":"Roy","sequence":"additional","affiliation":[{"name":"Hotchkiss Brain Institute"},{"name":"Department of Physiology and Pharmacology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aya","family":"Ebdalla","sequence":"additional","affiliation":[{"name":"Alberta Children\u2019s Hospital Research Institute"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quentin J.","family":"Pittman","sequence":"additional","affiliation":[{"name":"Alberta Children\u2019s Hospital Research Institute"},{"name":"Hotchkiss Brain Institute"},{"name":"Department of Physiology and Pharmacology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J. A.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Alberta Children\u2019s Hospital Research Institute"},{"name":"Hotchkiss Brain Institute"},{"name":"Department of Physiology and Pharmacology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morris H.","family":"Scantlebury","sequence":"additional","affiliation":[{"name":"Alberta Children\u2019s Hospital Research Institute"},{"name":"Hotchkiss Brain Institute"},{"name":"Department of Pediatrics"},{"name":"Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,1]]},"reference":[{"key":"2026012204194666300_bib1","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/s41558-022-01426-1","article-title":"Over half of known human pathogenic diseases can be aggravated by climate change","volume":"12","author":"Mora","year":"2022","journal-title":"Nat Clim Chang"},{"key":"2026012204194666300_bib2","doi-asserted-by":"crossref","first-page":"2346","DOI":"10.1016\/S0140-6736(23)01859-7","article-title":"The 2023 report of the Lancet Countdown on health and climate change: the imperative for a health-centred response in a world facing irreversible harms","volume":"402","author":"Romanello","year":"2023","journal-title":"Lancet"},{"key":"2026012204194666300_bib3","doi-asserted-by":"crossref","first-page":"e4224","DOI":"10.1136\/bmj.e4224","article-title":"Derivation and validation of age and temperature specific reference values and centile charts to predict lower respiratory tract infection in children with fever: prospective observational study","volume":"345","author":"Nijman","year":"2012","journal-title":"BMJ"},{"key":"2026012204194666300_bib4","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.nbd.2018.08.004","article-title":"Vagal TRPV1 activation exacerbates thermal hyperpnea and increases susceptibility to experimental febrile seizures in immature rats","volume":"119","author":"Barrett","year":"2018","journal-title":"Neurobiol Dis"},{"key":"2026012204194666300_bib5","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/nm1422","article-title":"Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis","volume":"12","author":"Schuchmann","year":"2006","journal-title":"Nat Med"},{"key":"2026012204194666300_bib6","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.resp.2005.01.012","article-title":"Influence of temperature on metabolism and breathing during mammalian ontogenesis","volume":"149","author":"Mortola","year":"2005","journal-title":"Respir Physiol Neurobiol"},{"key":"2026012204194666300_bib7","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1080\/23328940.2016.1143760","article-title":"Characteristics of hyperthermia-induced hyperventilation in humans","volume":"3","author":"Tsuji","year":"2016","journal-title":"Temperature"},{"key":"2026012204194666300_bib8","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1152\/japplphysiol.00210.2006","article-title":"Components and mechanisms of thermal hyperpnea","volume":"101","author":"White","year":"2006","journal-title":"J Appl Physiol (1985)"},{"key":"2026012204194666300_bib9","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1177\/0883073813513070","article-title":"Association between hypocapnia and febrile seizures","volume":"29","author":"Kilicaslan","year":"2014","journal-title":"J Child Neurol"},{"key":"2026012204194666300_bib10","doi-asserted-by":"crossref","first-page":"388","DOI":"10.4103\/JPN.JPN_73_18","article-title":"Association of hypocapnia in children with febrile seizures","volume":"13","author":"Sachan","year":"2018","journal-title":"J Pediatr Neurosci"},{"key":"2026012204194666300_bib11","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1111\/j.1528-1167.2011.03259.x","article-title":"Respiratory alkalosis in children with febrile seizures","volume":"52","author":"Schuchmann","year":"2011","journal-title":"Epilepsia"},{"key":"2026012204194666300_bib12","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/BF01426864","article-title":"Exposure to heat: comparison of responses of dog and man","volume":"10","author":"Iampietro","year":"1966","journal-title":"Int J Biometeorol"},{"key":"2026012204194666300_bib13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.eplepsyres.2009.11.002","article-title":"Febrile seizures and temporal lobe epileptogenesis","volume":"89","author":"Scantlebury","year":"2010","journal-title":"Epilepsy Res"},{"key":"2026012204194666300_bib14","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0165-3806(95)00205-7","article-title":"The influence of blood gas changes on hyperthermia-induced seizures in developing rats","volume":"92","author":"Morimoto","year":"1996","journal-title":"Brain Res Dev Brain Res"},{"key":"2026012204194666300_bib15","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/0034-5687(91)90039-L","article-title":"Thermal effects on ventilation in cats: participation of carotid body chemoreceptors","volume":"86","author":"Fadic","year":"1991","journal-title":"Respir Physiol"},{"key":"2026012204194666300_bib16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1113\/jphysiol.1968.sp008640","article-title":"Vagal control of thermal panting in mammals and birds","volume":"199","author":"Richards","year":"1968","journal-title":"J Physiol"},{"key":"2026012204194666300_bib17","doi-asserted-by":"crossref","first-page":"R541","DOI":"10.1152\/ajpregu.00016.2006","article-title":"Thermal sensitivity of isolated vagal pulmonary sensory neurons: role of transient receptor potential vanilloid receptors","volume":"291","author":"Ni","year":"2006","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"2026012204194666300_bib18","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1038\/39807","article-title":"The capsaicin receptor: a heat-activated ion channel in the pain pathway","volume":"389","author":"Caterina","year":"1997","journal-title":"Nature"},{"key":"2026012204194666300_bib19","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/j.bbi.2015.07.012","article-title":"Fever and sickness behavior: friend or foe?","volume":"50","author":"Harden","year":"2015","journal-title":"Brain Behav Immun"},{"key":"2026012204194666300_bib20","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1002\/ana.20358","article-title":"Interleukin-1beta contributes to the generation of experimental febrile seizures","volume":"57","author":"Dub\u00e9","year":"2005","journal-title":"Ann Neurol"},{"key":"2026012204194666300_bib21","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1111\/j.1528-1167.2005.00294.x","article-title":"Causal links between brain cytokines and experimental febrile convulsions in the rat","volume":"46","author":"Heida","year":"2005","journal-title":"Epilepsia"},{"key":"2026012204194666300_bib22","doi-asserted-by":"crossref","first-page":"15435","DOI":"10.1073\/pnas.93.26.15435","article-title":"A novel heat-activated current in nociceptive neurons and its sensitization by bradykinin","volume":"93","author":"Cesare","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026012204194666300_bib23","doi-asserted-by":"crossref","first-page":"5072","DOI":"10.1523\/JNEUROSCI.4476-07.2008","article-title":"Endogenous tumor necrosis factor alpha (TNFalpha) requires TNF receptor type 2 to generate heat hyperalgesia in a mouse cancer model","volume":"28","author":"Constantin","year":"2008","journal-title":"J Neurosci"},{"key":"2026012204194666300_bib24","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1038\/35050121","article-title":"Induction of vanilloid receptor channel activity by protein kinase C","volume":"408","author":"Premkumar","year":"2000","journal-title":"Nature"},{"key":"2026012204194666300_bib25","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1113\/JP280749","article-title":"PKC\u03b5 stimulation of TRPV1 orchestrates carotid body responses to asthmakines","volume":"599","author":"Jendzjowsky","year":"2021","journal-title":"J Physiol"},{"key":"2026012204194666300_bib26","doi-asserted-by":"crossref","first-page":"103357","DOI":"10.1016\/j.resp.2019.103357","article-title":"Impact of inflammation on developing respiratory control networks: rhythm generation, chemoreception and plasticity","volume":"274","author":"Beyeler","year":"2020","journal-title":"Respir Physiol Neurobiol"},{"key":"2026012204194666300_bib27","author":"Barrett","year":"2021"},{"key":"2026012204194666300_bib28","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41596-018-0097-3","article-title":"Systemic AAV vectors for widespread and targeted gene delivery in rodents","volume":"14","author":"Challis","year":"2019","journal-title":"Nat Protoc"},{"key":"2026012204194666300_bib29","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/nbt.3807","article-title":"Prediction of potent shRNAs with a sequential classification algorithm","volume":"35","author":"Pelossof","year":"2017","journal-title":"Nat Biotechnol"},{"key":"2026012204194666300_bib30","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/978-1-60761-950-5_12","article-title":"Imaging calcium sparks in cardiac myocytes","volume":"689","author":"Guatimosim","year":"2011","journal-title":"Methods Mol Biol"},{"key":"2026012204194666300_bib31","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.bbi.2010.03.005","article-title":"Effects of prenatal infection on brain development and behavior: a review of findings from animal models","volume":"24","author":"Boksa","year":"2010","journal-title":"Brain Behav Immun"},{"key":"2026012204194666300_bib32","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.3390\/pathogens10081061","article-title":"General characteristics of children with single- and co-infections and febrile seizures with a main focus on respiratory pathogens: preliminary results","volume":"10","author":"Rudolph","year":"2021","journal-title":"Pathogens"},{"key":"2026012204194666300_bib33","doi-asserted-by":"crossref","first-page":"e12688","DOI":"10.14814\/phy2.12688","article-title":"Cardiorespiratory control and cytokine profile in response to heat stress, hypoxia, and lipopolysaccharide (LPS) exposure during early neonatal period","volume":"4","author":"McDonald","year":"2016","journal-title":"Physiol Rep"},{"key":"2026012204194666300_bib34","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1084\/jem.183.1.311","article-title":"Interleukin (IL)-6 gene expression in the central nervous system is necessary for fever response to lipopolysaccharide or IL-1 beta: a study on IL-6-deficient mice","volume":"183","author":"Chai","year":"1996","journal-title":"J Exp Med"},{"key":"2026012204194666300_bib35","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.resp.2011.03.003","article-title":"Vagal afferents modulate cytokine-mediated respiratory control at the neonatal medulla oblongata","volume":"178","author":"Balan","year":"2011","journal-title":"Respir Physiol Neurobiol"},{"key":"2026012204194666300_bib36","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.resp.2016.06.003","article-title":"A critical postnatal period of heightened vulnerability to lipopolysaccharide","volume":"232","author":"Rourke","year":"2016","journal-title":"Respir Physiol Neurobiol"},{"key":"2026012204194666300_bib37","doi-asserted-by":"crossref","first-page":"103389","DOI":"10.1016\/j.resp.2020.103389","article-title":"Effects of inflammation on the developing respiratory system: focus on hypoglossal (XII) neuron morphology, brainstem neurochemistry, and control of breathing","volume":"275","author":"Williams","year":"2020","journal-title":"Respir Physiol Neurobiol"},{"key":"2026012204194666300_bib38","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1152\/ajplegacy.1972.222.1.68","article-title":"Effect of hyperthermia and Pa CO2 on the slowly adapting pulmonary stretch receptor","volume":"222","author":"Schoener","year":"1972","journal-title":"Am J Physiol"},{"key":"2026012204194666300_bib39","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/s11055-013-9803-3","article-title":"Developmental changes in the expression of TRPV1 channels in autonomic nervous system neurons","volume":"43","author":"Korobkin","year":"2013","journal-title":"Neurosci Behav Physiol"},{"key":"2026012204194666300_bib40","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/0306-4522(95)00394-X","article-title":"Acute, sequence-specific effects of oxytocin and vasopressin antisense oligonucleotides on neuronal responses","volume":"69","author":"Neumann","year":"1995","journal-title":"Neuroscience"},{"key":"2026012204194666300_bib41","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1177\/0022034511400225","article-title":"LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons","volume":"90","author":"Diogenes","year":"2011","journal-title":"J Dent Res"},{"key":"2026012204194666300_bib42","doi-asserted-by":"crossref","first-page":"108","DOI":"10.2174\/1876386301306010108","article-title":"TRPV1 antagonists as analgesic agents","volume":"6","author":"Trevisani","year":"2013","journal-title":"Open Pain J"},{"key":"2026012204194666300_bib43","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.neuropharm.2017.08.019","article-title":"The relevance of kalikrein-kinin system via activation of B2 receptor in LPS-induced fever in rats","volume":"126","author":"Soares","year":"2017","journal-title":"Neuropharmacology"},{"key":"2026012204194666300_bib44","doi-asserted-by":"crossref","first-page":"103314","DOI":"10.1016\/j.resp.2019.103314","article-title":"Time and dose-dependent impairment of neonatal respiratory motor activity after systemic inflammation","volume":"272","author":"Morrison","year":"2020","journal-title":"Respir Physiol Neurobiol"},{"key":"2026012204194666300_bib45","doi-asserted-by":"crossref","first-page":"e00348","DOI":"10.1002\/brb3.348","article-title":"Lipopolysaccharide potentiates hyperthermia-induced seizures","volume":"5","author":"Eun","year":"2015","journal-title":"Brain Behav"},{"key":"2026012204194666300_bib46","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1093\/jpids\/piac085","article-title":"Change in seizure incidence in febrile children with COVID-19 in the era of Omicron variant of concern","volume":"11","author":"Iijima","year":"2022","journal-title":"J Pediatric Infect Dis Soc"},{"key":"2026012204194666300_bib47","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.3390\/jcm12031076","article-title":"Incidence of febrile seizures in children with COVID-19","volume":"12","author":"Han","year":"2023","journal-title":"J Clin Med"},{"key":"2026012204194666300_bib48","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/S2352-4642(22)00027-X","article-title":"Paediatric hospitalisations due to COVID-19 during the first SARS-CoV-2 omicron (B.1.1.529) variant wave in South Africa: a multicentre observational study","volume":"6","author":"Cloete","year":"2022","journal-title":"Lancet Child Adolesc Health"},{"key":"2026012204194666300_bib49","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/B978-0-323-89932-1.00009-3","volume-title":"Febrile seizures","author":"Scantlebury","year":"2023","edition":"2nd ed."}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/71\/2\/195\/66196953\/ajrcmb_71_2_195.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/71\/2\/195\/66196953\/ajrcmb_71_2_195.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T09:21:38Z","timestamp":1769073698000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/71\/2\/195\/8405623"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,1]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,8,1]]},"published-print":{"date-parts":[[2024,8,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2023-0451oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,8]]},"published":{"date-parts":[[2024,8,1]]},"assertion":[{"value":"2023-12-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-01","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}