{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T14:45:29Z","timestamp":1786200329764,"version":"build-2736575974"},"reference-count":43,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T00:00:00Z","timestamp":1709164800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Otago Vice Chancellor\u2019s Strategic Development Fund","award":["2022J01777"],"award-info":[{"award-number":["2022J01777"]}]},{"name":"Maurice and Phyllis Paykel Trust grant","award":["2022J01777"],"award-info":[{"award-number":["2022J01777"]}]},{"DOI":"10.13039\/501100003392","name":"Natural Science Foundation of Fujian Province","doi-asserted-by":"publisher","award":["2022J01777"],"award-info":[{"award-number":["2022J01777"]}],"id":[{"id":"10.13039\/501100003392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Substance P (SP), encoded by the TAC1\/Tac1 gene, acts as a significant mediator in dysregulated systemic inflammatory response and associated organ injury in sepsis by activating the neurokinin-1 receptor (NK1R). This study investigated the impact of SP-NK1R signaling on ferroptosis in the liver and lungs of mice with sepsis. Sepsis was induced by caecal ligation puncture (CLP) surgery in mice. The SP-NK1R signaling was suppressed by Tac1 gene deletion, NK1R blockade, and a combination of these two approaches. The physiological conditions of mice were recorded. The profile of the SP-NK1R cascade, inflammatory response, ferroptosis, and tissue histology were investigated in the liver and lungs. Several manifestations of sepsis occurred in Tac1+\/+ mice during the development of sepsis. Notably, hypothermia became significant four hours after the induction of sepsis. In the liver and lungs of mice subjected to CLP surgery, the concentrations of SP and NK1R were upregulated. Additionally, the concentrations of pro-inflammatory mediators, including cytokines (IL-1\u03b2, IL-6, and TNF-\u03b1) and chemokines (MCP-1 and MIP-2), were increased. Moreover, ferroptosis was elevated, as evidenced by increased concentrations of iron and MDA and reduced concentrations of GSH, Nrf2, and Gpx4. Suppressing the SP-NK1R cascade significantly mitigated CLP-surgery-induced alterations in mice. Importantly, these three approaches used to suppress SP-NK1R signaling showed similar effects on protecting mice against sepsis. In conclusion, increased SP-mediated acute inflammatory response and injury in the liver and lungs in mice with CLP-surgery-induced sepsis was associated with elevated ferroptosis. The detrimental effect of SP on sepsis was predominantly mediated by NK1R. Therefore, the suppression of increased SP-NK1R signaling and ferroptosis may be a promising adjuvant therapeutic candidate for sepsis and associated acute liver and lung injury.<\/jats:p>","DOI":"10.3390\/antiox13030300","type":"journal-article","created":{"date-parts":[[2024,2,29]],"date-time":"2024-02-29T02:59:39Z","timestamp":1709175579000},"page":"300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Suppressing the Substance P-NK1R Signalling Protects Mice against Sepsis-Associated Acute Inflammatory Injury and Ferroptosis in the Liver and Lungs"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5991-3264","authenticated-orcid":false,"given":"Zhixing","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand"},{"name":"Department of Internal Medicine, Teaching and Research Section, The Second Clinical Medical School of Fujian Medical University, Quanzhou 362002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Chambers","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhav","family":"Bhatia","sequence":"additional","affiliation":[{"name":"Department of Pathology and Biomedical Science, University of Otago, Christchurch 8140, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S0140-6736(18)30696-2","article-title":"Sepsis and septic shock","volume":"392","author":"Cecconi","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e418","DOI":"10.1002\/mco2.418","article-title":"The pathogenesis and potential therapeutic targets in sepsis","volume":"4","author":"Zhang","year":"2023","journal-title":"MedComm"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1152\/physrev.00031.2013","article-title":"Tachykinins and their receptors: Contributions to physiological control and the mechanisms of disease","volume":"94","author":"Steinhoff","year":"2014","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zhu, Z., and Bhatia, M. (2023). Inflammation and Organ Injury the Role of Substance P and Its Receptors. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24076140"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Zhu, Z., Chambers, S., Zeng, Y., and Bhatia, M. (2022). Gases in Sepsis: Novel Mediators and Therapeutic Targets. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23073669"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Zhu, Z., Lian, X., and Bhatia, M. (2022). Hydrogen Sulfide: A Gaseous Mediator and Its Key Role in Programmed Cell Death, Oxidative Stress, Inflammation and Pulmonary Disease. Antioxidants, 11.","DOI":"10.3390\/antiox11112162"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1097\/SHK.0000000000001936","article-title":"Necroptosis, Pyroptosis, Ferroptosis in Sepsis and Treatment","volume":"57","author":"Qu","year":"2022","journal-title":"Shock"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/s41580-020-00324-8","article-title":"Ferroptosis: Mechanisms, biology and role in disease","volume":"22","author":"Jiang","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1016\/j.molcel.2022.03.022","article-title":"Ferroptosis at the intersection of lipid metabolism and cellular signaling","volume":"82","author":"Liang","year":"2022","journal-title":"Mol. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/s41422-020-00441-1","article-title":"Ferroptosis: Molecular mechanisms and health implications","volume":"31","author":"Tang","year":"2021","journal-title":"Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sun, Y., Chen, P., Zhai, B., Zhang, M., Xiang, Y., Fang, J., Xu, S., Gao, Y., Chen, X., and Sui, X. (2020). The emerging role of ferroptosis in inflammation. Biomed. Pharmacother., 127.","DOI":"10.1016\/j.biopha.2020.110108"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e20210518","DOI":"10.1084\/jem.20210518","article-title":"Ferroptosis in infection, inflammation, and immunity","volume":"218","author":"Chen","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1089\/dna.2021.1072","article-title":"The Emerging Role of Ferroptosis in Sepsis","volume":"41","author":"Liu","year":"2022","journal-title":"DNA Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"956361","DOI":"10.3389\/fimmu.2022.956361","article-title":"Ferroptosis in sepsis: The mechanism, the role and the therapeutic potential","volume":"13","author":"Lei","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"115438","DOI":"10.1016\/j.ejmech.2023.115438","article-title":"Pharmacological inhibition of ferroptosis as a therapeutic target for sepsis-associated organ damage","volume":"257","author":"Huo","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.freeradbiomed.2018.09.014","article-title":"Role of GPX4 in ferroptosis and its pharmacological implication","volume":"133","author":"Seibt","year":"2019","journal-title":"Free Radic. Biol. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.freeradbiomed.2020.02.027","article-title":"Lipid peroxidation and ferroptosis: The role of GSH and GPx4","volume":"152","author":"Ursini","year":"2020","journal-title":"Free Radic. Biol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dodson, M., Castro-Portuguez, R., and Zhang, D.D. (2019). NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol., 23.","DOI":"10.1016\/j.redox.2019.101107"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/s41417-020-0170-2","article-title":"Transcription factors in ferroptotic cell death","volume":"27","author":"Dai","year":"2020","journal-title":"Cancer Gene Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/s41420-022-01173-4","article-title":"Regulating Nrf2-GPx4 axis by bicyclol can prevent ferroptosis in carbon tetrachloride-induced acute liver injury in mice","volume":"8","author":"Zhao","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s41420-021-00807-3","article-title":"Itaconate inhibits ferroptosis of macrophage via Nrf2 pathways against sepsis-induced acute lung injury","volume":"8","author":"He","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1038\/s41418-022-00990-5","article-title":"PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2\/GPX4 pathway","volume":"29","author":"Wang","year":"2022","journal-title":"Cell Death Differ."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/s41419-023-05716-0","article-title":"The interaction between ferroptosis and inflammatory signaling pathways","volume":"14","author":"Chen","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1080\/08830185.2021.2016739","article-title":"Molecular mechanisms of ferroptosis and their role in inflammation","volume":"42","author":"Wang","year":"2023","journal-title":"Int. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Ang, S.F., Moochhala, S.M., MacAry, P.A., and Bhatia, M. (2011). Hydrogen sulfide and neurogenic inflammation in polymicrobial sepsis: Involvement of substance P and ERK-NF-\u03baB signaling. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0024535"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6265","DOI":"10.4049\/jimmunol.1001739","article-title":"Substance P upregulates cyclooxygenase-2 and prostaglandin E metabolite by activating ERK1\/2 and NF-kappaB in a mouse model of burn-induced remote acute lung injury","volume":"185","author":"Sio","year":"2010","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5050","DOI":"10.4049\/jimmunol.176.8.5050","article-title":"Substance P stimulates cyclooxygenase-2 and prostaglandin E2 expression through JAK-STAT activation in human colonic epithelial cells","volume":"176","author":"Koon","year":"2006","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/sj.bjp.0706660","article-title":"Substance P-induced cyclooxygenase-2 expression in human umbilical vein endothelial cells","volume":"147","author":"Gallicchio","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/32897","article-title":"Primary afferent tachykinins are required to experience moderate to intense pain","volume":"392","author":"Cao","year":"1998","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"G830","DOI":"10.1152\/ajpgi.00140.2002","article-title":"Preprotachykinin-A gene deletion protects mice against acute pancreatitis and associated lung injury","volume":"284","author":"Bhatia","year":"2003","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_32","first-page":"e2860","article-title":"Cecal ligation puncture procedure","volume":"51","author":"Toscano","year":"2011","journal-title":"J. Vis. Exp."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Shrum, B., Anantha, R.V., Xu, S.X., Donnelly, M., Haeryfar, S.M., McCormick, J.K., and Mele, T. (2014). A robust scoring system to evaluate sepsis severity in an animal model. BMC Res. Notes, 7.","DOI":"10.1186\/1756-0500-7-233"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1007\/s00595-006-3196-7","article-title":"Liver injury in sepsis and abdominal compartment syndrome in rats","volume":"36","author":"Muftuoglu","year":"2006","journal-title":"Surg. Today"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Jiang, J., Huang, K., Xu, S., Garcia, J.G.N., Wang, C., and Cai, H. (2020). Targeting NOX4 alleviates sepsis-induced acute lung injury via attenuation of redox-sensitive activation of CaMKII\/ERK1\/2\/MLCK and endothelial cell barrier dysfunction. Redox Biol., 36.","DOI":"10.1016\/j.redox.2020.101638"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/s41581-018-0005-7","article-title":"Mechanisms and treatment of organ failure in sepsis","volume":"14","author":"Lelubre","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Rochette, L., Dogon, G., Rigal, E., Zeller, M., Cottin, Y., and Vergely, C. (2022). Lipid Peroxidation and Iron Metabolism: Two Corner Stones in the Homeostasis Control of Ferroptosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24010449"},{"key":"ref_38","first-page":"2405943","article-title":"Mucin 1 Inhibits Ferroptosis and Sensitizes Vitamin E to Alleviate Sepsis-Induced Acute Lung Injury through GSK3\u03b2\/Keap1-Nrf2-GPX4 Pathway","volume":"2022","author":"Wang","year":"2022","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e173","DOI":"10.1002\/ctm2.173","article-title":"Serum irisin levels are decreased in patients with sepsis, and exogenous irisin suppresses ferroptosis in the liver of septic mice","volume":"10","author":"Wei","year":"2020","journal-title":"Clin. Transl. Med."},{"key":"ref_40","first-page":"605","article-title":"Biomarkers of lipid peroxidation: Analytical aspects","volume":"66","author":"Michel","year":"2008","journal-title":"Ann. Biol. Clin."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Gaddam, R.R., Chambers, S., Fraser, R., Cogger, V.C., Le Couteur, D.G., Ishii, I., and Bhatia, M. (2019). Cystathionine-Gamma-Lyase-Derived Hydrogen Sulfide-Regulated Substance P Modulates Liver Sieve Fenestrations in Caecal Ligation and Puncture-Induced Sepsis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20133191"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.intimp.2018.02.017","article-title":"Substance P-regulated leukotriene B4 production promotes acute pancreatitis-associated lung injury through neutrophil reverse migration","volume":"57","author":"Li","year":"2018","journal-title":"Int. Immunopharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1080\/15548627.2020.1810918","article-title":"Ferroptosis: Machinery and regulation","volume":"17","author":"Chen","year":"2021","journal-title":"Autophagy"}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/3\/300\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:06:49Z","timestamp":1760105209000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/13\/3\/300"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,29]]},"references-count":43,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,3]]}},"alternative-id":["antiox13030300"],"URL":"https:\/\/doi.org\/10.3390\/antiox13030300","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,29]]}}}