{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T19:44:45Z","timestamp":1793130285871,"version":"4.5.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T00:00:00Z","timestamp":1678320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Governmental funding for medical doctors for paralel research"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Chemokines are small cytokines that exert chemotactic actions on immune cells and are involved in many inflammatory processes. The present study aims to provide insight in the role of this relatively unexplored family of proteins in the inflammatory pathophysiology of subarachnoid hemorrhage (SAH).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Materials and methods<\/jats:title>\n<jats:p>Cerebrospinal fluid of 29 patients (17 female; mean age 57 years) was collected at days 1, 4 and 10 after SAH, centrifuged and frozen at -70\u00b0C. Analysis of 92 inflammation-related proteins was performed using Target 96 Inflammation <jats:sup>\u00ae<\/jats:sup> assay (Olink Proteomics, Uppsala, Sweden) based on Proximity Extension Assay technology. The panel included 20 chemokines (CCL2 (or MCP-1), CCL3, CCL4, CCL7 (or MCP-3), CCL8 (or MCP-2), CCL11 (or Eotaxin), CCL13 (or MCP-4), CCL19, CCL20, CCL23, CCL25, CCL28, CXCL1, CXCL5, CXCL6, CXCL8 (or IL-8), CXCL9, CXCL10, CXCL11 and CX3CL1 (or Fractalkine)) that were analyzed for their temporal patterns of expression and compared in dichotomized clinical groups based on World Federation of Neurosurgical Societies (WFNS) admission score and amount of blood on admission CT based on Fisher scale; presence of delayed cerebral ischemia(DCI)\/delayed ischemic neurological deficit (DIND); and clinical outcome based on Glasgow Outcome Scale. Protein expression levels were provided in output unit Normalized Protein Expression (NPX). ANOVA models were used for statistical analyses.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Four temporal patterns of expression were observed (i.e., early, middle, late peak and no peak). Significantly higher day 10 mean NPX values were observed in patients with poor outcome (GOS 1\u20133) for chemokines CCL2, CCL4, CCL7, CCL11, CCL13, CCL19, CCL20, CXCL1, CXCL5, CXCL6 and CXCL8. In the WFNS 4\u20135 group, CCL11 showed significantly higher day 4 and day 10 mean NPX values and CCL25 significantly higher day 4 values. In patients with SAH Fisher 4, CCL11 showed significantly higher mean NPX values on days 1, 4 and 10. Finally, patients with DCI\/DIND had significantly higher day 4 mean NPX values of CXCL5.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Higher levels of multiple chemokines at the late stage of SAH seemed to correlate with worse clinical outcome. A few chemokines correlated with WFNS score, Fisher score and occurrence of DCI\/DIND. Chemokines may be useful as biomarkers for describing the pathophysiology and prognosis of SAH. Further studies are needed to better understand their exact mechanism of action in the inflammatory cascade.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0282424","type":"journal-article","created":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T18:51:24Z","timestamp":1678387884000},"page":"e0282424","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Elevated levels of several chemokines in the cerebrospinal fluid of patients with subarachnoid hemorrhage are associated with worse clinical outcome"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8597-8862","authenticated-orcid":true,"given":"Pavlos","family":"Vlachogiannis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Hillered","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Enblad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Ronne-Engstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,3,9]]},"reference":[{"issue":"3","key":"pone.0282424.ref001","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1056\/NEJMcp1605827","article-title":"Subarachnoid Hemorrhage","volume":"377","author":"MT Lawton","year":"2017","journal-title":"The New England journal of medicine"},{"issue":"10069","key":"pone.0282424.ref002","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/S0140-6736(16)30668-7","article-title":"Spontaneous subarachnoid haemorrhage","volume":"389","author":"RL Macdonald","year":"2017","journal-title":"Lancet (London, England)."},{"issue":"2","key":"pone.0282424.ref003","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s12028-019-00710-x","article-title":"Neuroinflammation and Microvascular Dysfunction After Experimental Subarachnoid Hemorrhage: Emerging Components of Early Brain Injury Related to Outcome.","volume":"31","author":"JR Geraghty","year":"2019","journal-title":"Neurocritical care"},{"key":"pone.0282424.ref004","article-title":"Aneurysmal Subarachnoid Hemorrhage: an Overview of Inflammation-Induced Cellular Changes.","author":"AP Coulibaly","year":"2020","journal-title":"Neurotherapeutics: the journal of the American Society for Experimental NeuroTherapeutics"},{"key":"pone.0282424.ref005","article-title":"Inflammatory events following subarachnoid hemorrhage (SAH).","author":"UC Schneider","year":"2018","journal-title":"Current neuropharmacology"},{"key":"pone.0282424.ref006","doi-asserted-by":"crossref","first-page":"379","DOI":"10.3389\/fneur.2017.00379","article-title":"Cerebrospinal Fluid and Microdialysis Cytokines in Aneurysmal Subarachnoid Hemorrhage: A Scoping Systematic Review.","volume":"8","author":"FA Zeiler","year":"2017","journal-title":"Frontiers in neurology"},{"issue":"4","key":"pone.0282424.ref007","doi-asserted-by":"crossref","first-page":"497","DOI":"10.3390\/ijms17040497","article-title":"Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review","volume":"17","author":"BP Lucke-Wold","year":"2016","journal-title":"International journal of molecular sciences"},{"issue":"Pt 1","key":"pone.0282424.ref008","first-page":"191","article-title":"Monitoring of the inflammatory response after aneurysmal subarachnoid haemorrhage in the clinical setting: review of literature and report of preliminary clinical experience.","volume":"110","author":"C Muroi","year":"2011","journal-title":"Acta neurochirurgica Supplement"},{"issue":"1","key":"pone.0282424.ref009","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s12035-010-8155-z","article-title":"Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury","volume":"43","author":"FA Sehba","year":"2011","journal-title":"Molecular neurobiology"},{"issue":"4","key":"pone.0282424.ref010","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1007\/s12975-013-0257-2","article-title":"Early brain injury, an evolving frontier in subarachnoid hemorrhage research","volume":"4","author":"M Fujii","year":"2013","journal-title":"Translational stroke research"},{"issue":"2","key":"pone.0282424.ref011","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1179\/174313209X393564","article-title":"Cerebral vasospasm following subarachnoid hemorrhage: time for a new world of thought","volume":"31","author":"RM Pluta","year":"2009","journal-title":"Neurological research"},{"issue":"3","key":"pone.0282424.ref012","doi-asserted-by":"crossref","first-page":"e0263460","DOI":"10.1371\/journal.pone.0263460","article-title":"Temporal patterns of inflammation-related proteins measured in the cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage using multiplex Proximity Extension Assay technology","volume":"17","author":"P Vlachogiannis","year":"2022","journal-title":"PloS one"},{"key":"pone.0282424.ref013","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1146\/annurev-immunol-032713-120145","article-title":"Chemokines and chemokine receptors: positioning cells for host defense and immunity","volume":"32","author":"JW Griffith","year":"2014","journal-title":"Annual review of immunology"},{"issue":"4","key":"pone.0282424.ref014","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/cmi.2017.134","article-title":"Chemokines in homeostasis and diseases","volume":"15","author":"K Chen","year":"2018","journal-title":"Cellular & molecular immunology"},{"issue":"1","key":"pone.0282424.ref015","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1186\/s12974-020-01882-6","article-title":"CX3CL1\/CX3CR1 axis attenuates early brain injury via promoting the delivery of exosomal microRNA-124 from neuron to microglia after subarachnoid hemorrhage","volume":"17","author":"X Chen","year":"2020","journal-title":"Journal of neuroinflammation."},{"key":"pone.0282424.ref016","doi-asserted-by":"crossref","first-page":"155142","DOI":"10.1016\/j.cyto.2020.155142","article-title":"Elevated level of cerebrospinal fluid and systemic chemokine CCL5 is a predictive biomarker of clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH).","volume":"133","author":"SR Chaudhry","year":"2020","journal-title":"Cytokine"},{"issue":"1","key":"pone.0282424.ref017","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s12974-019-1578-1","article-title":"Inflammation in delayed ischemia and functional outcomes after subarachnoid hemorrhage","volume":"16","author":"SH Ahn","year":"2019","journal-title":"Journal of neuroinflammation"},{"issue":"1","key":"pone.0282424.ref018","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s12974-016-0675-7","article-title":"Interleukin-6, MCP-1, IP-10, and MIG are sequentially expressed in cerebrospinal fluid after subarachnoid hemorrhage","volume":"13","author":"A Niwa","year":"2016","journal-title":"Journal of neuroinflammation"},{"key":"pone.0282424.ref019","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jns.2016.01.024","article-title":"Elevation of serum CXC chemokine ligand-12 levels predicts poor outcome after aneurysmal subarachnoid hemorrhage","volume":"362","author":"DS Pan","year":"2016","journal-title":"Journal of the neurological sciences"},{"issue":"1","key":"pone.0282424.ref020","doi-asserted-by":"crossref","first-page":"38","DOI":"10.3171\/JNS\/2008\/109\/7\/0038","article-title":"Monocyte chemoattractant protein-1 predicts outcome and vasospasm following aneurysmal subarachnoid hemorrhage","volume":"109","author":"GH Kim","year":"2008","journal-title":"Journal of neurosurgery"},{"key":"pone.0282424.ref021","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.bdq.2015.04.002","article-title":"Proximity assays for sensitive quantification of proteins","volume":"4","author":"C Greenwood","year":"2015","journal-title":"Biomolecular detection and quantification"},{"issue":"4","key":"pone.0282424.ref022","doi-asserted-by":"crossref","first-page":"e95192","DOI":"10.1371\/journal.pone.0095192","article-title":"Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability","volume":"9","author":"E Assarsson","year":"2014","journal-title":"PloS one"},{"issue":"4","key":"pone.0282424.ref023","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1080\/01616412.1998.11740528","article-title":"Cisternal CSF levels of cytokines after subarachnoid hemorrhage","volume":"20","author":"P Gaetani","year":"1998","journal-title":"Neurological research"},{"issue":"11","key":"pone.0282424.ref024","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1136\/jnnp.51.11.1457","article-title":"A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies","volume":"51","author":"GM Teasdale","year":"1988","journal-title":"Journal of neurology, neurosurgery, and psychiatry"},{"issue":"1","key":"pone.0282424.ref025","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1227\/00006123-198001000-00001","article-title":"Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning","volume":"6","author":"CM Fisher","year":"1980","journal-title":"Neurosurgery"},{"issue":"7905","key":"pone.0282424.ref026","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/S0140-6736(75)92830-5","article-title":"Assessment of outcome after severe brain damage","volume":"1","author":"B Jennett","year":"1975","journal-title":"Lancet (London, England)."},{"issue":"6","key":"pone.0282424.ref027","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1007\/s12975-019-00764-1","article-title":"Immune Characterization in Aneurysmal Subarachnoid Hemorrhage Reveals Distinct Monocytic Activation and Chemokine Patterns.","volume":"11","author":"M Mohme","year":"2020","journal-title":"Translational stroke research"},{"key":"pone.0282424.ref028","doi-asserted-by":"crossref","first-page":"577610","DOI":"10.1016\/j.jneuroim.2021.577610","article-title":"Sequential expression of neutrophil chemoattractants in cerebrospinal fluid after subarachnoid hemorrhage","volume":"357","author":"K Osuka","year":"2021","journal-title":"Journal of neuroimmunology"},{"key":"pone.0282424.ref029","doi-asserted-by":"crossref","first-page":"154778","DOI":"10.1016\/j.cyto.2019.154778","article-title":"Compartmentalisation of the inflammatory response following aneurysmal subarachnoid haemorrhage","volume":"123","author":"YZ Al-Tamimi","year":"2019","journal-title":"Cytokine"},{"issue":"3","key":"pone.0282424.ref030","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s12028-009-9276-y","article-title":"High-mobility group box 1 protein in CSF of patients with subarachnoid hemorrhage.","volume":"11","author":"T Nakahara","year":"2009","journal-title":"Neurocritical care"},{"key":"pone.0282424.ref031","doi-asserted-by":"crossref","first-page":"e1131","DOI":"10.1016\/j.wneu.2019.05.102","article-title":"Plasma Levels of IL-6, IL-8, IL-10, ICAM-1, VCAM-1, IFNgamma, and TNFalpha are not Associated with Delayed Cerebral Ischemia, Cerebral Vasospasm, or Clinical Outcome in Patients with Subarachnoid Hemorrhage","volume":"128","author":"R Rasmussen","year":"2019","journal-title":"World neurosurgery"},{"issue":"16","key":"pone.0282424.ref032","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1212\/WNL.0000000000003842","article-title":"Systematic model of peripheral inflammation after subarachnoid hemorrhage","volume":"88","author":"JPJ Savarraj","year":"2017","journal-title":"Neurology"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0282424","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,3,9]],"date-time":"2023-03-09T18:51:50Z","timestamp":1678387910000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0282424"}},"subtitle":[],"editor":[{"given":"Markus Harboe","family":"Olsen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,3,9]]},"references-count":32,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0282424","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,9]]}}}