{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:59:47Z","timestamp":1792198787429,"version":"4.4.0"},"reference-count":117,"publisher":"National Academy of Sciences","issue":"18","license":[{"start":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T00:00:00Z","timestamp":1635292800000},"content-version":"vor","delay-in-days":183,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2021,5,4]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>Disruption of the blood\u2013brain barrier (BBB) for drug delivery to the central nervous system (CNS) is achieved clinically through intracarotid artery hyperosmotic mannitol (ICAHM) infusions. However, ICAHM is often viewed as a simple drug delivery mechanism, and biological implications have been largely overlooked. This study demonstrates that BBB disruption by ICAHM generates a transient sterile neuroinflammatory response marked by increased production of cytokines, chemokines, and trophic factors leading activation of astrocytes, microglia, and macrophages. Additionally, unilateral ICAHM generates plasma increases in inflammatory molecules with evidence of sterile inflammation on the untreated contralateral hemisphere. These biological responses to ICAHM suggest its potential for immune modulation in several CNS pathologies.<\/jats:p>","DOI":"10.1073\/pnas.2021915118","type":"journal-article","created":{"date-parts":[[2021,4,27]],"date-time":"2021-04-27T15:37:03Z","timestamp":1619537823000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":69,"title":["Blood\u2013brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses"],"prefix":"10.1073","volume":"118","author":[{"given":"Scott R.","family":"Burks","sequence":"first","affiliation":[{"name":"Frank Laboratory, Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, MD 20895;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cymon N.","family":"Kersch","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health &amp; Science University, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2443-1660","authenticated-orcid":false,"given":"Jaclyn A.","family":"Witko","sequence":"additional","affiliation":[{"name":"Frank Laboratory, Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, MD 20895;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Pagel","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health &amp; Science University, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Sundby","sequence":"additional","affiliation":[{"name":"Frank Laboratory, Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, MD 20895;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5583-2304","authenticated-orcid":false,"given":"Leslie L.","family":"Muldoon","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health &amp; Science University, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6679-6203","authenticated-orcid":false,"given":"Edward A.","family":"Neuwelt","sequence":"additional","affiliation":[{"name":"Department of Neurology, Oregon Health &amp; Science University, Portland, OR 97239;"},{"name":"Department of Neurological Surgery, Oregon Health &amp; Science University, Portland, OR 97239;"},{"name":"Portland Veterans Affairs Medical Center, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8636-7273","authenticated-orcid":false,"given":"Joseph A.","family":"Frank","sequence":"additional","affiliation":[{"name":"Frank Laboratory, Radiology and Imaging Sciences, NIH Clinical Center, Bethesda, MD 20895;"},{"name":"National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD 20895"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2021,4,27]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a020412"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.10.067"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2015.21"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2014.10.004"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2010.05.003"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R116.760215"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00405"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.01.002"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nox175"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apha.2014.06.002"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12426-9"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04529-6"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf6086"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-36340-0"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.3171\/2019.10.Jns192206"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-020-03435-6"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-016-2099-8"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006123-199805000-00082"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.2214\/ajr.141.4.829"},{"key":"e_1_3_4_20_2","first-page":"166","article-title":"Non-AIDS primary CNS lymphoma: First example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy","volume":"2","author":"Dahlborg S. A.","year":"1996","unstructured":"S. A. Dahlborg ., Non-AIDS primary CNS lymphoma: First example of a durable response in a primary brain tumor using enhanced chemotherapy delivery without cognitive loss and without radiotherapy. Cancer J. Sci. Am. 2, 166\u2013174 (1996).","journal-title":"Cancer J. Sci. Am."},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1614777114"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.3171\/2014.10.JNS14229"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(07)70326-5"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2002571117"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2202001804"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ultrasmedbio.2007.11.009"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0430-09.2009"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.05.019"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2012.11.007"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0071477"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2015.00147"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2873"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2018.10.012"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.24512"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2014.00315"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.021908.132528"},{"key":"e_1_3_4_37_2","first-page":"555","article-title":"Non-invasive opening of BBB by focused ultrasound","volume":"86","author":"Hynynen K.","year":"2003","unstructured":"K. Hynynen, N. McDannold, N. Vykhodtseva, F. A. Jolesz, Non-invasive opening of BBB by focused ultrasound. Acta Neurochir. Suppl. (Wien) 86, 555\u2013558 (2003).","journal-title":"Acta Neurochir. Suppl. (Wien)"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3109\/02656736.2015.1009179"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep45657"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.21630"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.24181"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.08.001"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.35892"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2013.52.7747"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(20000201)88:3<637::AID-CNCR22>3.0.CO;2-Y"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.3171\/2010.9.JNS101223"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.19.3789"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.1991.9.9.1580"},{"key":"e_1_3_4_49_2","first-page":"261","article-title":"Durability of single dose intra-arterial bevacizumab after blood\/brain barrier disruption for recurrent glioblastoma","volume":"11","author":"Chakraborty S.","year":"2016","unstructured":"S. Chakraborty ., Durability of single dose intra-arterial bevacizumab after blood\/brain barrier disruption for recurrent glioblastoma. J. Exp. Ther. Oncol. 11, 261\u2013267 (2016).","journal-title":"J. Exp. Ther. Oncol."},{"key":"e_1_3_4_50_2","first-page":"110","article-title":"The potential for complete and durable response in nonglial primary brain tumors in children and young adults with enhanced chemotherapy delivery","volume":"4","author":"Dahlborg S. A.","year":"1998","unstructured":"S. A. Dahlborg ., The potential for complete and durable response in nonglial primary brain tumors in children and young adults with enhanced chemotherapy delivery. Cancer J. Sci. Am. 4, 110\u2013124 (1998).","journal-title":"Cancer J. Sci. Am."},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1007049806660"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2009.07.028"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02106-16"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867321666131227162634"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2011.12.045"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1159\/000098260"},{"key":"e_1_3_4_57_2","first-page":"217","article-title":"A physiological barrier distal to the anatomic blood-brain barrier in a model of transvascular delivery","volume":"20","author":"Muldoon L. L.","year":"1999","unstructured":"L. L. Muldoon ., A physiological barrier distal to the anatomic blood-brain barrier in a model of transvascular delivery. AJNR Am. J. Neuroradiol. 20, 217\u2013222 (1999).","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00688236"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.3MIR0220-270R"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn.2018.13"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrneurol.2010.74"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1167.2012.03666.x"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00288"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2013.04.022"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2014.11.002"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1615\/CritRevImmunol.v21.i5.20"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.01049"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-14-05865.2002"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.05-4829fje"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.03.020"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn3898"},{"key":"e_1_3_4_72_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2007.0336"},{"key":"e_1_3_4_73_2","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1377"},{"key":"e_1_3_4_74_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2009.06.081"},{"key":"e_1_3_4_75_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-01919-w"},{"key":"e_1_3_4_76_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.mp.4000813"},{"key":"e_1_3_4_77_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01484-6"},{"key":"e_1_3_4_78_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1971.51.2.273"},{"key":"e_1_3_4_79_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.25604"},{"key":"e_1_3_4_80_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003748"},{"key":"e_1_3_4_81_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2018.03.028"},{"key":"e_1_3_4_82_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M200077-MCP200"},{"key":"e_1_3_4_83_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.2004.21.1553"},{"key":"e_1_3_4_84_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.97105"},{"key":"e_1_3_4_85_2","doi-asserted-by":"publisher","DOI":"10.1177\/0271678X19855875"},{"key":"e_1_3_4_86_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.29.12.2631"},{"key":"e_1_3_4_87_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2013.06.001"},{"key":"e_1_3_4_88_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2008.08.027"},{"key":"e_1_3_4_89_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-013-1459-1"},{"key":"e_1_3_4_90_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103460"},{"key":"e_1_3_4_91_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-015-0346-0"},{"key":"e_1_3_4_92_2","first-page":"559","article-title":"The influence of anesthetic choice, PaCO2, and other factors on osmotic blood-brain barrier disruption in rats with brain tumor xenografts","volume":"88","author":"Remsen L. G.","year":"1999","unstructured":"L. G. Remsen ., The influence of anesthetic choice, PaCO2, and other factors on osmotic blood-brain barrier disruption in rats with brain tumor xenografts. Anesth. Analg. 88, 559\u2013567 (1999).","journal-title":"Anesth. Analg."},{"key":"e_1_3_4_93_2","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.14140245"},{"key":"e_1_3_4_94_2","doi-asserted-by":"publisher","DOI":"10.4155\/tde.11.5"},{"key":"e_1_3_4_95_2","doi-asserted-by":"publisher","DOI":"10.1002\/jum.14256"},{"key":"e_1_3_4_96_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaa2512"},{"key":"e_1_3_4_97_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24933"},{"key":"e_1_3_4_98_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awx052"},{"key":"e_1_3_4_99_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0002175"},{"key":"e_1_3_4_100_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.28717"},{"key":"e_1_3_4_101_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-32250-3"},{"key":"e_1_3_4_102_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2014.07.051"},{"key":"e_1_3_4_103_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.20621"},{"key":"e_1_3_4_104_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.49"},{"key":"e_1_3_4_105_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9020263"},{"key":"e_1_3_4_106_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-020-03450-7"},{"key":"e_1_3_4_107_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-018-0007-y"},{"key":"e_1_3_4_108_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1129139"},{"key":"e_1_3_4_109_2","doi-asserted-by":"publisher","DOI":"10.1002\/mrm.22686"},{"key":"e_1_3_4_110_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-39263-6"},{"key":"e_1_3_4_111_2","first-page":"953","article-title":"Optimizing the delivery of antineoplastic therapies to the central nervous system","volume":"30","author":"Naidoo J.","year":"2016","unstructured":"J. Naidoo, H. Panday, S. Jackson, S. A. Grossman, Optimizing the delivery of antineoplastic therapies to the central nervous system. Oncology (Williston Park) 30, 953\u2013962 (2016).","journal-title":"Oncology (Williston Park)"},{"key":"e_1_3_4_112_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006123-199810000-00090"},{"key":"e_1_3_4_113_2","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v025.i01"},{"key":"e_1_3_4_114_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"e_1_3_4_115_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btr260"},{"key":"e_1_3_4_116_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004"},{"key":"e_1_3_4_117_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013984"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2021915118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T06:05:49Z","timestamp":1649829949000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2021915118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,27]]},"references-count":117,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2021,5,4]]}},"alternative-id":["10.1073\/pnas.2021915118"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2021915118","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,27]]},"assertion":[{"value":"2021-04-27","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2021915118"}}