{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:30:53Z","timestamp":1790382653496,"version":"4.1.0"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2009,2,6]],"date-time":"2009-02-06T00:00:00Z","timestamp":1233878400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2009,2,6]],"date-time":"2009-02-06T00:00:00Z","timestamp":1233878400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Crit Care"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Septic encephalopathy secondary to a breakdown of the blood-brain barrier (BBB) is a known complication of sepsis. However, its pathophysiology remains unclear. The present study investigated the effect of complement C5a blockade in preventing BBB damage and pituitary dysfunction during experimental sepsis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using the standardised caecal ligation and puncture (CLP) model, Sprague-Dawley rats were treated with either neutralising anti-C5a antibody or pre-immune immunoglobulin (Ig) G as a placebo. Sham-operated animals served as internal controls.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Placebo-treated septic rats showed severe BBB dysfunction within 24 hours, accompanied by a significant upregulation of pituitary C5a receptor and pro-inflammatory cytokine expression, although gene levels of growth hormone were significantly attenuated. The pathophysiological changes in placebo-treated septic rats were restored by administration of neutralising anti-C5a antibody to the normal levels of BBB and pituitary function seen in the sham-operated group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Collectively, the neutralisation of C5a greatly ameliorated pathophysiological changes associated with septic encephalopathy, implying a further rationale for the concept of pharmacological C5a inhibition in sepsis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/cc7710","type":"journal-article","created":{"date-parts":[[2009,2,20]],"date-time":"2009-02-20T14:13:56Z","timestamp":1235139236000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":90,"title":["Inhibition of complement C5a prevents breakdown of the blood-brain barrier and pituitary dysfunction in experimental sepsis"],"prefix":"10.1186","volume":"13","author":[{"given":"Michael A","family":"Flierl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip F","family":"Stahel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rittirsch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Huber-Lang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas D","family":"Niederbichler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L Marco","family":"Hoesel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Basel M","family":"Touban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J","family":"Morgan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wade R","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyros","family":"Ipaktchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2009,2,6]]},"reference":[{"key":"7143_CR1","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1097\/01.CCM.0000261890.41311.E9","volume":"35","author":"VY Dombrovskiy","year":"2007","unstructured":"Dombrovskiy VY, Martin AA, Sunderram J, Paz HL: Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003.\n                           Crit Care Med 2007, 35: 1244-1250.","journal-title":"Crit Care Med"},{"key":"7143_CR2","first-page":"1","volume":"56","author":"HC Kung","year":"2008","unstructured":"Kung HC, Hoyert DL, Xu J, Murphy SL: Deaths: final data for 2005.\n                           Natl Vital Stat Rep 2008, 56: 1-120.","journal-title":"Natl Vital Stat Rep"},{"key":"7143_CR3","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1038\/nri2402","volume":"8","author":"D Rittirsch","year":"2008","unstructured":"Rittirsch D, Flierl MA, Ward PA: Harmful molecular mechanisms in sepsis.\n                           Nat Rev Immunol 2008, 8: 776-787.","journal-title":"Nat Rev Immunol"},{"key":"7143_CR4","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1097\/01.CCM.0000050454.01978.3B","volume":"31","author":"MM Levy","year":"2003","unstructured":"Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM\/ESICM\/ACCP\/ATS\/SIS International Sepsis Definitions Conference.\n                           Crit Care Med 2003, 31: 1250-1256.","journal-title":"Crit Care Med"},{"key":"7143_CR5","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/S0140-6736(04)17667-8","volume":"365","author":"D Annane","year":"2005","unstructured":"Annane D, Bellissant E, Cavaillon JM: Septic shock.\n                           Lancet 2005, 365: 63-78.","journal-title":"Lancet"},{"key":"7143_CR6","first-page":"189","volume":"84","author":"H Nakae","year":"1994","unstructured":"Nakae H, Endo S, Inada K, Takakuwa T, Kasai T, Yoshida M: Serum complement levels and severity of sepsis.\n                           Res Commun Chem Pathol Pharmacol 1994, 84: 189-195.","journal-title":"Res Commun Chem Pathol Pharmacol"},{"key":"7143_CR7","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1007\/BF00311579","volume":"26","author":"H Nakae","year":"1996","unstructured":"Nakae H, Endo S, Inada K, Yoshida M: Chronological changes in the complement system in sepsis.\n                           Surg Today 1996, 26: 225-229.","journal-title":"Surg Today"},{"key":"7143_CR8","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1128\/cdli.3.2.175-183.1996","volume":"3","author":"S Stove","year":"1996","unstructured":"Stove S, Welte T, Wagner TO, Kola A, Klos A, Bautsch W, Kohl J: Circulating complement proteins in patients with sepsis or systemic inflammatory response syndrome.\n                           Clin Diagn Lab Immunol 1996, 3: 175-183.","journal-title":"Clin Diagn Lab Immunol"},{"key":"7143_CR9","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/0002-9343(89)90224-6","volume":"86","author":"CE Hack","year":"1989","unstructured":"Hack CE, Nuijens JH, Felt-Bersma RJ, Schreuder WO, Eerenberg-Belmer AJ, Paardekooper J, Bronsveld W, Thijs LG: Elevated plasma levels of the anaphylatoxins C3a and C4a are associated with a fatal outcome in sepsis.\n                           Am J Med 1989, 86: 20-26.","journal-title":"Am J Med"},{"key":"7143_CR10","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1038\/10512","volume":"5","author":"BJ Czermak","year":"1999","unstructured":"Czermak BJ, Sarma V, Pierson CL, Warner RL, Huber-Lang M, Bless NM, Schmal H, Friedl HP, Ward PA: Protective effects of C5a blockade in sepsis.\n                           Nat Med 1999, 5: 788-792.","journal-title":"Nat Med"},{"key":"7143_CR11","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1096\/fj.00-0653fje","volume":"15","author":"MS Huber-Lang","year":"2001","unstructured":"Huber-Lang MS, Sarma JV, McGuire SR, Lu KT, Guo RF, Padgaonkar VA, Younkin EM, Laudes IJ, Riedemann NC, Younger JG, Ward PA: Protective effects of anti-C5a peptide antibodies in experimental sepsis.\n                           Faseb J 2001, 15: 568-570.","journal-title":"Faseb J"},{"key":"7143_CR12","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1172\/JCI0215409","volume":"110","author":"NC Riedemann","year":"2002","unstructured":"Riedemann NC, Guo RF, Neff TA, Laudes IJ, Keller KA, Sarma VJ, Markiewski MM, Mastellos D, Strey CW, Pierson CL, Lambris JD, Zetoune FS, Ward PA: Increased C5a receptor expression in sepsis.\n                           J Clin Invest 2002, 110: 101-108.","journal-title":"J Clin Invest"},{"key":"7143_CR13","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1084\/jem.20051207","volume":"203","author":"AD Niederbichler","year":"2006","unstructured":"Niederbichler AD, Hoesel LM, Westfall MV, Gao H, Ipaktchi KR, Sun L, Zetoune FS, Su GL, Arbabi S, Sarma JV, Wang SC, Hemmila MR, Ward PA: An essential role for complement C5a in the pathogenesis of septic cardiac dysfunction.\n                           J Exp Med 2006, 203: 53-61.","journal-title":"J Exp Med"},{"key":"7143_CR14","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1038\/nm1753","volume":"14","author":"D Rittirsch","year":"2008","unstructured":"Rittirsch D, Flierl MA, Nadeau BA, Day DE, Huber-Lang M, Mackay CR, Zetoune FS, Gerard NP, Cianflone K, Kohl J, Gerard C, Sarma JV, Ward PA: Functional roles for C5a receptors in sepsis.\n                           Nat Med 2008, 14: 551-557.","journal-title":"Nat Med"},{"key":"7143_CR15","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1056\/NEJMcibr022995","volume":"348","author":"C Gerard","year":"2003","unstructured":"Gerard C: Complement C5a in the sepsis syndrome \u2013 too much of a good thing?\n                           N Engl J Med 2003, 348: 167-169.","journal-title":"N Engl J Med"},{"key":"7143_CR16","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1038\/nri1269","volume":"4","author":"PA Ward","year":"2004","unstructured":"Ward PA: The dark side of C5a in sepsis.\n                           Nat Rev Immunol 2004, 4: 133-142.","journal-title":"Nat Rev Immunol"},{"key":"7143_CR17","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1172\/JCI10793","volume":"106","author":"RF Guo","year":"2000","unstructured":"Guo RF, Huber-Lang M, Wang X, Sarma V, Padgaonkar VA, Craig RA, Riedemann NC, McClintock SD, Hlaing T, Shi MM, Ward PA: Protective effects of anti-C5a in sepsis-induced thymocyte apoptosis.\n                           J Clin Invest 2000, 106: 1271-1280.","journal-title":"J Clin Invest"},{"key":"7143_CR18","doi-asserted-by":"publisher","first-page":"e2560","DOI":"10.1371\/journal.pone.0002560","volume":"3","author":"MA Flierl","year":"2008","unstructured":"Flierl MA, Rittirsch D, Chen AJ, Nadeau BA, Day DE, Sarma JV, Huber-Lang MS, Ward PA: The complement anaphylatoxin C5a induces apoptosis in adrenomedullary cells during experimental sepsis.\n                           PLoS ONE 2008, 3: e2560.","journal-title":"PLoS ONE"},{"key":"7143_CR19","doi-asserted-by":"publisher","first-page":"1567","DOI":"10.1096\/fj.02-0209com","volume":"16","author":"MS Huber-Lang","year":"2002","unstructured":"Huber-Lang MS, Riedeman NC, Sarma JV, Younkin EM, McGuire SR, Laudes IJ, Lu KT, Guo RF, Neff TA, Padgaonkar VA, Lambris JD, Spruce L, Mastellos D, Zetoune FS, Ward PA: Protection of innate immunity by C5aR antagonist in septic mice.\n                           Faseb J 2002, 16: 1567-1574.","journal-title":"Faseb J"},{"key":"7143_CR20","doi-asserted-by":"publisher","first-page":"3223","DOI":"10.4049\/jimmunol.169.6.3223","volume":"169","author":"MS Huber-Lang","year":"2002","unstructured":"Huber-Lang MS, Younkin EM, Sarma JV, McGuire SR, Lu KT, Guo RF, Padgaonkar VA, Curnutte JT, Erickson R, Ward PA: Complement-induced impairment of innate immunity during sepsis.\n                           J Immunol 2002, 169: 3223-3231.","journal-title":"J Immunol"},{"key":"7143_CR21","doi-asserted-by":"publisher","first-page":"1867","DOI":"10.1016\/S0002-9440(10)61133-9","volume":"160","author":"IJ Laudes","year":"2002","unstructured":"Laudes IJ, Chu JC, Sikranth S, Huber-Lang M, Guo RF, Riedemann N, Sarma JV, Schmaier AH, Ward PA: Anti-c5a ameliorates coagulation\/fibrinolytic protein changes in a rat model of sepsis.\n                           Am J Pathol 2002, 160: 1867-1875.","journal-title":"Am J Pathol"},{"key":"7143_CR22","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.4049\/jimmunol.166.2.1193","volume":"166","author":"M Huber-Lang","year":"2001","unstructured":"Huber-Lang M, Sarma VJ, Lu KT, McGuire SR, Padgaonkar VA, Guo RF, Younkin EM, Kunkel RG, Ding J, Erickson R, Curnutte JT, Ward PA: Role of C5a in multiorgan failure during sepsis.\n                           J Immunol 2001, 166: 1193-1199.","journal-title":"J Immunol"},{"key":"7143_CR23","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/1742-2094-5-38","volume":"5","author":"A Semmler","year":"2008","unstructured":"Semmler A, Hermann S, Mormann F, Weberpals M, Paxian SA, Okulla T, Schafers M, Kummer MP, Klockgether T, Heneka MT: Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism.\n                           J Neuroinflammation 2008, 5: 38.","journal-title":"J Neuroinflammation"},{"key":"7143_CR24","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1093\/bja\/aem201","volume":"99","author":"O Piazza","year":"2007","unstructured":"Piazza O, Russo E, Cotena S, Esposito G, Tufano R: Elevated S100B levels do not correlate with the severity of encephalopathy during sepsis.\n                           Br J Anaesth 2007, 99: 518-521.","journal-title":"Br J Anaesth"},{"key":"7143_CR25","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.neuint.2007.08.006","volume":"52","author":"JJ Alexander","year":"2008","unstructured":"Alexander JJ, Jacob A, Cunningham P, Hensley L, Quigg RJ: TNF is a key mediator of septic encephalopathy acting through its receptor, TNF receptor-1.\n                           Neurochem Int 2008, 52: 447-456.","journal-title":"Neurochem Int"},{"key":"7143_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S0265021507003444","volume":"42","author":"ML Wratten","year":"2008","unstructured":"Wratten ML: Therapeutic approaches to reduce systemic inflammation in septic-associated neurologic complications.\n                           Eur J Anaesthesiol Suppl 2008, 42: 1-7.","journal-title":"Eur J Anaesthesiol Suppl"},{"key":"7143_CR27","doi-asserted-by":"publisher","first-page":"H1712","DOI":"10.1152\/ajpheart.00476.2008","volume":"295","author":"O Handa","year":"2008","unstructured":"Handa O, Stephen J, Cepinskas G: Role of eNOS-derived nitric oxide (NO) in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis.\n                           Am J Physiol Heart Circ Physiol 2008, 295: H1712-1719.","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"7143_CR28","volume-title":"J Surg Res","author":"HZ Toklu","year":"2008","unstructured":"Toklu HZ, Uysal MK, Kabasakal L, Sirvanci S, Ercan F, Kaya M: The effects of riluzole on neurological, brain biochemical, and histological changes in early and late term of sepsis in rats.\n                           J Surg Res 2008."},{"key":"7143_CR29","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.jss.2007.07.021","volume":"146","author":"S Hofer","year":"2008","unstructured":"Hofer S, Bopp C, Hoerner C, Plaschke K, Faden RM, Martin E, Bardenheuer HJ, Weigand MA: Injury of the blood brain barrier and up-regulation of icam-1 in polymicrobial sepsis.\n                           J Surg Res 2008, 146: 276-281.","journal-title":"J Surg Res"},{"key":"7143_CR30","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00309339","volume":"89","author":"PM Faustmann","year":"1995","unstructured":"Faustmann PM, Krause D, Dux R, Dermietzel R: Morphological study in the early stages of complement C5a fragment-induced experimental meningitis: activation of macrophages and astrocytes.\n                           Acta Neuropathol 1995, 89: 239-247.","journal-title":"Acta Neuropathol"},{"key":"7143_CR31","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/S0166-2236(98)01390-3","volume":"22","author":"S Nataf","year":"1999","unstructured":"Nataf S, Stahel PF, Davoust N, Barnum SR: Complement anaphylatoxin receptors on neurons: new tricks for old receptors?\n                           Trends Neurosci 1999, 22: 397-402.","journal-title":"Trends Neurosci"},{"key":"7143_CR32","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1586\/1744666X.2.3.445","volume":"2","author":"PF Stahel","year":"2006","unstructured":"Stahel PF, Barnum SR: The role of the complement system in CNS inflammatory diseases.\n                           Expert Rev Clin Immunol 2006, 2: 445-456.","journal-title":"Expert Rev Clin Immunol"},{"key":"7143_CR33","doi-asserted-by":"crossref","first-page":"861","DOI":"10.4049\/jimmunol.159.2.861","volume":"159","author":"PF Stahel","year":"1997","unstructured":"Stahel PF, Frei K, Eugster HP, Fontana A, Hummel KM, Wetsel RA, Ames RS, Barnum SR: TNF-alpha-mediated expression of the receptor for anaphylatoxin C5a on neurons in experimental Listeria meningoencephalitis.\n                           J Immunol 1997, 159: 861-869.","journal-title":"J Immunol"},{"key":"7143_CR34","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1016\/S0306-4522(98)00372-8","volume":"88","author":"H Osaka","year":"1999","unstructured":"Osaka H, McGinty A, Hoepken UE, Lu B, Gerard C, Pasinetti GM: Expression of C5a receptor in mouse brain: role in signal transduction and neurodegeneration.\n                           Neuroscience 1999, 88: 1073-1082.","journal-title":"Neuroscience"},{"key":"7143_CR35","doi-asserted-by":"publisher","first-page":"4154","DOI":"10.4049\/jimmunol.166.6.4154","volume":"166","author":"SA O'Barr","year":"2001","unstructured":"O'Barr SA, Caguioa J, Gruol D, Perkins G, Ember JA, Hugli T, Cooper NR: Neuronal expression of a functional receptor for the C5a complement activation fragment.\n                           J Immunol 2001, 166: 4154-4162.","journal-title":"J Immunol"},{"key":"7143_CR36","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1128\/iai.46.1.81-86.1984","volume":"46","author":"JD Ernst","year":"1984","unstructured":"Ernst JD, Hartiala KT, Goldstein IM, Sande MA: Complement (C5)-derived chemotactic activity accounts for accumulation of polymorphonuclear leukocytes in cerebrospinal fluid of rabbits with pneumococcal meningitis.\n                           Infect Immun 1984, 46: 81-86.","journal-title":"Infect Immun"},{"key":"7143_CR37","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/S0165-5728(85)80004-7","volume":"9","author":"CA Williams","year":"1985","unstructured":"Williams CA, Schupf N, Hugli TE: Anaphylatoxin C5a modulation of an alpha-adrenergic receptor system in the rat hypothalamus.\n                           J Neuroimmunol 1985, 9: 29-40.","journal-title":"J Neuroimmunol"},{"key":"7143_CR38","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1038\/labinvest.3700686","volume":"87","author":"A Jacob","year":"2007","unstructured":"Jacob A, Hensley LK, Safratowich BD, Quigg RJ, Alexander JJ: The role of the complement cascade in endotoxin-induced septic encephalopathy.\n                           Lab Invest 2007, 87: 1186-1194.","journal-title":"Lab Invest"},{"key":"7143_CR39","first-page":"331","volume":"94","author":"CC Baker","year":"1983","unstructured":"Baker CC, Chaudry IH, Gaines HO, Baue AE: Evaluation of factors affecting mortality rate after sepsis in a murine cecal ligation and puncture model.\n                           Surgery 1983, 94: 331-335.","journal-title":"Surgery"},{"key":"7143_CR40","doi-asserted-by":"publisher","first-page":"5962","DOI":"10.4049\/jimmunol.169.10.5962","volume":"169","author":"IJ Laudes","year":"2002","unstructured":"Laudes IJ, Chu JC, Huber-Lang M, Guo RF, Riedemann NC, Sarma JV, Mahdi F, Murphy HS, Speyer C, Lu KT, Lambris JD, Zetoune FS, Ward PA: Expression and function of C5a receptor in mouse microvascular endothelial cells.\n                           J Immunol 2002, 169: 5962-5970.","journal-title":"J Immunol"},{"key":"7143_CR41","doi-asserted-by":"publisher","first-page":"503","DOI":"10.4049\/jimmunol.170.1.503","volume":"170","author":"NC Riedemann","year":"2003","unstructured":"Riedemann NC, Neff TA, Guo RF, Bernacki KD, Laudes IJ, Sarma JV, Lambris JD, Ward PA: Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression.\n                           J Immunol 2003, 170: 503-507.","journal-title":"J Immunol"},{"key":"7143_CR42","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1006\/mvre.1995.1028","volume":"49","author":"D Wong","year":"1995","unstructured":"Wong D, Dorovini-Zis K: Expression of vascular cell adhesion molecule-1 (VCAM-1) by human brain microvessel endothelial cells in primary culture.\n                           Microvasc Res 1995, 49: 325-339.","journal-title":"Microvasc Res"},{"key":"7143_CR43","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/0304-3940(96)12837-8","volume":"213","author":"DC Hess","year":"1996","unstructured":"Hess DC, Thompson Y, Sprinkle A, Carroll J, Smith J: E-selectin expression on human brain microvascular endothelial cells.\n                           Neurosci Lett 1996, 213: 37-40.","journal-title":"Neurosci Lett"},{"key":"7143_CR44","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/0304-3940(94)90450-2","volume":"168","author":"DC Hess","year":"1994","unstructured":"Hess DC, Bhutwala T, Sheppard JC, Zhao W, Smith J: ICAM-1 expression on human brain microvascular endothelial cells.\n                           Neurosci Lett 1994, 168: 201-204.","journal-title":"Neurosci Lett"},{"key":"7143_CR45","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1016\/0304-3940(95)11282-2","volume":"186","author":"P Rieckmann","year":"1995","unstructured":"Rieckmann P, Michel U, Albrecht M, Bruck W, Wockel L, Felgenhauer K: Cerebral endothelial cells are a major source for soluble intercellular adhesion molecule-1 in the human central nervous system.\n                           Neurosci Lett 1995, 186: 61-64.","journal-title":"Neurosci Lett"},{"key":"7143_CR46","doi-asserted-by":"crossref","first-page":"1857","DOI":"10.4049\/jimmunol.158.4.1857","volume":"158","author":"MS Mulligan","year":"1997","unstructured":"Mulligan MS, Schmid E, Till GO, Hugli TE, Friedl HP, Roth RA, Ward PA: C5a-dependent up-regulation in vivo of lung vascular P-selectin.\n                           J Immunol 1997, 158: 1857-1861.","journal-title":"J Immunol"},{"key":"7143_CR47","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1172\/JCI117430","volume":"94","author":"KE Foreman","year":"1994","unstructured":"Foreman KE, Vaporciyan AA, Bonish BK, Jones ML, Johnson KJ, Glovsky MM, Eddy SM, Ward PA: C5a-induced expression of P-selectin in endothelial cells.\n                           J Clin Invest 1994, 94: 1147-1155.","journal-title":"J Clin Invest"},{"key":"7143_CR48","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/S0002-9440(10)63173-2","volume":"164","author":"EA Albrecht","year":"2004","unstructured":"Albrecht EA, Chinnaiyan AM, Varambally S, Kumar-Sinha C, Barrette TR, Sarma JV, Ward PA: C5a-induced gene expression in human umbilical vein endothelial cells.\n                           Am J Pathol 2004, 164: 849-859.","journal-title":"Am J Pathol"},{"key":"7143_CR49","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1172\/JCI118818","volume":"98","author":"MS Mulligan","year":"1996","unstructured":"Mulligan MS, Schmid E, Beck-Schimmer B, Till GO, Friedl HP, Brauer RB, Hugli TE, Miyasaka M, Warner RL, Johnson KJ, Ward PA: Requirement and role of C5a in acute lung inflammatory injury in rats.\n                           J Clin Invest 1996, 98: 503-512.","journal-title":"J Clin Invest"},{"key":"7143_CR50","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1097\/00024382-199708000-00010","volume":"8","author":"E Schmid","year":"1997","unstructured":"Schmid E, Piccolo MT, Friedl HP, Warner RL, Mulligan MS, Hugli TE, Till GO, Ward PA: Requirement for C5a in lung vascular injury following thermal trauma to rat skin.\n                           Shock 1997, 8: 119-124.","journal-title":"Shock"},{"key":"7143_CR51","doi-asserted-by":"publisher","first-page":"11393","DOI":"10.1073\/pnas.91.24.11393","volume":"91","author":"CD Breder","year":"1994","unstructured":"Breder CD, Hazuka C, Ghayur T, Klug C, Huginin M, Yasuda K, Teng M, Saper CB: Regional induction of tumor necrosis factor alpha expression in the mouse brain after systemic lipopolysaccharide administration.\n                           Proc Natl Acad Sci USA 1994, 91: 11393-11397.","journal-title":"Proc Natl Acad Sci USA"},{"key":"7143_CR52","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/0165-5728(93)90281-3","volume":"47","author":"Z Fabry","year":"1993","unstructured":"Fabry Z, Fitzsimmons KM, Herlein JA, Moninger TO, Dobbs MB, Hart MN: Production of the cytokines interleukin 1 and 6 by murine brain microvessel endothelium and smooth muscle pericytes.\n                           J Neuroimmunol 1993, 47: 23-34.","journal-title":"J Neuroimmunol"},{"key":"7143_CR53","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/S0006-8993(99)02189-7","volume":"851","author":"TM Reyes","year":"1999","unstructured":"Reyes TM, Fabry Z, Coe CL: Brain endothelial cell production of a neuroprotective cytokine, interleukin-6, in response to noxious stimuli.\n                           Brain Res 1999, 851: 215-220.","journal-title":"Brain Res"},{"key":"7143_CR54","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/0165-5728(95)00148-4","volume":"64","author":"HE de Vries","year":"1996","unstructured":"de Vries HE, Blom-Roosemalen MC, van Oosten M, de Boer AG, van Berkel TJ, Breimer DD, Kuiper J: The influence of cytokines on the integrity of the blood-brain barrier in vitro.\n                           J Neuroimmunol 1996, 64: 37-43.","journal-title":"J Neuroimmunol"},{"key":"7143_CR55","doi-asserted-by":"publisher","first-page":"3019","DOI":"10.1097\/00003246-200008000-00057","volume":"28","author":"MC Papadopoulos","year":"2000","unstructured":"Papadopoulos MC, Davies DC, Moss RF, Tighe D, Bennett ED: Pathophysiology of septic encephalopathy: a review.\n                           Crit Care Med 2000, 28: 3019-3024.","journal-title":"Crit Care Med"},{"key":"7143_CR56","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1007\/s00134-007-0598-y","volume":"33","author":"T Sharshar","year":"2007","unstructured":"Sharshar T, Carlier R, Bernard F, Guidoux C, Brouland JP, Nardi O, de la Grandmaison GL, Aboab J, Gray F, Menon D, Annane D: Brain lesions in septic shock: a magnetic resonance imaging study.\n                           Intensive Care Med 2007, 33: 798-806.","journal-title":"Intensive Care Med"},{"key":"7143_CR57","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/cc2951","volume":"9","author":"T Sharshar","year":"2005","unstructured":"Sharshar T, Hopkinson NS, Orlikowski D, Annane D: Science review: The brain in sepsis \u2013 culprit and victim.\n                           Crit Care 2005, 9: 37-44.","journal-title":"Crit Care"},{"key":"7143_CR58","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/glia.10161","volume":"40","author":"UK Hanisch","year":"2002","unstructured":"Hanisch UK: Microglia as a source and target of cytokines.\n                           Glia 2002, 40: 140-155.","journal-title":"Glia"},{"key":"7143_CR59","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1023\/A:1022453332560","volume":"23","author":"RS Ghirnikar","year":"1998","unstructured":"Ghirnikar RS, Lee YL, Eng LF: Inflammation in traumatic brain injury: role of cytokines and chemokines.\n                           Neurochem Res 1998, 23: 329-340.","journal-title":"Neurochem Res"},{"key":"7143_CR60","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1016\/S0166-2236(97)01198-3","volume":"21","author":"RM Ransohoff","year":"1998","unstructured":"Ransohoff RM, Tani M: Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation?\n                           Trends Neurosci 1998, 21: 154-159.","journal-title":"Trends Neurosci"},{"key":"7143_CR61","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/S0165-5728(00)00304-0","volume":"109","author":"PF Stahel","year":"2000","unstructured":"Stahel PF, Kariya K, Shohami E, Barnum SR, Eugster H, Trentz O, Kossmann T, Morganti-Kossmann MC: Intracerebral complement C5a receptor (CD88) expression is regulated by TNF and lymphotoxin-alpha following closed head injury in mice.\n                           J Neuroimmunol 2000, 109: 164-172.","journal-title":"J Neuroimmunol"},{"key":"7143_CR62","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/S0162-3109(00)80302-1","volume":"49","author":"P Gasque","year":"2000","unstructured":"Gasque P, Dean YD, McGreal EP, VanBeek J, Morgan BP: Complement components of the innate immune system in health and disease in the CNS.\n                           Immunopharmacology 2000, 49: 171-186.","journal-title":"Immunopharmacology"},{"key":"7143_CR63","doi-asserted-by":"publisher","first-page":"4708","DOI":"10.4049\/jimmunol.173.7.4708","volume":"173","author":"L Boos","year":"2004","unstructured":"Boos L, Campbell IL, Ames R, Wetsel RA, Barnum SR: Deletion of the complement anaphylatoxin C3a receptor attenuates, whereas ectopic expression of C3a in the brain exacerbates, experimental autoimmune encephalomyelitis.\n                           J Immunol 2004, 173: 4708-4714.","journal-title":"J Immunol"},{"key":"7143_CR64","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1016\/j.molimm.2003.08.009","volume":"40","author":"NJ Lynch","year":"2004","unstructured":"Lynch NJ, Willis CL, Nolan CC, Roscher S, Fowler MJ, Weihe E, Ray DE, Schwaeble WJ: Microglial activation and increased synthesis of complement component C1q precedes blood-brain barrier dysfunction in rats.\n                           Mol Immunol 2004, 40: 709-716.","journal-title":"Mol Immunol"},{"key":"7143_CR65","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/S0083-6729(08)60434-3","volume":"40","author":"JC Porter","year":"1983","unstructured":"Porter JC, Sissom JF, Arita J, Reymond MJ: Hypothalamic-hypophysial vasculature and its relationship to secretory cells of the hypothalamus and pituitary gland.\n                           Vitam Horm 1983, 40: 145-174.","journal-title":"Vitam Horm"},{"key":"7143_CR66","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1097\/01.WCB.0000084250.20114.2C","volume":"23","author":"M Rancan","year":"2003","unstructured":"Rancan M, Morganti-Kossmann MC, Barnum SR, Saft S, Schmidt OI, Ertel W, Stahel PF: Central nervous system-targeted complement inhibition mediates neuroprotection after closed head injury in transgenic mice.\n                           J Cereb Blood Flow Metab 2003, 23: 1070-1074.","journal-title":"J Cereb Blood Flow Metab"},{"key":"7143_CR67","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/S0169-328X(97)00189-7","volume":"50","author":"PF Stahel","year":"1997","unstructured":"Stahel PF, Kossmann T, Morganti-Kossmann MC, Hans VH, Barnum SR: Experimental diffuse axonal injury induces enhanced neuronal C5a receptor mRNA expression in rats.\n                           Brain Res Mol Brain Res 1997, 50: 205-212.","journal-title":"Brain Res Mol Brain Res"},{"key":"7143_CR68","first-page":"31","volume":"150","author":"P Gasque","year":"1997","unstructured":"Gasque P, Singhrao SK, Neal JW, Gotze O, Morgan BP: Expression of the receptor for complement C5a (CD88) is up-regulated on reactive astrocytes, microglia, and endothelial cells in the inflamed human central nervous system.\n                           Am J Pathol 1997, 150: 31-41.","journal-title":"Am J Pathol"},{"key":"7143_CR69","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S1462399403006252","volume":"5","author":"K Francis","year":"2003","unstructured":"Francis K, van Beek J, Canova C, Neal JW, Gasque P: Innate immunity and brain inflammation: the key role of complement.\n                           Expert Rev Mol Med 2003, 5: 1-19.","journal-title":"Expert Rev Mol Med"},{"key":"7143_CR70","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1002\/(SICI)1098-1136(199905)26:3<201::AID-GLIA2>3.0.CO;2-M","volume":"26","author":"N Davoust","year":"1999","unstructured":"Davoust N, Jones J, Stahel PF, Ames RS, Barnum SR: Receptor for the C3a anaphylatoxin is expressed by neurons and glial cells.\n                           Glia 1999, 26: 201-211.","journal-title":"Glia"},{"key":"7143_CR71","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1096\/fj.02-1103fje","volume":"17","author":"K Francis","year":"2003","unstructured":"Francis K, Lewis BM, Akatsu H, Monk PN, Cain SA, Scanlon MF, Morgan BP, Ham J, Gasque P: Complement C3a receptors in the pituitary gland: a novel pathway by which an innate immune molecule releases hormones involved in the control of inflammation.\n                           Faseb J 2003, 17: 2266-2268.","journal-title":"Faseb J"},{"key":"7143_CR72","first-page":"P602","volume":"11","author":"BM Lewis","year":"2006","unstructured":"Lewis BM, Francis K, Monk P, Scanlon MF, Ham J: Complement C5a inhibits the secretion of macrophage migration inhibitory factor in anterior pituitary cell lines.\n                           Endocrine Abstracts 2006, 11: P602.","journal-title":"Endocrine Abstracts"},{"key":"7143_CR73","doi-asserted-by":"publisher","first-page":"S596","DOI":"10.1097\/01.CCM.0000279097.67263.52","volume":"35","author":"V Maxime","year":"2007","unstructured":"Maxime V, Siami S, Annane D: Metabolism modulators in sepsis: the abnormal pituitary response.\n                           Crit Care Med 2007, 35: S596-601.","journal-title":"Crit Care Med"},{"key":"7143_CR74","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1111\/j.1365-2265.1991.tb03495.x","volume":"35","author":"R Ross","year":"1991","unstructured":"Ross R, Miell J, Freeman E, Jones J, Matthews D, Preece M, Buchanan C: Critically ill patients have high basal growth hormone levels with attenuated oscillatory activity associated with low levels of insulin-like growth factor-I.\n                           Clin Endocrinol (Oxf) 1991, 35: 47-54.","journal-title":"Clin Endocrinol (Oxf)"},{"key":"7143_CR75","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1530\/eje.0.1490079","volume":"149","author":"ML Raffin-Sanson","year":"2003","unstructured":"Raffin-Sanson ML, de Keyzer Y, Bertagna X: Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions.\n                           Eur J Endocrinol 2003, 149: 79-90.","journal-title":"Eur J Endocrinol"},{"key":"7143_CR76","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1210\/er.2007-0027","volume":"29","author":"T Brzoska","year":"2008","unstructured":"Brzoska T, Luger TA, Maaser C, Abels C, Bohm M: Alpha-melanocyte-stimulating hormone and related tripeptides: biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases.\n                           Endocr Rev 2008, 29: 581-602.","journal-title":"Endocr Rev"},{"key":"7143_CR77","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1097\/00003246-200005000-00024","volume":"28","author":"A Catania","year":"2000","unstructured":"Catania A, Cutuli M, Garofalo L, Airaghi L, Valenza F, Lipton JM, Gattinoni L: Plasma concentrations and anti-L-cytokine effects of alpha-melanocyte stimulating hormone in septic patients.\n                           Crit Care Med 2000, 28: 1403-1407.","journal-title":"Crit Care Med"},{"key":"7143_CR78","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1189\/jlb.0806542","volume":"81","author":"D Rittirsch","year":"2007","unstructured":"Rittirsch D, Hoesel LM, Ward PA: The disconnect between animal models of sepsis and human sepsis.\n                           J Leukoc Biol 2007, 81: 137-143.","journal-title":"J Leukoc Biol"},{"key":"7143_CR79","doi-asserted-by":"publisher","first-page":"S219","DOI":"10.1097\/01.CCM.0000127036.27343.48","volume":"32","author":"CT Esmon","year":"2004","unstructured":"Esmon CT: Why do animal models (sometimes) fail to mimic human sepsis?\n                           Crit Care Med 2004, 32: S219-222.","journal-title":"Crit Care Med"},{"issue":"Suppl 1","key":"7143_CR80","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1097\/SHK.0b013e318181a343","volume":"30","author":"LF Poli-de-Figueiredo","year":"2008","unstructured":"Poli-de-Figueiredo LF, Garrido AG, Nakagawa N, Sannomiya P: Experimental models of sepsis and their clinical relevance.\n                           Shock 2008,30(Suppl 1):53-59.","journal-title":"Shock"},{"key":"7143_CR81","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.neulet.2007.07.012","volume":"424","author":"JW Crane","year":"2007","unstructured":"Crane JW, Buller KM: Systemic blockade of complement C5a receptors reduces lipopolysacharride-induced responses in the paraventricular nucleus and the central amygdala.\n                           Neurosci Lett 2007, 424: 10-15.","journal-title":"Neurosci Lett"}],"container-title":["Critical Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/cc7710.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/cc7710\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/cc7710.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,7]],"date-time":"2024-10-07T08:42:08Z","timestamp":1728290528000},"score":1,"resource":{"primary":{"URL":"https:\/\/ccforum.biomedcentral.com\/articles\/10.1186\/cc7710"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,6]]},"references-count":81,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2009,2]]}},"alternative-id":["7143"],"URL":"https:\/\/doi.org\/10.1186\/cc7710","relation":{},"ISSN":["1364-8535"],"issn-type":[{"value":"1364-8535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,2,6]]},"assertion":[{"value":"12 January 2008","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 February 2009","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 February 2009","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"R12"}}