title: Characterization of RAGE, HMGB1, and S100beta in inflammation-induced preterm birth and fetal tissue injury.
abstract: Immune activation represents an adaptive reaction triggered by both noxious exogenous (microbes) and endogenous [high mobility group box-1 protein (HMGB1), S100 calcium binding proteins] inducers of inflammation. Cell stress or necrosis lead the release of HMGB1 and S100 proteins in the extracellular compartment where they act as damage-associated molecular pattern molecules (or alarmins) by engaging the receptor for advanced glycation end-products (RAGE). Although the biology of RAGE is dictated by the accumulation of damage-associated molecular pattern molecules at sites of tissue injury, the role of RAGE in mediating antenatal fetal injury remains unknown. First, we studied the relationships at birth between the intensity of human fetal inflammation and sRAGE (an endogenous RAGE antagonist), HMGB1, and S100beta protein. We found significantly lower sRAGE in human fetuses that mounted robust inflammatory responses. HMGB1 levels correlated significantly with levels of interleukin-6 and S100beta in fetal circulation. We then evaluated the levels and areas of tissue expression of RAGE, HMGB1, and S100beta in specific organs of mouse fetuses on E16. Using an animal model of endotoxin-induced fetal damage and preterm birth, we determined that inflammation induces a significant change in expression of RAGE and HMGB1, but not S100beta, at sites of tissue damage. Our findings indicate that RAGE and HMGB1 may be important mediators of cellular injury in fetuses delivered in the setting of inflammation-induced preterm birth.
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University, 333 Cedar Street, New Haven, CT 06520, USA. catalin.buhimschi@yale.edu
authors.forename: Catalin S
authors.initials: CS
authors.lastname: Buhimschi
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Baumbusch
authors.forename: Antonette T
authors.initials: AT
authors.lastname: Dulay
authors.forename: Emily A
authors.initials: EA
authors.lastname: Oliver
authors.forename: Sarah
authors.initials: S
authors.lastname: Lee
authors.forename: Guomao
authors.initials: G
authors.lastname: Zhao
authors.forename: Vineet
authors.initials: V
authors.lastname: Bhandari
authors.forename: Richard A
authors.initials: RA
authors.lastname: Ehrenkranz
authors.forename: Carl P
authors.initials: CP
authors.lastname: Weiner
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Madri
authors.forename: Irina A
authors.initials: IA
authors.lastname: Buhimschi
mesh_terms: D000818:Animals; D004731:Endotoxins / Q000633:toxicity; D005260:Female; D005333:Fetus / Q000276:immunology / Q000473:pathology; D017127:Glycation End Products, Advanced / Q000096:biosynthesis*; D024243:HMGB1 Protein / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D009336:Necrosis; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D011247:Pregnancy; D047928:Premature Birth / Q000139:chemically induced / Q000276:immunology*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000096:biosynthesis*
chemical_list: D004731:Endotoxins; D017127:Glycation End Products, Advanced; D024243:HMGB1 Protein; D015850:Interleukin-6; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins
references.citation: J Neurosci Res. 2008 May 1;86(6):1227-42
references.pmid: 18092360
references.citation: J Biol Chem. 1990 Sep 15;265(26):15537-43
references.pmid: 2394738
references.citation: Br J Haematol. 2000 May;109(2):280-7
references.pmid: 10848813
references.citation: Obstet Gynecol Surv. 2001 Jul;56(7):433-6
references.pmid: 11435951
references.citation: J Biol Chem. 1999 Jul 9;274(28):19919-24
references.pmid: 10391939
references.citation: Lancet Neurol. 2008 May;7(5):378-9
references.pmid: 18420149
references.citation: FASEB J. 2008 May;22(5):1572-80
references.pmid: 18089847
references.citation: Dev Biol. 1972 Dec;29(4):372-84
references.pmid: 4656081
references.citation: Biochim Biophys Acta. 2009 Jun;1793(6):1008-22
references.pmid: 19110011
references.citation: Crit Care. 2007;11(6):R122
references.pmid: 18042296
references.citation: JAMA. 2007 Jun 27;297(24):2733-40
references.pmid: 17595274
references.citation: J Clin Ultrasound. 1983 Aug;11(6):313-6
references.pmid: 6413538
references.citation: J Pathol. 2001 May;194(1):27-34
references.pmid: 11329138
references.citation: Obstet Gynecol. 1989 Mar;73(3 Pt 1):383-9
references.pmid: 2915862
references.citation: J Neurosci. 1998 Aug 15;18(16):6241-53
references.pmid: 9698317
references.citation: Hepatology. 2004 Feb;39(2):422-32
references.pmid: 14767995
references.citation: Am J Obstet Gynecol. 2007 Feb;196(2):181.e1-13
references.pmid: 17306673
references.citation: Cell. 1999 Jun 25;97(7):889-901
references.pmid: 10399917
references.citation: Obstet Gynecol. 2000 Aug;96(2):201-6
references.pmid: 10908763
references.citation: J Immunol. 2007 Feb 15;178(4):2483-90
references.pmid: 17277156
references.citation: Free Radic Biol Med. 2007 Aug 15;43(4):511-8
references.pmid: 17640561
references.citation: Curr Opin Pediatr. 2000 Apr;12(2):99-104
references.pmid: 10763757
references.citation: BJOG. 2009 Jan;116(2):257-67
references.pmid: 18947340
references.citation: Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):296-301
references.pmid: 14695889
references.citation: Obstet Gynecol. 2007 Apr;109(4):1007-19
references.pmid: 17400872
references.citation: Nature. 2000 May 18;405(6784):354-60
references.pmid: 10830965
references.citation: Curr Opin Neurol. 2008 Apr;21(2):123-8
references.pmid: 18317268
references.citation: J Neurosci. 2008 Nov 12;28(46):12023-12031
references.pmid: 19005067
references.citation: Nature. 2008 Jul 24;454(7203):428-35
references.pmid: 18650913
references.citation: Crit Care Med. 2005 Dec;33(12 Suppl):S472-4
references.pmid: 16340425
references.citation: Pediatr Infect Dis J. 2005 Jul;24(7):635-9
references.pmid: 15999007
references.citation: Eur J Pediatr. 2001 Jun;160(6):345-50
references.pmid: 11421413
references.citation: Semin Perinatol. 2006 Aug;30(4):219-26
references.pmid: 16860162
references.citation: Am J Obstet Gynecol. 2008 Apr;198(4):426.e1-9
references.pmid: 18395034
references.citation: Am J Pathol. 2008 Jun;172(6):1571-9
references.pmid: 18467705
references.citation: J Biol Chem. 1992 Jul 25;267(21):14998-5004
references.pmid: 1378843
references.citation: Am J Physiol Heart Circ Physiol. 2008 Aug;295(2):H491-8
references.pmid: 18539754
references.citation: J Immunol. 2005 Sep 15;175(6):3463-8
references.pmid: 16148087
references.citation: Brain Pathol. 2005 Jul;15(3):225-33
references.pmid: 16196389
references.citation: Immunology. 1994 Sep;83(1):140-7
references.pmid: 7821959
references.citation: BMC Dev Biol. 2007 Mar 15;7:17
references.pmid: 17362503
references.citation: J Comp Neurol. 2003 Jan 27;456(1):1-11
references.pmid: 12508309
references.citation: Exp Biol Med (Maywood). 2005 Nov;230(10):771-6
references.pmid: 16246905
references.citation: J Neuroimmunol. 2007 Mar;184(1-2):214-22
references.pmid: 17254641
references.citation: Am J Obstet Gynecol. 2009 Feb;200(2):203.e1-11
references.pmid: 19185102
references.citation: Am J Respir Crit Care Med. 2008 Aug 15;178(4):356-62
references.pmid: 18535257
references.citation: J Gastroenterol Hepatol. 2006 Apr;21(4):682-8
references.pmid: 16677153
references.citation: Pediatrics. 2008 Jan;121(1):129-34
references.pmid: 18166566
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9580-4
references.pmid: 7568176
references.citation: Clin Chim Acta. 2003 Sep;335(1-2):1-7
references.pmid: 12927678
references.citation: J Biol Chem. 1995 Oct 27;270(43):25752-61
references.pmid: 7592757
references.citation: BJOG. 2005 Mar;112 Suppl 1:4-9
references.pmid: 15715586
references.citation: J Rheumatol. 2008 May;35(5):752-6
references.pmid: 18322992
references.citation: Pediatr Infect Dis J. 1993 May;12(5):372-6
references.pmid: 8327296
references.citation: JAMA. 1997 Jul 16;278(3):247-8
references.pmid: 9218675
references.citation: Am J Respir Cell Mol Biol. 2009 Dec;41(6):651-60
references.pmid: 19265175
references.citation: Neuroscientist. 2007 Apr;13(2):173-85
references.pmid: 17404377
references.citation: BJOG. 2005 Feb;112(2):173-81
references.pmid: 15663581
references.citation: J Surg Res. 2008 Jun 1;147(1):79-83
references.pmid: 17981300
references.citation: Am J Obstet Gynecol. 2008 Apr;198(4):466.e1-466.e11
references.pmid: 18395043
references.citation: Gut. 2003 Jun;52(6):847-53
references.pmid: 12740341
references.citation: J Perinatol. 1992 Mar;12(1):3-8
references.pmid: 1560287
references.citation: Cell Mol Biol (Noisy-le-grand). 1998 Nov;44(7):1147-57
references.pmid: 9846897
references.citation: Eur J Pediatr. 2000 Mar;159(3):156-7
references.pmid: 10664226
references.citation: Arch Pathol Lab Med. 1985 Aug;109(8):716-21
references.pmid: 3893381
references.citation: Arthritis Res Ther. 2005;7(4):R817-24
references.pmid: 15987483
references.citation: J Matern Fetal Med. 1997 Sep-Oct;6(5):254-9
references.pmid: 9360181
references.citation: Nature. 2002 Jul 11;418(6894):191-5
references.pmid: 12110890
references.citation: J Clin Pathol. 2007 Apr;60(4):415-8
references.pmid: 16775125
references.citation: PLoS Med. 2007 Jan;4(1):e18
references.pmid: 17227133
references.citation: Am J Obstet Gynecol. 2003 Jan;188(1):203-8
references.pmid: 12548218
references.citation: Arterioscler Thromb Vasc Biol. 2005 May;25(5):1032-7
references.pmid: 15731496
references.citation: Adv Drug Deliv Rev. 2002 Dec 7;54(12):1615-25
references.pmid: 12453678
references.citation: Immunol Rev. 2007 Dec;220:60-81
references.pmid: 17979840
references.citation: Am J Obstet Gynecol. 2003 Jun;188(6):1438-4; discussion 1444-6
references.pmid: 12824976
references.citation: Curr Mol Med. 2007 Dec;7(8):725-34
references.pmid: 18331230
references.citation: J Leukoc Biol. 2007 Jan;81(1):1-5
references.pmid: 17032697
references.citation: FASEB J. 2008 Oct;22(10):3716-27
references.pmid: 18603587
references.citation: J Neurochem. 2004 Sep;90(6):1389-401
references.pmid: 15341523
references.citation: Restor Neurol Neurosci. 2003;21(3-4):97-108
references.pmid: 14530573
references.citation: Am J Pathol. 1993 Dec;143(6):1699-712
references.pmid: 8256857
references.citation: N Engl J Med. 2004 Nov 4;351(19):1985-95
references.pmid: 15525724
references.citation: Dev Med Child Neurol. 1993 Jun;35(6):553-8
references.pmid: 8504899
references.citation: N Engl J Med. 2008 Apr 17;358(16):1672-81
references.pmid: 18420500