аЯрЁБс>ўџ .0ўџџџ-џџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџьЅС` №П*$bjbjЫsЫs.&ЉЉв џџџџџџЄЈЈЈЈЈЈЈМ  Мз Ж((((((2Zn        $ hѕR4 ]Ја ((а а 4 ЈЈ((‘    а тЈ(Ј(  а    ЈЈ ( А)-ˆЎЦВ "  Ї 0з  Gд (G  МGЈТ Lz’ h tTШzzz4 4 ќ zzzз а а а а МММ$р$МММрМММЈЈЈЈЈЈџџџџ The protective effect of interleukin 1a№ and IL-1b№ on the acetaminophen induced liver toxicity relies on the early induction of their endogenous expression by acetaminophen itself Josko Aleksic , Melanie-Ivana Culo, Ljiljana Poljak, Tomas Matic and Filip Culo Department of Physiology, School of Medicine, University of Zagreb, Zagreb, Croatia It is known that inflammatory cytokines influence the effect of hepatotoxic chemicals on liver. Previously we have shown that IL-1Б and IL-6 have hepatoprotective effect if given to mice before administration of acetaminophen (APAP) and that this effect is partially mediated by PGE2. In these experiments we investigated the influence of IL-1В in the same model, since we have been able to modulate its effect with specific antagonists (IL-1Ra and polyclonal anti- IL-1В antibodies). APAP (300 mg/kg for survival and 200 mg/kg for determination of aminotransferases) or saline in controls were administered intragastrically to mice which were given phenobarbitone in drinking water for 7 days and fasted overnight IL-1В (1500 IU /mouse) or IL-1В antibody (0.5 ml of rabbit to mouse IL-1, obtained by three consecutive injection of IL-1 В, first in complete FCA ) were given i.p. 3 hours before APAP and IL-Ra (2.5 mg/mouse) Н hours before APAP. The survival of mice was followed for 72 hours and concentration aminotransferases (AST and ALT) serum were determined 18-24 hours after administration of APAP. IL- IL-1LN`bn Р є і zК№ђТи!œ!ь!ю!($*$їыїыїреЩеЧерИрИр­р­рИрІ hqGhZ LhqGhqGCJaJhqGhчSЇCJOJQJaJUhqGhO&іCJH*aJhqGhO&іCJaJhqGhчSЇCJaJhqGhчSЇ5OJQJhqGhчSЇ5l n  И К Р "($*$њњњёњњњњя ЦцgdчSЇgdчSЇ *$§В significantly increased the survival mice and decreased serum level of AST and ALT (p < 0.05). Just opposite effect had IL-1В antibodies, but the effects were not significant. Similarly IL-1Ra, significantly increased serum concentration of AST and ALT (p < 0.05 or better) (the survival was not tested in this model). The finding that that IL-1Ra alone raised serum level of aminotranferases as well that potency IL-1В antibodies alone showed the tendency to worse the manifestations of intoxication, promoted us to analyze the synthesis if IL-1 cytokines in non-treated animals intoxicated with AAP. RT-PCR analysis of the IL-1a№ and IL-1b№ expression level in liver samples from APAP intoxicated mice has revealed that acetaminophen induces the expression of both cytokines already 1 hour after its intragastric administration. This expression was even higher at 6 hours following APAP administration and could be blocked by intravenous administration of aspirin at the dose which inhibits the activity of NF-k№B transcription factor. Based on these results we hypothesized that organism intoxicated with APAP synthesizes its own IL-1 early on following APAP administration, which would represent a host defense reaction that could be helped by applying appropriate dose of exogenous cytokines. ,1hАа/ Ар=!А"А# $ %ААФАФ Ф†œ@`ёџ@ NormalCJ_HaJmH sH tH >A@ђџЁ> Zadani font odlomkaVi@ѓџГV Obi na tablicaі4ж l4жaі .k@єџС. Bez popisaв & џџџџЖЗ\]`Ь б д ˜0€€˜0€€˜0€€˜0€€˜0€€˜0€€˜0€€˜0€€˜0€€ЖЗ\]`Ь б д jЫ000­hЫ000­hЫ000­jЫ000­hЫ000€hЫ000€jЫ000€jЫ000€ 00ž *$ *$ *$ џџrevinfos verification]^д ^^д џџ   Ž c< Ё ŽмЉЂ Žдo< Ѓ ŽlшЄ Ž-8 Ѕ Žj}І ŽL1Ї ŽŒ.8 Ј ŽЌшЉ Ž<ЮЯль",6DLLTд  гъї(4@JR[[д  B*€urn:schemas-microsoft-com:office:smarttags€country-region€8*€urn:schemas-microsoft-com:office:smarttags€City€=*€urn:schemas-microsoft-com:office:smarttags €PlaceName€=*€urn:schemas-microsoft-com:office:smarttags €PlaceType€9*€urn:schemas-microsoft-com:office:smarttags€place€> *€urn:schemas-microsoft-com:office:smarttags €PersonName€ ˜Н €Ljiljana Poljak €ProductID €Tomas Matic  ЗМНФЯдейлуфъђїќ Ћђ†—СбыљЭаUf8Hрьд НЦд 33žЉ… ‹ Ь д д  M)Щ{7k{‘Щ{7 FЂЩ{7v$Щ{7™ я,Щ{7Щ{7$М|—(h?Щ{7FpнEЩ{7;JFЩ{7М*(NЩ{7Б/м`Щ{7№,sЩ{7$М| х qGT' Ÿ:2Z LНnUN?pЕ[†j‡ЋjЁчSЇѓNьlDђO&іџ@€žž0Lе žžXНв          џџUnknownџџџџџџџџџџџџGю‡z €џTimes New Roman5€Symbol3&ю ‡z €џArial"qˆ№аhНЇ-НЇ,НЇ 5 5 ‘#№ ДД24dЭ Э  2ƒq№HP,№џ?фџџџџџџџџџџџџџџџџџџџџџчSЇ2џџ Filip ulo Filip uloўџр…ŸђљOhЋ‘+'Гй0p˜ЄАФар є  , 8 DPX`hт Filip ШuloNormal Filip Шulo5Microsoft Office Word@H'­@и#і‡ЎЦ@v†ЎЦ@чˆЎЦ5 ўџеЭеœ.“—+,љЎ0ш hp|„Œ” œЄЌД М ЩтЭ Ј  Naslov ўџџџўџџџ !"#$ўџџџ&'()*+,ўџџџ§џџџ/ўџџџўџџџўџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџRoot Entryџџџџџџџџ РF@ШC-ˆЎЦ1€1TableџџџџџџџџGWordDocumentџџџџџџџџ.&SummaryInformation(џџџџDocumentSummaryInformation8џџџџџџџџџџџџ%CompObjџџџџџџџџџџџџsџџџџџџџџџџџџџџџџџџџџџџџџўџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџўџ џџџџ РF!Microsoft Office Wordov dokument MSWordDocWord.Document.8є9Вq