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The Investigation of Therapy Multiple Organ Disfunction Syndrome by Regulated NF-κB/IκB Inflammation Signal Transduction Pass

Author: AiYuHang
Tutor: ZhangYangDe
School: Central South University
Course: Surgery
Keywords: multiple organ disfunction syndrome NF-κB AdlκB gene therapy apoptosis Fas Fas ligand
CLC: R459.7
Type: PhD thesis
Year: 2007
Downloads: 445
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Abstract


Objective: multiple organ disfunction syndrome was a corporatedifficulty problem in systemic inflammation, trauma, burn, and diseases.overexpression of inflammation factors and handicap of monocyte andmacrophages apoptosis had deteriorated diseases .one of the focus tacheswas the activation of nuclear factor -κB .in the past studies,manyscholars wanted to therapy multiple organ disfunction syndrome byinterdiction expression of inflammation factors .but the effect was notperfect,some even increased mortality rate.the main cause was likely tointerventens a sort of inflammatorymediators and metabolizablesubstances could not carried anticipatable point, nuclear factor -κBwas a importmont transfer factor compound.it had importment functionin the pathophysiological process of multiple organ disfunctionsyndrome by activated series reactions of cytokines ,createdinflammatory mediators and controlled cells apoptosis.so it was a newmethods to therapy multiple organ dis function syndrome by modulatednuclear factor -κB activation .in the sudy , we want to interdictdevelopmental of multiple organ disfunction syndrome by directly increase endogenic inhibitor of NF-κB, inhibition NFκ-B activation andinflammation factor and enzyme Releasing by infusing IκB genetansported adenovirus through central vein.Methods:part one: pathogen-free rats were randomly divided intoseven scheduling: before inject adenovirus , afte inject adenovirus oneday, afte inject adenovirus three days, afte inject adenovirus seven days,afte inject adenovirus fourteen days, afte inject adenovirus twenty-onedays, afte inject adenovirus twenty-eight days,Recombinant adenovirusvector containing LacZ was transferred to SD rats by injecting intointernal jugular vein. To identify the sites and periods of LacZ geneexpression,X-gal staining was used to detectβ-gal level and period ofLacZ gene expression of different organs in the transfected andnon-transfected rats at different time intervals, part two: 30pathogen-free rats were randomly divided into three groups: A group(control group) , B group (MODS24 hours), C group(MODS72hours),The rats of A groups was infused Saline at the dose of 0.25ml/kg, Band C groups were infused oleic acid at the dose of 0.25ml/kg andlipopolysaccharide at the dose of 3.5ml/kg through central vein(4 hoursinterval), the stimulatory reaction, activity, the morality rate and thefunction of the heart, liver, kidney, and lung after injection wereobserved, part three: 50 pathogen-free rats were randomly divided intofive groups: A group (control group), B group (MODS24 hours), Cgroup (MODS72hours), D group (AdIκB therapy one day), E group (AdIκB therapy seven day). The rats of A groups was infused Saline atthe dose of 0.25ml/kg, B, C, D and E groups were infused oleic acid atthe dose of 0.25ml/kg and lipopolysaccharide at the dose of 3.5ml/kgthrough central vein(4 hours interval). At the same time, C and D groupwere infused 1ml IκB gene tansported adenovirus (tite:1×10~9pfu), thestimulatory reaction, activity, th morality rate and the function of theheart ,liver, kidney, and lung were observed after injection one day andsenven days. plasm content of TNF-α, IL-6, expression of NF-κBP65 inlung and liver tissue through immunohistochemical staining andwestblotting means, expression of Fas and Fas ligand in lung and livertissue through westblotting means were recorded after injection oneand seven 7 days.Result:1. The 1st day after the injection, the lungs, livers, kidneys ,and spleensexpressed few level ofβ-gal ; the 3rd day after the injection, the lungs,livers, kidneys and spleens expressedβ-gal obviously ;their peak levelswere on the 7th days;theβ-gal level decreased on the 14th day;.β-galexpression disappeared in most organs except lungs on the 28th days.Inall animals ,the brain did not appear anyβ-gal expression2. the level of creatinine, alanine aminotranferase ,total bilirubin ,creatinephosphokinase in group B and C were significantly higher than Agroup(P<0.05).but its in D and E group had little differences than in Agroup(P>0.05), the level of alanine aminotranferase, total bilirubin, creatine phosphokinase in group D was significantly lowerer than Bgroup (P<0.05). but the level of creatinine had no difference(P>0.05).the level of creatinine, alanine aminotranferase, total bilirubin, creatinephosphokinase in group E were significantly lower than C group(P<0.05).there were no difference in B and C group, D and Egroup(P>0.05).the lever of partial pressure of arterial oxygen(PaO2) inB, C, D, E group was significantly lower in group A (p<0.05),but thelever of partial pressure of arterial oxygen(PaO2) in E group wassignificantly higher in group C(p<0.05), there were no difference in Band D group, B and C group, D and E group(P>0.05), the lever of PH inC group was lower than A and B group(p<0.05).although PaCO2 in fivegroup had little differences.3. the serum content of TNF-αwas the highest in group C and the lowestin group A(group A vs C and group E vs C, P<0.05,respectively). theserum content of IL-6 was the highest in group C and the lowest ingroup A(group A vs C and group E vs C, P<0.05,respectively).4. in lung of group A,the male cells of NF-κBP65 were distribution inpulmonary alveolus macrophage ,neutrophilic granulocyte and vascularendothelial cell .cytoplasmic is male .in group C the male cells were innuclei mainly , a small quantity male cell were in cytoplasmic butstaining was superficial than the normal group, in group E. the malecells were in nuclei and cytoplasmic, the male cells in nuclei reducedobviously than group C. the scale of immunohistochemistry was the highest in group C and the lowest in group A(group A vs C group E vsAand group E vs C, P<0.05, respectively). in liver of group A, the malecells of NF-κBP65 were distribution in hepatic cells , cytoplasmic ismale in group C the male cells were in nuclei mainly, a small quantitymale cell were in cytoplasmic but staining was superficial than thenormal group, in group E. the male cells were in nuclei and cytoplasmic.the male cells in nuclei reduced obviously than group C. the scale ofimmunohistochemistry was the highest in group C and the lowest ingroup A(group A vs C group E vs Aand group E vs C, P<0.05,respectively).5.. the experssions of NF-κBP65、Fas and FasL protein in group B andC were significantly higher than A group.but its in D and E group hadlittle differences than in A group, the level of NF-κd3P65、Fas and FasLprotein in group E was significantly lowerer than C groupConclusions:1. The adenovirus-mediated IκB gene transfer in internal jugular veinmay be an effective approach of gene therapy in some diseases such aslungs,livers, and kidneys.2. The adenovirus-mediated IκB gene transfer in internal jugular veincan not be an approach of gene therapy in central nervous systemdiseases3.the model established by injection of oleic acid and lipopolysaccharidesubsequently is a suitable modle for the studies of the primordial role of lung in the pathogenesis of the multiple organ disfunction syndrome.4..Infusing IκB gene tansported adenovirus through central vein canreduced the lever of creatinine, alanine aminotranferase ,total bilirubin,creatine phosphokinase in multiple organ disfunction syndrome rats.andalso improved the lever of partial pressure of arterial oxygen.5. Infusing IκB gene tansported adenovirus through central vein canreduced the lever of the serum content of TNF-αand IL-6,and suppressthe activation of nuclear factor-κB in lung and liver tissues,accordinglyabated expression of NF-κBP65.6. Infusing IκB gene tansported adenovirus through central vein canreduced the expression of Fas and Fas ligand in lung and liver tissues,accordingly alleviate the excessive cells apoptosis in multiple organdisfunction syndrome rats.7..To increased expression of IκB gene can relieve rat multiple organdisfunction syndrome result in infuse by internal jugular vein.themechanism of therapy multiple organ disfunction syndrome was enhanceendogenic inhibitor of NFκ-B inhibition NF-κB activation andinflammation cascade reaction

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