Dissertation > Medicine, health > Clinical > Therapy > Dialysis therapy

The Study on Expression and Significance of NF-κB in Preventing and Treating Multiple Organ Dysfunction Syndrome with High Volume Hemofiltration

Author ZhaoWeiGuo
Tutor FangGuoEn;BiJianWei
School Second Military Medical University
Course General Surgery
Keywords Multiple organ dysfunction syndrome High - volume hemofiltration Cytokines Nuclear factor -KappaB
CLC R459.5
Type PhD thesis
Year 2004
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Multiple organ dysfunction syndrome (multiple organ dysfunction syndrome MODS) is one of the main causes of death in critically ill patients. Its pathogenesis is not yet clear, the lack of effective means of treatment. Since 1977, Kramer et al [1] first proposed continuous arteriovenous hemofiltration and used in the clinical treatment of severe acute renal failure after 20 years of research, continuous renal replacement therapy (continuous renal replacement therapy CRRT) concept The occurrence of a fundamental change in the understanding of the use of the technology in recent years MODS therapy research has also made very big progress. The presence of a large number of inflammatory cytokines, the major cause of death in patients with MODS, most of that CRRT by repeated ultrafiltration and adsorption to remove high concentrations in the circulation of patients with sepsis soluble inflammatory cytokines (TNFα, IL-1β, IL-6), which is considered to be an important mechanism of CRRT treatment of MODS. With the further study of the pathogenesis of MODS, the researchers believe that the immune imbalance is an important stage, and therefore within the steady state to rebuild the immune system is the best way to treat MODS MODS development, continuous blood purification therapy (continuous blood purification CBP) via weaken the proinflammatory and antiinflammatory mediators peak concentration of the two substances in the blood circulation, to reduce inflammation and immune suppression, and rebuild the immune system within the metastable state. As a ubiquitous nuclear transcription factor nuclear factor-kappa B (nuclear factor-kappa B NF-κB), through the regulation of inflammatory molecules (such as pro-inflammatory cytokines, adhesion molecules and cyclooxygenase) expression involved in the inflammatory process. In this study, in establishing pig the MODS model of the foundation, with a high volume hemofiltration (Highvolume hemofiltration HVHF) to combat MODS, by observing the function of various organs and plasma the inflammatory factor before and after treatment, and NF-κB in the treatment of before and after the change and the impact of the regulation of gene expression of TNFα, IL-10, prevention MODS provide a new theoretical basis for clinical HVHF. The first part of the use of combat for the first time (hemorrhagic shock recovery reperfusion) and two hits (endotoxin) composite the factors successfully established porcine model of MODS. Methods: 15 pigs were randomly divided into hemorrhagic shock and resuscitation reperfusion endotoxin group (M group, n = 9); normal control group (group C, n = 6). To pig bloodletting caused mean arterial pressure 50 ± 5mmHg, maintain a 1.5-2h, then back to lose 60% of the loss of blood and twice the equilibrium liquid recovery, 12h after intravenous continuous infusion of endotoxin (Escherichia coli endotoxin E.colO111B4) 1.5mg/kg, 24-hour drip End. Continuous dynamic monitoring of heart and lung function, and the surviving animals were sacrificed after seven days. ALT, AST, Cr, BUN, PaO2 indicators with automatic analyzer to detect the point in time to observe the morphological changes of the major organ pathology. Results: M peripheral blood ALT, AST, Cr, BUN significantly increased before the death of the animals was significantly higher than normal, PaO2 decreased; pathological changes are mainly non-specific inflammatory changes. M group, the rate of organ failure: lung 77.8%, gastrointestinal tract, 66.7%, 55.6% of the liver, kidney 33.3%, 22.2% heart of MODS occurrence rate of 88.9%, the mortality rate of 77.8%, significantly higher than that of the control group. Conclusion: The use of two-hit method can successfully replicate the animal model of MODS, and mold - 2 - lt; WP = gt; Second Military Medical University Doctoral Dissertation ordinary surgical specialties MODS high incidence and high mortality, repeatability injury factors, pathogenesis, clinical manifestations and diagnostic criteria and clinical typical the biphasic delayed MODS similar. The second part of HVHF major organ function and cytokine. Methods: 19 pigs were randomly divided into hemorrhagic shock and resuscitation reperfusion endotoxin group HVHF (Group HF, n = 10); hemorrhagic shock recovery reperfusion to endotoxin group (group M, n = 9). One hour after injection of endotoxin HVHF treatment 12 hours a day, for three days of continuous dynamic monitoring of heart and lung function, the surviving animals were sacrificed after the seventh day. Detected by automatic analyzer each time point ALT, AST, Cr, BUN, PaO2, ELISA plasma of TNFα, IL-10 concentrations observed pathomorphological changes of major organs. Results: The treatment group peripheral blood ALT, AST, Cr, BUN was significantly lower than the MODS group, PaO2 significantly increased; after the start of treatment, TNFα levels begin to decline and reached the lowest level in the first four hours after the application of each of the new filter, and thereafter gradually increased until the first 24 hours, but was still significantly lower than before treatment, and maintained at a relatively stable concentration in the treatment of stage showed a similar change, then the change with a new filter, TNFα concentration and M group at each time point after treatment There were significant differences, but not detected in the filtrate of TNFα. Decreased IL-10 after the start of treatment, 6h reach the lowest point, and thereafter maintained at the steady state, can be detected in the filtrate of IL-10, reduces treatment time to extend the filtration coefficient. Antiinflammatory mediators IL-10 and proinflammatory mediators TNFα ratio with the duration of treatment remains in a relatively stable state, major organ function were significantly improved, before the death of the animals was significantly lower than the control group. Pathological changes compared with the control group was significantly reduced. The treatment group of MODS was 20%, the mortality rate was 20%, significantly lower than the control group. Conclusion: High-volume hemofiltration can effectively reduce the plasma levels of cytokines, tends dynamic equilibrium so that the anti-inflammatory and pro-inflammatory and inflammatory response in the body to ease; significantly improved major organ function, reduce the incidence of MODS and death rate. The third part of the NF-κB HVHF treatment before and after the change, and the impact of the regulation of gene expression of TNFα, IL-10. Methods: The immunohistochemical staining was observed decision liver, lung, kidney tissue NF-κB and I-κBα strength and intracellular distribution; Western blot technology complemented by image analysis system, at the protein level detection PBMC nuclear cells (PBMC) cytoplasmic I-κBα protein and nucleus the NF-κBp65 protein; TNFα and IL-10 mRNA expression was detected by RT-PCR in PBMC and liver, lung, kidney tissue. Results: (1) Immunohistochemical staining showed that the M group of NF-κB positive staining intensity than the HF group enhanced positive I-κBα staining intensity than the HF group decreased 27 M of liver, kidney, lung organ NF-κB expression between intensity and organ failure analysis of NF-κB moderately positive organ MODS was 70% (14/20)

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