The Injury Mechanisms Of Multiple Organ Dysfuntion Syndrome In The Elderly Rats Induced By Zymosan And The Protective Effects Of Aspirin

BackgroudMultiple organ dysfunction syndrome in the elderly(MODSE) is one of the most common cause of mortality in critically ill elderly patients, and it is different from MODS in the adult in clinic. It is the key to identify the etiopathogenesis of MODSE ,so we can prevent and cure it directly.Rare studies have been done on its apoptosis pathway and other related factors in MODSE. In this research,we emphasize the function of NF-κB and apoptosis in MODSE and seek the development of rational interventions. Elucidation of the mechanisms involved in the development of MODSE. ObjectiveInvestigating the injury mechanisms of multiple organs dysfunction syndrome in the elderly rats induced by zymosan and the protective effects of aspirin in order to provide theoretical basis for the prevention and treatment of MODSE. MethodsIn the first of this study, Male Sprague-Dawley rats were intraperitoneally injected with zymosan (0.5g/kg) to incite MODSE. And the changes of the function and morphology of vital organs including the heart, liver, brain, lungs, and kidneys were observed by analysising of blood gas,blood biochemistry as well as histopathologic examination. In the second part of our study,The levels of serum tumor necrosis factor a (TNF-α) were detected by radioimmunoassay (RIA), and the levels of serum interleukin 6 (IL-6) and interleukin 10 (IL-10) were assayed by enzyme-linked immunosorbent assays (ELISA). The expression and activity of NF-κB in these models were detected with immunohistochemistry ,respectively. In the third part, we had also explored the role of apoptosis , expression of apoptosis-regulating Bcl-2 and caspase-3 genes with immunohistochemistry and TUNEL.The last part, To observe the protective effect of aspirin(ASA) in lung injury of MODSE. We investigated thechanges of NF-κB activation and Bcl-2 and caspase-3 genes with EMSA , WesternBlot technology.Results(1)Compared with the normal adult and elderly rat controls, the blood gas and blood biochemistry changed to different extents in the different groups.The pathological changes were also observed in the vital organs including the lungs, heart, liver, brain, kidneys, etc.After injection of zymosan, the reductions of respiratory, cardiac and renal functions in the different groups, severer inflammation in lung than other organs indicative of the possible roles of lung in triggering MODSE. (2)In MODSE aged rats, the activity of serum SOD was decreased and the content of serum MDA was increased (P<0.05). Compared with the normal controls, the levels of serum TNF-α, IL-6 and IL-10 were all enhanced in MODS and MODSE group(P<0.05), moreover, compared with the adult MODS group, the serum TNF-α was much higher, whereas serum IL-10 was lower in MODSE group(P<0.05). Compared with the normal controls, the activity of NF-κB were much higher in MODS and MODSE group(P<0.05). (3) Both the survival gene(Bcl-2) and death promoting gene(caspase-3) were seen in lungs liver heart of rats with MODS and MODSE. Bcl-2 levels were obviously higher in model groups as compared with control group, The expression of caspase-3 was up-regulated markedly in all model groups(P<0.05). (4) Compared with the MODSE group, We observed that the activity of NF-κB were much lower,the expression of Bcl-2 was up-regulated and the expression of caspase-3 was down-regulated markedly in ASA group(P<0.05). Conclusions(l)Zymosan-induced MODSE animal model is an ideal one, which simulated clinical features of delayed two-phase MODSE. It was successful to reproduce the animal model of MODSE by this simple and easy method. (2) Compared with other groups, the activity of NF-κB were much higher in MODSE group.All the data suggested that the mechanisms of MODSE might be that free radical accumulated in ageing processes and activited NF-κB which promoted genes expession related to inflammation and then triggered the development of MODSE.The results from rat model for MODSE induced by zymosan appoved that NF-κB indeed play an important role in MODSE, severer inflammation in lung than other organs indicative of the possible roles of lung in triggering MODSE. (3) Cell apoptosis and the expression of caspase-3 and Bcl-2 increased after zymosan interference, which indicated cell apoptosis process played a great role in MODS and MODSE rats, severer apoptosis in lung than other organs indicative of the important roles of lung in triggering MODSE. (4) Aspirin might inhibit NF-κB activation and suppress apoptosis to decrease the the injury of lung in MODSE induced by zymosan.