الفهرس 
Introduction and Aim of the Workيوجد فقط 14 صفحة متاحة للعرض العام
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المستخلص
The present thesis was conducted to investigate the protective effects of RAAS inhibition, through different mechanisms, ramipril an ACE-inhibitor, losartan an ARB and spironolactone an aldosterone antagonist in reducing liver and kidney injury induced by sepsis. In addition, the study attempted to use the silymarin to compare between their protective effects.
The study involved two separate designs: mechanistic and survival studies. Induction of sepsis was achieved via CLP. 48 Female Wister rats were randomized into six groups: sham, CLP-nontreated, CLP-treated by silymarin, ramipril, losartan and spironolactone after 1 hour from surgery. Sham rats were subjected to the same procedure except the ligation of cecum. After 24 hours, rats were sacrificed for blood and tissue samples collection. The same set of groups were applied in a separate number of rats for the survival study, each composed of 10 rats except the septic group which was composed of 20 rats. The period of observation was for 10 days.
Various tests have been done using liver and kidney as well as serum. These analyses include:
• Motor activity before and after CLP induction relative to sham group.
• Biochemical analyses involving measurement of liver and kidney enzymes. ALT, AST, albumin and total-bilirubin for liver, creatinine, and cystatin-c for kidney.
• Oxidative stress; malondialdehyde and total nitrite concentrations and antioxidant activity; reduced glutathione and superoxide dismutase activity in the liver and kidney tissues.
• Serum levels of Ang-II, TNF-α and IL-6.
• Immuno-histochemical findings for activated caspase-3 in liver and kidney tissues from each group.
• Histopathological examination of liver and kidney tissues from each group.
Results showed:
1- The induction of sepsis via CLP produced harmful effects on liver and kidney in both structure and function.
2- Demonstrated histopathological and immuno-histochemical changes were observed in septic rats and were compared to normal rats. These changes were associated with increased liver and kidney enzymes, oxidative stress as shown by increased levels of MDA and NOx and reduced activity of SOD with low level of GSH. Moreover, the pro-inflammatory cytokines TNF-α and IL-6 were elevated. These results were associated with an elevation in serum Ang-II level. In addition, CLP-rats were associated with low motor activity and high mortality at the first day of observation.
3- Treatment with ramipril (10 mg/kg), losartan (20 mg/kg) and spironolactone (25 mg/kg) attenuated the biochemical changes in septic liver and kidney. The rats treated by RAAS inhibitors showed improvement in motor activity and survival with restoration of normal architecture and normal functions in both liver and kidney tissues and serum. In addition to the prevention of sepsis induced elevation in cellular oxidative stress which was demonstrated as decrease in MDA and NOx and rise in the activity of SOD and GSH level. Also, the levels of inflammatory cytokines were reduced. The activation of caspase-3 also was reduced. Thus, these results clarify the role of Ang-II in sepsis as an important inflammatory mediator.
4- These results compared with silymarin protective effect. The results showed that silymarin reduces sepsis-induced mortality in experimental animals, which was associated protection of liver and kidney against sepsis-induced acute organ damage. The hepatorenal protective effects of silymarin can be attributed, at least in part, to its ability to balance tissue oxidant-antioxidant status acting as a free-radical scavenger and lipid peroxidation inhibitor as well as induction of endogenous antioxidant mechanisms.
In addition, silymarin-mediated protection of kidney and liver can also be attributed to its anti-inflammatory activity. Taken together, our results suggest a potential role of silymarin in the management of multiorgan failure during sepsis.