الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Multiple Organ Dysfunction Is characterized By Development Of Progressive And Potentially Reversible Physiological Dysfunction In Two Or More Organs That Is Induced By A Variety Of Acute Insults Like Sepsis. Furthermore, It Has Been Also Defined In Terms Of Involvement Of Six Organ Systems, Namely Pulmonary, Renal, Hepatic, Central Neurologic, Cardiovascular, And Hematologic Systems. It Develops Due To Uncontrolled Infection, Especially Gram-Negative Sepsis.
Sepsis Is Defined As A Systemic Inflammatory Response To Severe Infection, Leading To Hyperactive And Unbalanced Levels Of Pro-Inflammatory Mediators. Generally, Sepsis Causes An Increase In Vascular Permeability, Changes In Cardiac Function And Alteration In Metabolic Balance, Which Results In Tissue Necrosis, Multiple Organ Failure And Finally Death.
Evidences Suggested A Role Of Localized Renin-Angiotensin System (RAS) In The Progression Of Different Pathologies. RAS Stimulation Mediates Oxidative And An Inflammatory Damage, Mostly Through Activation Of NADPH Oxidase, Inos Expression Whereas It Cause Inhibition Of Enos. Alternatively, A Physiological Antagonist To The Classic RAS Exists, where ACE Is Replaced By ACE2 In Which The Product Is Ang-1-7 Instead Of Ang-II, And The Receptor Is Mas Receptor Instead Of AT1 Receptor. In Contrast With The Classical System, This System Is Reported To Possess Potent Antioxidant And Anti-Inflammatory Effects.
Depending On The Pharmacological Properties Of Perindopril, The Current Study Aims To Investigate The Protective Effects Of Perindopril On Localized RAS Modification Against LPS-Induced Brain And Cardiopulmonary Injuries In Rats With Or Without Exogenous Ang-II. To Evaluate The Hypothesis Of This Study, ACE/ACE2 Systems, AKT, P-AKT, NF-Κb-P65, P-Iκba, P-NF-Κb-P65 Signaling Pathway, Inos/Enos Expressions, MPO, NADPH, MDA, GSH, NO2-, GST, SOD, CAT Biomarkers Were Examined.
In order To Achieve This Goal, The Study Has Been Designed As Follows: Fifty-Four Rats Were Randomly Divided Into Nine Groups, Each Of 6 Rats. group I, Rats Received Sterile Pyrogen-Free Saline (2 Ml/Kg/Day, I.P.) For 7 Days Represented As Normal Control Group. group II, Rats Received Sterile Pyrogen-Free Saline (2 Ml/Kg/Day, I.P.) For 7 Days Followed By I.C.V. Injection Of Ang-II (5 µl) On The 7th Day, Served As Sham Control Group. group III, Rats Received A Single I.P. Dose Of LPS (3 Mg/Kg) On The 7th Day Of The Experiment. group IV, Rats Received Perindopril (1 Mg/Kg/Day, I.P.) For 7 Days. group V, Rats Received Perindopril (2 Mg/Kg/Day, I.P.) For 7-Days. group VI, Rats Received Perindopril (1 Mg/Kg/Day, I.P.) For 7 Days Followed By LPS (3 Mg/Kg/Day, I.P.) On The 7th Day Of The Experiment. group VII, Rats Received Perindopril (2 Mg/Kg/Day, I.P.) For 7 Days Followed By A LPS (3 Mg/Kg/Day, I.P.) On The 7th Day Of The Experiment. group VIII, Rats Received Perindopril (1 Mg/Kg/Day, I.P.) For 7 Days, Followed By LPS (3 Mg/Kg/Day, I.P.) On The 7th Day Of The Experiment And Finally Injected With Ang-II Solution (1 Μg/Μl; 5 Μl, I.C.V.) On The 8th Day Of The Experiment. group VIIII, Rats Received Perindopril (2 Mg/Kg/Day, I.P.) For 7 Days, Followed By LPS (3 Mg/Kg/Day, I.P.) On The 7th Day Of The Experiment And Finally Injected With Ang-II Solution (1 Μg/Μl; 5 Μl, I.C.V.) On The 8th Day Of The Experiment.
After 12 H After The Last Dose Of Ang-II Administration Brain, Heart And Lung from Different Groups Were Quickly Removed And Trimmed Of Adipose Tissue And Harvested Immediately After Cervical Dislocation Of Rats. Cerebral Cortex Together With The Minimal Part Of The Adjacent Striatum, Lungs And Hearts Were Collected To Investigate Biochemical Markers Ang-II, Ang-1-7, NADPH Oxidase, MDA, GSH, NO2-, GST, SOD, CAT And MPO, P-NF-Κb-P65, AKT, P-AKT And P-Iκba. Furthermore, Histopathological Study Was Performed To Confirm These Results.
The Present Study Revealed That, LPS-Induced Noticeably Increased In Oxidative Stress, Inflammatory Biomarkers And Alteration In RAS As Compared To Normal Control Rats. Moreover, Up-Regulation Of NF-Κb-P65, AKT, P-AKT, Iκba, Inos Expressions And MPO Activity, Paradoxically With Down-Regulation Of Enos Expression Were Observed With LPS-Intoxicated Rats. Pretreatment With Perindopril Significantly Ameliorated The Disturbance Induced By LPS On Brain And Cardiopulmonary Tissues. These Results Were Further Supported By Improvement In Histopathological Features. The Results Of The Present Study Were Illustrated In Figure (37).
Fig. (6.36): The Schematic Illustration Of The Possible Signaling Mechanisms By Which Perindopril Ameliorated The LPS-Induced Multiple Organ Injury In Rats.
Conclusion
1- Lipopolysaccharides Stimulate Innate Immune System, Ang-II And Systemic Inflammatory Response.
2- Up-Regulation Of RAS, It Mediates Oxidative And Inflammatory Damage, Mostly Through Activation Of NADPH Oxidase And Inhibition Expression Of Enos.
3- Parameters That Were Measured In This Study Provide A Strong Evidence For Antioxidant And Anti-Inflammatory Of Perindopril Parallel To Its ACE Inhibitor.
4- The Possible Protective Effect Of Perindopril Is Could Be Attributed To Their Effect On RAS Through Significantly Decreased Of Ang-II Coupled With Elevation Of Ang-1-7 Levels, Anti-Inflammatory Effects Via Modulation Of NF-Κb-P65 And MPO As Well As Antioxidant Effects Through Corrected The Disturbance Between Oxidant And Antioxidant Enzymes Defense Mechanisms.
5- Perindopril Ameliorates LPS-Induced Multiple Organ Oxidative And Inflammatory Damage Through Suppression Of Ang-II And Enhancement Of Ang-1-7 Production. This Effect Is Mediated, At Least Partly, With Modulation Of Akt And NF-Κb Signaling Pathways As Well As Modulation Of Inos/Enos Expressions. However, Further Clinical Trials Are Required To Confirm These Mechanisms.