الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
Liver Cirrhosis Has Been Identified As An Important Cause Of Human Morbidity And Mortality. It Is The End Stage Of chronic Liver Disease In Which chronic Hepatic Exposure To Injury Leads To Activation Of Hepatic Stellate Cells (Hscs) And Subsequent Production Of Collagen And Fibrous Tissue, Then Prolonged Liver Fibrosis Results In Hepatic Cirrhosis. One Of The Reliable And Effective Experimental Animal Models That Mimic The Pathological Response Of Cholestatic Liver Cirrhosis Is Bile Duct Ligation (BDL) Model. Although The Pathogenesis Of BDL Hasn’t Been Well Explained Yet, Accumulated Guides Have Demonstrated That Oxidative Stress And Inflammation Play A Crucial Role In Acute And chronic Stages Of Liver Diseases. In This Model, The Hydrophobic Bile Salts Retained And Accumulated In The Liver Produce An Alteration In Redox-Sensitive Response And Increase Reactive Oxygen Species (ROS) Production. The Dramatic Increases Of Free Radicals Activate Inflammatory Response To Induce More ROS And Subsequent More Inflammation. Moreover, Hscs Are Activated In Response To Free Radicals Production To Induce Collagen Deposition In Liver.
Accordingly, Any Pharmacological Agent That Has The Ability To Attenuate Inflammation And Oxidative Stress Could Minimize The Harmful Effects Of BDL-Induced Liver Damage. Therefore, The Present Study Was Designed To Investigate The Hepatoprotective, Anti-Oxidant, Anti-Inflammatory And Anti-Fibrotic Effects Of Diosmin (DS), Sildenafil (Sild), Pentoxifylline (PTX) And Their Combinations Against BDL-Induced Liver Cirrhosis And Their Role In The Modulation Of P38-MAPK/NF-Κb-P65 And Keap-1/Nrf-2 Signaling Pathways As Well As Cytoglobin Expression.
In order To Achieve This Goal, The Study Has Been Designed As Follows: Seventy Adult Male Albino Rats Were Divided Randomly Into Seven Groups Each Of Ten Rats; group I Received Gum Acacia (2%) At A Dose Of (0.5 Ml/100g) Orally Once Daily For 28 Days And Subjected To An Identical Laparotomy And Exposure Of The Common Bile Duct Without Ligation And Served As Sham Control. group II Subjected To Common Bile Duct Ligation And Received Gum Acacia (2%) At A Dose Of 0.5 Ml/100g Orally Once Daily For 28 Days And Served As BDL Control. group III Subjected To Common Bile Duct Ligation And Treated With DS (100 Mg/Kg, P.O.) Once Daily For 28 Days. group IV Subjected To Common Bile Duct Ligation And Treated With Sild (10 Mg/Kg, P.O.) Twice Daily For 28 Days. group V Subjected To Common Bile Duct Ligation And Treated With PTX (50 Mg/Kg, P.O.) Once Daily For 28 Days. group VI Subjected To Common Bile Duct Ligation And Treated With DS (100 Mg/Kg, P.O.) Once Daily And Sild (10 Mg/Kg, P.O.) Twice Daily For 28 Days. group VII Subjected To Common Bile Duct Ligation And Treated With DS (100 Mg/Kg, P.O.) Once Daily And PTX (50 Mg/Kg, P.O.) Once Daily For 28 Days.
After 12 Hours Fasting from The Last Dose, Blood Samples Were Collected Through Cardiac Puncture Technique Under Ketamine (100 Mg/Kg; I.P.) Anesthesia And Then Livers Were Dissected Out. Both Serum And Tissue Samples Were Collected To Investigate Biochemical Markers (Liver Function Biomarkers, Oxidative Stress Markers, And Antifibrotic Markers), Mrna Expression Of Nrf-2, Keap-1, NF-Κb-P65 And P38-MAPK, Protein Expression Of Cytoglobin And Inducible Nitric Oxide Synthase (Inos) And Endothelial Nitric Oxide Synthase (Enos). In Addition, Histopathological Study Was Performed To Confirm These Results.
The Results Revealed That, 28 Days Of BDL Induced A Significant Alteration In Liver Functions, Fibrotic And Oxidative Stress Markers As Compared To Sham Control. Furthermore, Up-Regulation Of NF-Κb-P65, P38-MAPK, Keap-1 And Inos Concomitantly With Down-Regulation Of Nrf-2, Cytoglobin And Enos Expressions Were Observed After BDL. Treatment With DS, Sild, PTX And Their Combinations Significantly Alleviated The Disturbance Induced By BDL. These Findings Were Further Supported By The Improvement In Histopathological Features. Additionally, Co-Administration Of DS And Sild Or PTX Was Found To Significantly Improve Liver Defects Due To BDL As Compared To The Individual Drugs.
Finally, It Could Be Concluded That
1- The Hepatic Dysfunction Due To BDL Model Is At Least Partly Due To Oxidative Stress And Inflammatory Processes.
2- Parameters That Were Measured In This Study; Provide A Strong Evidence For Antioxidant And Anti-Inflammatory Power Of Diosmin, Sildenafil And Pentoxifylline.
3- The Protective Mechanisms Of These Drugs Are Attributed To Their Antifibrotic Effects Via Reduction Of HYP And TGF-Β, Anti-Inflammatory Effects Via Modulation Of NF-Κb-P65/P38-MAPK And Antioxidant Effects Through Modulation Of Nrf-2/Keap-1 Signaling Pathway.
4- Combination Of Diosmin With Either Sildenafil Or Pentoxifylline Is More Effective Than Administration Of Each Drug Alone For Protection Against Liver Cirrhosis.
5- The Results Of The Present Study Suggest The Therapeutic Potential Of These Drugs In Treatment Of Liver Fibrosis. However, Further Clinical Trials Are Required To Confirm That.