الفهرس 
IntroductionOnly 14 pages are availabe for public view
 |  | from | 206 |  |  |
| | | from | 206 | | |
Abstract
Hepatic Fibrosis Is One Of The Most Serious Diseases That Occur In Humans As A Result Of chronic Liver Disease. It Is Defined As An Abnormal Response Of The Liver To Persistent Injury, characterized By The Excessive Accumulation Of ECM. The Proper Liver Tissue Is Replaced By A Fibrous Tissue, Which Causes The Liver To Loss Its Normal Function. The Most Common Causes Of HF Are Alcoholism, Hepatitis, And Fatty Liver. There Are Also Many Other Causes That Can Lead To HF And Some Cases That Are Unknown. Hence, In The Present Study The Possible Protective Effects Of Hesperidin, Nicorandil, Atorvastatin As Well As Allopurinol On HF Were Tested In Comparison To The Reference Drugs Silymarin And NAC In Adult Male Albino Rats. Induction Of Liver Fibrosis Was Performed By Intraperitoneal Injection Of Rats With Ccl4 In Corn Oil (1:1) At A Dose Of 2 Ml. Kg-1 Twice Weekly For Five Consecutive Weeks.
To Study The Protective Effects Of The selected Agents On HF Induced By Ccl4, Rats Were Randomly Allocated Into 9 Groups. The First group Was Kept As A Normal Control group And Received Only Saline (5 Ml.Kg-1 P.O). The Second group Was Kept As A Corn Oil group And Received Only Corn Oil (1 Ml.Kg-1 I.P.) Two Times Per Week For 5 Consecutive Weeks. The Third group Received Ccl4 In Corn Oil (2 Ml.Kg-1 I.P.) Twice Per Week For 5 Consecutive Weeks. The Remaining Groups Received The Following Treatments In Addition To Intraperitoneal Administration Of Ccl4 In Corn Oil ; Silymarin (100 Mg.Kg-1) And NAC (300 Mg.Kg-1) As A Reference Drugs, As Well As Hesperidin (200 Mg. Kg-1), Nicorandil (15 Mg.Kg-1), Atorvastatin (20 Mg. Kg-1) And Allopurinol (100 Mg.Kg-1). All The Treatments Were Administrated Orally On A Daily Basis For Five Consecutive Weeks Starting from The First Day Of Induction.
At The End Of The Experiment, Animals Were Anesthetized With Light Ether And Blood Samples Were Withdrawn from The Retro-Orbital Plexus For Serum Preparation. Liver Was Cut Into Small Pieces Then Homogenized To Be Used For Biochemical, Histological And Immunohistochemical Studies.
The Degree Of Fibrosis Was Assessed By Measuring Liver Function Tests [Serum Alanine Transaminase (ALT), Aspartate Transaminase (AST), Albumin And Total Bilirubin], Lipid Profile [Total Cholesterol, Serum Triglycerides, High Density Lipoprotein Cholesterol (HDL-C) And Low Density Lipoprotein Cholesterol (LDL-C)], Also [Serum Tumor Necrosis Factor Alpha (TNF-Α), Hepatic Myeloperoxidase (MPO), Relative Liver Weight] As Indication For Inflammation, As Well As Oxidative Stress Markers [Hepatic Malondialdehyde (MDA), Glutathione (GSH) And Catalase ( CAT )] And Specific Fibrosis Biomarkers [Hepatic Transforming Growth Factor Β1(TGF-Β1) And Hepatic Hydroxyproline (HYP)], Supported By Liver Histopathological Study And Immunohistochemical Staining Of Α-SMA In Liver Sections.
The Main Findings Of The Present Investigation Can Be Summarized As Follow:
1. Effect Of Ccl4 On Normal Adult Male Albino Rats:
Carbon Tetrachloride Showed Significant Increase In Tissue Content Of TGF-Β1 And HYP. It Also Caused Significant Elevation In The Serum Liver Function Markers Of ALT, AST And Total Bilirubin And Significant Decrease In Albumin. In Addition, Ccl4 Increased Oxidative Stress Biomarkers Evidenced By A Significant Increase In Hepatic Content Of MDA And Significant Decrease In GSH Content And CAT Activity. On The Other Hand, Ccl4 Increased Inflammatory Biomarkers Evidenced By Significant Increase In MPO Activity, The Serum Pro-Inflammatory Cytokine TNF-Α, And Relative Liver Weight. It Also Caused Significant Increased The Serum Lipid Profile Markers Of Total Cholesterol, Triglycerides And LDL-C. It Showed Significant Decrease In HDL-C.
Histopathological Examination Of Liver Showed That Ccl4 Caused Accumulation Of Fibrous Tissue With Dilated Blood Vessels And Activation Of Von Kupffer Cells In Liver Sections. Immunohistochemical Staining Of Α-SMA Antigen Showed Strong Positive Expression Of Α-SMA In Rats Liver Sections Of Ccl4 group Which Further Supported HF Induced By Ccl4.
2. Effect Of Silymarin On Ccl4-Induced HF:
Treatment Of Rats With Silymarine Significantly Decreased The Elevated Serum Level Of ALT, AST, Bilirubin, Tnfα And Lipid Profile Markers Of [Tgs, Total Cholesterol And LDL-C], The Hepatic Activity Of MPO As Well As The Hepatic Content Of Tgfβ1, HYP And MDA As Compared To The Fibrosis Group.
On The Other Hand, It Significantly Increased The Decreased Serum Level Of Albumin And The Lipid Profile Of HDL-C As Well As The Hepatic GSH Content And CAT Activity As Compared To The Fibrosis Group. Besides, It Restored The Elevated Relative Liver Body Weight Back To Normal.
Histopathological Study Showed That Silymarin Nearly Restored The Normal Hepatic Architecture But With Slight Dilatation Of Central Vein And Von Kupffer Cells Can Also Be Noticed. Immunohistochemical Staining Of Α-SMA Antigen Showed Moderate Positive Expression.
3. Effect Of NAC On Ccl4-Induced HF:
Treatment Of Rats With NAC Significantly Decreased The Elevated Serum Level Of ALT, AST, Bilirubin, Tnfα And Lipid Profile Markers Of [Tgs, Total Cholesterol And LDL-C], The Hepatic Activity Of MPO As Well As The Hepatic Content Of Tgfβ1, HYP And MDA As Compared To The Fibrosis Group.
On The Other Hand, It Significantly Increased The Decreased Serum Level Of Albumin And The Lipid Profile Of HDL-C As Well As The Hepatic GSH Content And CAT Activity As Compared To The Fibrosis Group. Besides, It Restored The Elevated Relative Liver Body Weight Back To Normal.
The Histopathological Study Showed Reappearance Of Normal Hepatic Architecture But Activated Von Kupffer Cells Can Be Noticed. Immunohistochemical Staining Of Α-SMA Antigen Showed Weak Positive Expression.
4. Effect Of Hesperidin On Ccl4-Induced HF:
Oral Administration Of Hesperidin Significantly Decreased The Elevated Serum Level Of ALT, AST, Bilirubin, Tnfα And Lipid Profile Markers Of [Tgs, Total Cholesterol And LDL-C], The Hepatic Activity Of MPO As Well As The Hepatic Content Of Tgfβ1, HYP And MDA As Compared To The Fibrosis Group. The Hepatic Content Of MDA Was Significantly Reduced As Compared To The Reference Standards Silymarin And NAC.
On The Other Hand, It Significantly Increased The Decreased Serum Level Of Albumin And The Lipid Profile Of HDL-C As Well As The Hepatic GSH Content And CAT Activity As Compared To The Fibrosis Group. Besides, It Restored The Elevated Relative Liver Body Weight Back To Normal.
The Histopathological Study Showed Restoration Of Normal Architecture Of The Liver With Only Slightly Dilated Congested Blood Sinusoids And Activation Of Some Von Kupffer Cells. Immunohistochemical Staining Of Α-SMA Antigen Showed Moderate Positive Expression.
5. Effect Of Nicorandil On Ccl4-Induced HF:
Oral Administration Of Nicorandil Significantly Decreased The Elevated Serum Level Of ALT, AST, Bilirubin, Tnfα And Lipid Profile Markers Of [Tgs, Total Cholesterol And LDL-C], The Hepatic Activity Of MPO As Well As The Hepatic Content Of Tgfβ1, HYP And MDA As Compared To The Fibrosis Group.
On The Other Hand, It Significantly Increased The Decreased Serum Level Of Albumin And The Lipid Profile Of HDL-C As Well As The Hepatic GSH Content And CAT Activity As Compared To The Fibrosis Group. Besides, It Restored The Elevated Relative Liver Body Weight Back To Normal.
Nicorandil Showed Significantly Better Improvement In The Serum Level Of Cholesterol, Hepatic Tgfβ1 Content And MPO Activity As Compared To The Reference Silymarin. It Showed Significantly Better Improvement Of Serum ALT And AST As Compared To The Reference NAC. It Showed Significantly Better Improvement Of The Serum Level Of LDL And Hepatic MDA Content, As Compared To The Reference Silymarin And NAC.
Nicorandil Showed Histopathological Improvement In The Liver Architecture, Except Dilated Central Vein With Little Congested Blood Sinusoids. Immunohistochemical Staining Of Α-SMA Antigen Showed Weak Positive Expression.
6. Effect Of Atorvastatin On Ccl4-Induced HF:
Oral Administration Of Atorvastatin Significantly Decreased The Elevated Serum Level Of ALT, AST, Bilirubin, Tnfα And Lipid Profile Markers Of [Tgs, Total Cholesterol And LDL-C], The Hepatic Activity Of MPO As Well As The Hepatic Content Of Tgfβ1, HYP And MDA As Compared To The Fibrosis Group.
On The Other Hand, It Significantly Increased The Decreased Serum Level Of Albumin And The Lipid Profile Of HDL-C As Well As The Hepatic GSH Content And CAT Activity As Compared To The Fibrosis Group. Besides, It Restored The Elevated Relative Liver Body Weight Back To Normal.
Atorvastatin Showed Significantly Better Improvement In The Serum Level Of Cholesterol And The Hepatic Content Of Tgfβ1 As Compared To The Reference Silymarin. It Also Showed Significantly Better Improvement In The Serum Levels Of ALT, Tnfα And LDL-C And The Hepatic Content Of MDA, As Compared To The Reference Standards Silymarin And NAC.
Atorvastatin Showed Normal Histopathological Examination Except Some Von Kupffer Cells Can Be Observed. Immunohistochemical Staining Of Α-SMA Antigen Showed Moderate Positive Expression.
7. Effect Of Allopurinol On Ccl4-Induced HF:
Oral Administration Of Allopurinol Significantly Decreased The Elevated Serum Level Of ALT, AST, Bilirubin, Tnfα And Lipid Profile Markers Of [Tgs, Total Cholesterol And LDL-C], The Hepatic Activity Of MPO As Well As The Hepatic Content Of Tgfβ1, HYP And MDA As Compared To The Fibrosis Group.
On The Other Hand, It Significantly Increased The Decreased Serum Level Of Albumin And The Lipid Profile Of HDL-C As Well As The Hepatic GSH Content And CAT Activity As Compared To The Fibrosis Group. Besides, It Restored The Elevated Relative Liver Body Weight Back To Normal.
It Showed Significantly Better Improvement In The Serum Level Of Tnfα And The Hepatic Content Of Tgfβ1 As Compared To The Reference Silymarin. It Showed Significantly Better Improvement In The Serum Level Of Cholesterol, And Tgs And The Activity Of CAT As Compared To The Reference NAC. Moreover, It Showed Significantly Better Improvement In The Serum Level Of HDL-C And LDL-C And The Hepatic Content Of MDA As Compared To The Reference Silymarin And NAC.
Liver Histopathology Showed An Improvement Of Histopathological character With Restoration Of Normal Hepatic Architecture Except For Somewhat Congested Central Vein And Some Activated Von Kupffer Cells. Immunohistochemical Staining Of Α-SMA Antigen Showed Weak Positive Expression.
Depending On The Previous Findings, It Could Be Concluded That:
1. Carbon Tetrachloride Caused HF In Rats Evident Through Estimation Of Specific Fibrotic Markers, Cytokines, Inflammatory Mediators And Oxidative Stress, Activation Of Hscs, And Strong Positive Expression Of Α-SMA.
2. Hesperidin, Nicorandil, Atorvastatin And Allopurinol Could Protect Against Ccl4-Induced HF To Degrees Similar To Or Better Than That Of The Reference Drugs Silymarin And NAC Making Them A Potential Therapeutic Option To Prevent Liver Fibrosis.
3. The Anti-Fibrotic Effects Are, At Least Partly, Due To Their Antioxidant, Anti-Inflammatory And Antilipidemic Activities. These Effects Would Reduce Hscs Activation And The Progression Of Fibrosis.
4. These Drugs Seem To Be Promising For Liver Protection But Further Clinical Trials Are Needed To Prove These Findings On Human Beings.