Excessive healing in the liver Flashcards
What is the result of end stage liver fibrosis?
Cirrhotic liver
What is fibrosis?
Formation of excess fibrous connective tissue in an organ
Marked by quantitative and qualitative changes in the composition of hepatic ECM
What are liver diseases associated with hepatic fibrosis?
Chronic viral hepatitis
Early alcoholic disease
Portal hypertension
Steatohepatitis
How does hepatic fibrosis develop?
With different morphological and spatial patterns
Different etiologies cause different patterns of fibrosis
Liver lobule contains centrilobular vein and portal tract
What is pericentral disease?
Caused by chronic alcohol hepatitis and steatohepatitis
Fibrosis accumulates in the centrilobular vein and makes contaft with the portal tract
What is portal to central disease?
Caused by primary cirrhosis and chronic viral hepatitis
Formed at the portal tract and damage spreads to the center
What is common in both pericentral disease and portal to central disease?
There is progressive sinusoidal arterialization leading to cirrhosis
What are key components of the ECM in liver fibrosis?
Kupffer cells
Hepatocytes
Stellate cells
Sinusoidal epithelial cells
What are the different stages of chronic liver disease?
Patients with different stages of cirrhosis are staged by a system to investigate progression of CLD
F0 = no fibrosis F1 = fibrosis withour septa F2 = few septa F3 = numerous septa without cirrhosis F4 = numerous septa with cirrhosis
What is a septum?
A wall made of ECM that divides a tissue into smaller compartments
What is the definition of cirrhosis?
Advanted stage of fibrosis
CHaracterised by the formation of regenerative nodules of liver parenchyma
Separated by and encapsulated in fibrotic septa
What changes to the ECM leads to fibrosis?
Marked accumulation of high amounts of collagen and ECM
Qualitative change in ECM
MMPs production is decreased
Elastin and acellular fibrosis
Thick ECM septa with no space for cells
What is the basal lamina?
Layer of low-density matrix
Allows for perdusion between blood and cells for nutrients, hromones and metabolites
WHat type of ECM forms the liver?
Type IV matrix
Contains collagen type IV, Heparan sulphate, Proteoglycans, Enctactin and Laminin
Structure of laminin
A chain - binds to proteoglycan
B1 chain - binds to collagen type IV
B2 chain - binds to enctactin
WHat happens to laminin during fibrosis?
Increased laminin expression
Basal lamina will become fibrillar matrix and more dense than healthy basal lamina
What are the major proteins in ECM?
Collagens
Structure of collagens
Polypeptide with repeating sequence
Glycine, proline and hydroxyproline
Use repeating sequences to measure the accumulation of collagens
Formation of a collagen fibril
- Pro-a chain is synthesised in the RER
- Pro-a chain assembles into 3 pro-a chains
- Form triple helix
- Secreted in the process of exocytosis
- In the ECM propeptides will be cleaved and allow fibril formation
- Self-assembly into a collagen fibril
- A lot of fibrils to form one fiber
What will the stimulus which causes liver fibrosis induce?
Inflammation
Oxidative stress
Apoptosis
Cytokine secretion
What is the key cell that leads to hepatic fibrosis?
Hepatic stellate cell
95-97% of cells responsible for fibrosis
Produce GF and chemokines
Which other cells are responsible for hepatic fibrosis?
Portal fibroblasts, hepatocytes, mesenchymal stem cells, circulating fibrocytes and hepatic stellate cells differentiate into myofibroblasts
Can lead to fibrosis
Apoptosis of these MFs leads to fibrosis regression
How are hepatic stellate cells activated?
Upon liver damage
Produce collagen type IV
MMPs still working, but GF receptors are expressed
They then transition into myofibroblast-like cells
What happens when stellate cells transition into myofibroblast-like cells?
Less ECM degradation
Large amount of fibrillar ECM
Key collagen produced - collagen I
Glycoproteins produced (Proteoglycans and lamina)
Autocrine loops of PDGF, TGF-b and ET-1
Benefits of activated hepatic stellate cells
Production of new blood vessels
What is the purpose of the contractile phenotype during portal hypertension development?
Important
MCP-1 = chemotactic protein that recruits monocytes and neutrophils to the site of damage
Role of ROS in the development of excessive liver healing
Oxidative stress induced by an increased generation of ROS released by damaged or activated neighboring cells can directly affect the behavior of hepatocytes
Injured hepatocytes release ROS
Activate Kupffer cells and sinusoidal endothelial cells
Produce PDGF, TGF b and GFs
Activate stellate cells
Produce free radicals and TGFb, procollagen alpha 1 and MCP-1
Recruitment of WBCs
What are ROSs?
Chemically reactive molecuels containing oxygen
Formed as natural byproducts of the normal metabolism of oxygen
Excessive production of ROS is associate with lipid peroxidation and cell injury
