Lecture 10-Chronic inflammation Liver and TB Flashcards
What are the potential causes of liver damage leading to fibrosis?
Viral infection, alcohol abuse, diet induced metabolic disease, cholestasis, fubal aflatoxin B1, abnormal copper and iron storage
What is Non-alcoholic fatty liver disease?
Accumulation of fat in the liver, linked to diabetes, obseity and heart disease
What is the progression of NAFLD?
Steatosis which is benign accumulation of fat in the liver, this progresses to non-alcoholic steatohepatitis which is steatosis plus injury where inflammatory cells and fibrosis are often seen this will then progress to end stage liver disease or cirrohosis where liver structure is lost
What is lipotoxicity?
When cell damage occurs as result of excess free fatty acids as these impair mitochondrial function resulting in ROS release causing oxidative stress
If there is increased amounts of unsaturated fats then this can cause the ER to malufunction causing the unfolded protein response
What is the mechanism by which fibrotic change occurs in the liver?
Cells surrounding the sinusoids lay down collagen
The stellate cells will then differentiate into myofibrils which store less lipid, are more proliferative, make collagen I and III, express alpha SMA, are contractile, synthesize inhibitors of matrix mellatoprotease resulting in the retention of scar tissue
What is the normal function of hepatic stellate cells?
The hepatic stellate cells which are in the space of disse, then store lipids, have low proliferative and make a small amount of extracellular matrix
What causes hepatic stellate cells to transdifferentiate into myfibrils?
Kupffer cells release TGFBeta and PDGF when PAMPs or DAMPs are detected
Myofibrils also produce TGFBeta and Connective tissue growth factor
Relase of ROS from neutrophils
Low ration of interferon gamma/IL-4
What is ascites?
Fluid accumulation in the abdominal cavity
What are the effects of the portal hypertension seen in cirrhosis?
Ascites, Varices (varacose veins) which have weak vessel walls, renal failure
What are the effects of liver failure which may be seen in cirrhosis?
Hyperbilirubinaemia (excess bilirubin in blood) with jaundice
Loss of blood proteins
Encephalopathy (brain malfunctions due to increased nitrogen compoungs like ammonia)
What are the two types of granulomas?
Foreign body granulomas which are formed in response to endogenous or exongenous substances
Immune granulomas which are formed in response to infectious agents
What are the cellular changes induced by tuberculosis?
Mtb is phagocytosied by alveolar macrophages, but capsule prevents phagosomal destruction allowing the bacteria to replicate intracellularly
This causes recruitment of tH1 cells and macrophages
IFNGamma and TNF secreted by the tH1 increases the phagocytic activity of macrophages
Macrophages lose their motility, and become epithelioid and lipid storing
How might tuberculosis be controlled?
Macrophage apoptosis will kill the bacterium
The fibrous capsule forming around the granuloma prevents spread of the bacteria
A center of caseous necrosis forms due to cell and bacterial death
Long term control may be provided by this granuloma
What are the pathological effects when a granuloma is not adequately controlled?
Excessive fibrosis seen around granuloma, this damages air ways and compromises lung function
Mtb may cause liqufactive necrosis and cavitation which is up-regulated by cytokines (TNF, IL-1Beta) and oncotic macrophage death and peptidases from Mtb
How might Mtb spread in an uncontrolled granuloma?
Macrophage oncosis releases free bacteria, or as macrophages cannot survive in necrotic tissue allowing Mtb to replicate extracellularly
If a cavitation involves blood vessels then Mtb can spread systemically and be dispersed by Mtb aerosols
