Lecture 12: Chronic Inflammation: Liver And TB Flashcards
Which viral infections can cause liver damage leading to fibrosis?
Hep B, Hep C, HBV and HCV
What can liver damage, leading to fibrosis arise from?
- viral infections
- alcohol abuse
- diet induced metabolic disease
- conditions that prevent bile flow
- fungal aflatoxin B1 in poorly stored food
- abnormal iron and copper storage
What is the term given to prevention of bile flow
Cholestasis
What is haemochromatosis
Abnormal iron storage
What is wilson’s disease
Abnormal copper storage
What is non alcoholic fatty liver disease?
A range of conditions characterised by triglyceride accumulation in liver
What is NAFLD associated with?
Obesity, type 2 diabetes, and risk of heart disease
In the USA, what proportion of the population may NAFLD affect?
30% of population
Up to 9% of children
What is steatosis?
Benign, Fat accumulation in the liver
What may steatosis arise from?
High fat and fructose diet
Increase in fat liberated from insulin resistant adios yes
Increase in fatty acid synthesis in the liver as a result of insulin resistance
What is non alcoholic steatohepatitis characterised by?
Steatosis plus injury inflammation and (often) fibrosis
What may NASH arise from?
Two events, or hits:
What is the first hit which could lea to NASH?
Non-toxic steatosis, increases the vulnerability of liver cells to damage
What is the second hit that may lead to NASH
Agents like ROS, pro-inflammatory cytokines and endotoxin from gut bacteria
What may cell damage arise from?
An excess of free fatty acids
What is lipotoxicity
Cell damage due to excess of free fatty acids
What are the two stresses that cause/ are affected by lipotoxicity?
Oxidative stress and ER stress
How does lipotoxicity lead to ER stress?
The Endoplasmic reticulum makes up for more than 10% of cell volume.
It folds and assembles proteins
An increased ratio of saturated to unsaturated fatty acids perturb ER environment, generating ER stress which leads to an unfolded protein response caused by accumulation of unfolded protein in ER
What do the two stresses, Oxidative stress and ER stress result in?
Cell death - both apoptosis and oncosis
Liver damage
Inflammation
Fibrosis
What is liver fibrosis
A wound healing process which occurs in chronic liver diseea
Which cells start the fibrotic response to injury?
Cells surrounding the sinusoids (capillaries which connect portal tracts and central vein)
How do these cells respond to tissue damage and inflammation?
They lay down fibrillar collagen
What are hepatic stellate cells?
Liver specific pericytes
Where do hepatic stellate cells reside?
In the gap between he
Atrocities and sinusoidal endothelial cells
The space where HSCs usually reside in is also known as…. .?
The space of disse
What do HSCs do?
Store lipids - especially retinoids like vitamin A
They have low proliferative ability
They synthesise low amounts of (basement membrane type) extracellular matrix
What are pericytes? - hepatic stellate cells are a specified type of them…
Contractile cells which wrap around endothelial cells of venules and capillaries throughout the body
Embedded within basement membrane
Communicate via paracrine signals and direct physical contact with blood vessels smallest endothelial cells
[from wiki]
What happens after liver damage?
Hepatic stellate cells trans-differentiate into myofibroblasts (MFs)
What do myofibroblasts do?
They store less lipid
More proliferative
Synthesise fibrillar collagen I and III
Express αSMA and are contractile
Synthesise tissue inhibitors of MMPs (TIMPs) which prevent the removal of excess fibrous tissue
What are some other sources of MFs?
Bone marrow derived cells (fibroblasts)
Portal fibroblasts
Epithelial cells that undergo Epithelial mesenchymal transition
What are MMPs?
Matrix metalloproteinases
What mediators induce the transdifferentiation of HSCs to MFs and fibrogenesis
Kupffer cells
MFs and TGFβ- inducible connective tissue growth factor CTGF
Neutrophils releasing ROS which are fibrogenic
The low ration of TH1 (IFNγ) : TH2 (IL-4) , which are fibrogenic
What are Kupffer cells?
Liver macrophages, which make up 15% of cells in the liver
They release TGFβ and PDFF when their TLRs bind bacterial products and DAMPs
Where are bacterial products from? Which the TLRs of TGFβ and
PDGF bind to
Leaky gut mucosa
Where do DAMPs come from?
Oncotic cells
What causes haemodynamic resistance and portal hypertension?
The narrowing of the sinusoid lumen
What is portal hypertension?
Increased blood pressure on the portal vein
What does chronic injury with hepatocytes death lead to?
Inflammation
Regeneration
Healing by repair with fibrogenesis and cirrhosis
What is cirrhosis?
The loss of liver architecture with septa of fibrous tissue surrounding nodules of regenerating hepatocytes
When does cirrhosis occur?
After 15-20 years of hepatocytes death
What are septa?
Sheets
What are the consequences of cirrhosis?
Portal hypertension
Liver failure
Liver cancer
How does portal hypertension arise?
From resistance to blood flow in the liver with possible ascites, varies and renal failure
What is ascites?
Accumulation of fluid in the abdominal cavity
This is due to elevated hydrostatic pressure in mesenteric capillaries, decreased concentrations of plasma albumin and sodium and water retention
What is varices?
Dilated oesophageal varicose veins which occurs as a result of increased pressure in the portal veins
Why can varices rupture and bleed?
They have weak walls
What can occur with liver failure?
Hyperbilirubinaemia with jaundice,
loss of blood proteins with oedema and bleeding
Ecephalopathy
What is hyperbilirubinaemia?
Excess bilirubin in the blood
What blood proteins are loss with liver failure?
Albumins clotting factors
What is encephalopathy?
Brain malfunction
How does encephalopathy occur?.
It occurs in response to increased concentrations of nitrogenous catabolites like ammonia in the blood.
This can progress through mild changes (sleep disturbance, irritability) to a coma
What is hepatocellular carcinoma?
Liver cancer, a late complication of cirrhosis
What are granulomas?
Aggregations of specialised macrophages in response to indigestible substances
How do foreign body granulomas arise?
They arise in response to endogenous or exogenous materials
What are endogenous materials in which foreign body granulomas may arise from?
Fragments of bone
What are exogenous materials in which foreign body granulomas may arise from?.
Silica
What are immune granulomas?
Localised inflammatory responses to infectious agents like mycobacterium tuberculosis, M leprae, treponema pallidum, schistosoma, eggs
What are the infectious agents which can cause immune granulomas and what diseases do they cause?
Mycobacterium tuberculosis - Tuberculosis M leprae - leprosy Treponema pallidum - syphilis Schistosoma - fluke Schistosoma eggs - schistosomiasis
What are Mtb bacteria entering the lung phagocytosed by?
Alveolar macrophages
Which Mtb are not killed?
Those which block phagosome maturation.
These will proliferate inside macrophages
What cellular changes occur in tuberculosis?
Initially the M tuberculosis which enter the lung, are phagocytosed by alveolar macrophages.
Some of these will block phagosome maturation and thus won’t be killed but will proliferate inside macrophages
Cytokines recruit neutrophils, then TH1 lymphocytes and macrophages .
The IFNγ and TNF secreted by TH1 lymphocytes will activate macrophages by increasing phagocytic activity and lysosomal enzyme content
Where are immune responses to Mtb centred?
On the granulomas
What do macrophages transform into after they lose their motility?
Epithelioid cells
Which are epithelial like
Why do Mtb induce epithelioid cells to develop into lipid storing cells?
So that they can provide nourishment for Mtb
What may the immune response towards Mtb result in?
Sterilisation of MTb or latent infection
What may happen with the granulomas?
They may be dissolved by proteases and phagocytosis with minimal scarring
Name the three mechanisms which may control the MTb infection
Macrophage and T cell derived TNF
Development of fibrosis capsule
Caseous necrosis
How do macrophages and T cell derived TNF control the infection?
Macrophage and T cell-derived TNF are essential for immunity to MTb
Cells containing MTb are sensitive to killing by TNF
T cell-mediated macrophage apoptosis kills intracellular Mtb
How does development of fibrous capsule control MTb infection?
Development of the fibrous tissue (TNF, TGFβ) may contain the infection, but it also excludes lymphocytes and so impedes immunity
How does caseous necrosis control the infection?
Caseous necrosis arises from granulocyte activity with cell lysis, and from a
Opposite and oncosis of macrophages and T cells
Macrophage death leads to lipid spillage, this is an important component of caseum.
Long term control can be maintained at this stage
What happens in a minority of cases.
Mtb will not be controlled
What can happen if Mtb is not controlled?
Accumulation if fibroblasts and formation of fibrous tissue around granuloma
Liquefactive necrosis and cavitation
Macrophage oncosis which releases free bacteria
Macrophages can’t survive in necrotic tissue, bacteria multiply extracellular lay
Cavitation involving blood vessels which will release Mtb into circulation causing systemic disease
Cavities involving airways leading to dispersal of Mtb in aerosols
What happens when accumulation of fibroblasts and excessive formation of fibrous tissue occur around granuloma?
TH2 cytokines and IL-4 and IL-13 are fibrogenic
Fibrosis will damage airways (bronchiectasis)
This will compromise lung function
What happens when liquefactive necrosis and cavitation occur?
Cytokines like TNF, IL-1β up regulate proteases
Oncotic macrophages release lysosomal proteases
Mtb may produce peptidases
Why can’t macrophages survive in necrotic tissue?
Macrophages cannot survive with toxic concentrations of fatty acids, like that in necrotic tissue
What happens when Mtb is dispersed in aerosols?
Coughing can infect other people
What are some environmental influences on chronic inflammation?
Many inflammatory diseases rapidly increase in frequency in rich industrialised countries
This may be because our bodies may be in a low grade inflammation which affect our chances of developing inflammatory diseases
What are the lifestyle influences which can cause chronic inflammation?
Psychological stress,
Lack of exercise
Diet
Obesity
Commensal microbes
How does psychological stress influence chronic inflammation?
Psychological stress can act through the sympathetic nervous system via Noradrenaline
This induces inflammatory cytokines IL-1β, IL-6, TNF
These influence mood, and risk of inflammatory diseases
How can exercise influence chronic inflammation?
Exercise suppresses inflammatory cytokines and reduces risk of chronic metabolic and CVD
How does diet influence chronic inflammation?
Short chain fatty acids acetate, propionate, butyrate, are produced in the colon by fermentation of plant fibre.
These interact with receptors GPR41 and GPR43 and suppress inflammation
Omega-3-fatty acids bind GPR120, also anti-inflammatory
How can obesity influence chronic inflammation?
Hypertrophic adipose tissue releases:
IL-1β and TNF,
saturated fatty acids which stimulate TLRs, ROS from malfunctioning mitochondria and
DAMPs from necrotic adipocytes
These all recruit inflammatory macrophages and TH1 cells
How do commensal microbes influence chronic inflammation?
Increased hygiene and antibiotic use changes composition of commensal organisms in our bodies
Research aims to restore the balance between symbionts and pathobionts using probiotics.
Sometimes fecal transplants and helminths may be used to treat inflammatory bowel disease
How does lipotoxicity affect oxidative stress ?
TNF is generated within adipose tissue and promotes lipolysis and release of fatty acids
FAs impair mitochondrial respiration
This generates ROS
ROS consumes SOD, catalase and glutathione
This oxidative stress generates lipid peroxides and aldehydes which further damage mitochondria.
TNF also contributes to mitochondrial dysfunction and ROS
