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NancyMEDSCI203 > Lecture 12: Chronic Inflammation: Liver And TB > Flashcards

Lecture 12: Chronic Inflammation: Liver And TB Flashcards

0
Q

Which viral infections can cause liver damage leading to fibrosis?

A

Hep B, Hep C, HBV and HCV

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1
Q

What can liver damage, leading to fibrosis arise from?

A
  • 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
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2
Q

What is the term given to prevention of bile flow

A

Cholestasis

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3
Q

What is haemochromatosis

A

Abnormal iron storage

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4
Q

What is wilson’s disease

A

Abnormal copper storage

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5
Q

What is non alcoholic fatty liver disease?

A

A range of conditions characterised by triglyceride accumulation in liver

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6
Q

What is NAFLD associated with?

A

Obesity, type 2 diabetes, and risk of heart disease

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7
Q

In the USA, what proportion of the population may NAFLD affect?

A

30% of population

Up to 9% of children

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8
Q

What is steatosis?

A

Benign, Fat accumulation in the liver

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9
Q

What may steatosis arise from?

A

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

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10
Q

What is non alcoholic steatohepatitis characterised by?

A

Steatosis plus injury inflammation and (often) fibrosis

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11
Q

What may NASH arise from?

A

Two events, or hits:

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12
Q

What is the first hit which could lea to NASH?

A

Non-toxic steatosis, increases the vulnerability of liver cells to damage

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13
Q

What is the second hit that may lead to NASH

A

Agents like ROS, pro-inflammatory cytokines and endotoxin from gut bacteria

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14
Q

What may cell damage arise from?

A

An excess of free fatty acids

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15
Q

What is lipotoxicity

A

Cell damage due to excess of free fatty acids

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16
Q

What are the two stresses that cause/ are affected by lipotoxicity?

A

Oxidative stress and ER stress

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18
Q

How does lipotoxicity lead to ER stress?

A

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

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19
Q

What do the two stresses, Oxidative stress and ER stress result in?

A

Cell death - both apoptosis and oncosis

Liver damage

Inflammation

Fibrosis

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20
Q

What is liver fibrosis

A

A wound healing process which occurs in chronic liver diseea

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21
Q

Which cells start the fibrotic response to injury?

A

Cells surrounding the sinusoids (capillaries which connect portal tracts and central vein)

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22
Q

How do these cells respond to tissue damage and inflammation?

A

They lay down fibrillar collagen

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23
Q

What are hepatic stellate cells?

A

Liver specific pericytes

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24
Q

Where do hepatic stellate cells reside?

A

In the gap between he

Atrocities and sinusoidal endothelial cells

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25
Q

The space where HSCs usually reside in is also known as…. .?

A

The space of disse

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26
Q

What do HSCs do?

A

Store lipids - especially retinoids like vitamin A

They have low proliferative ability

They synthesise low amounts of (basement membrane type) extracellular matrix

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27
Q

What are pericytes? - hepatic stellate cells are a specified type of them…

A

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]

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28
Q

What happens after liver damage?

A

Hepatic stellate cells trans-differentiate into myofibroblasts (MFs)

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29
Q

What do myofibroblasts do?

A

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

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30
Q

What are some other sources of MFs?

A

Bone marrow derived cells (fibroblasts)

Portal fibroblasts

Epithelial cells that undergo Epithelial mesenchymal transition

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31
Q

What are MMPs?

A

Matrix metalloproteinases

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32
Q

What mediators induce the transdifferentiation of HSCs to MFs and fibrogenesis

A

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

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33
Q

What are Kupffer cells?

A

Liver macrophages, which make up 15% of cells in the liver

They release TGFβ and PDFF when their TLRs bind bacterial products and DAMPs

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34
Q

Where are bacterial products from? Which the TLRs of TGFβ and
PDGF bind to

A

Leaky gut mucosa

35
Q

Where do DAMPs come from?

A

Oncotic cells

36
Q

What causes haemodynamic resistance and portal hypertension?

A

The narrowing of the sinusoid lumen

37
Q

What is portal hypertension?

A

Increased blood pressure on the portal vein

38
Q

What does chronic injury with hepatocytes death lead to?

A

Inflammation

Regeneration

Healing by repair with fibrogenesis and cirrhosis

39
Q

What is cirrhosis?

A

The loss of liver architecture with septa of fibrous tissue surrounding nodules of regenerating hepatocytes

40
Q

When does cirrhosis occur?

A

After 15-20 years of hepatocytes death

41
Q

What are septa?

A

Sheets

42
Q

What are the consequences of cirrhosis?

A

Portal hypertension

Liver failure

Liver cancer

43
Q

How does portal hypertension arise?

A

From resistance to blood flow in the liver with possible ascites, varies and renal failure

44
Q

What is ascites?

A

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

45
Q

What is varices?

A

Dilated oesophageal varicose veins which occurs as a result of increased pressure in the portal veins

46
Q

Why can varices rupture and bleed?

A

They have weak walls

47
Q

What can occur with liver failure?

A

Hyperbilirubinaemia with jaundice,

loss of blood proteins with oedema and bleeding

Ecephalopathy

48
Q

What is hyperbilirubinaemia?

A

Excess bilirubin in the blood

49
Q

What blood proteins are loss with liver failure?

A

Albumins clotting factors

50
Q

What is encephalopathy?

A

Brain malfunction

51
Q

How does encephalopathy occur?.

A

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

52
Q

What is hepatocellular carcinoma?

A

Liver cancer, a late complication of cirrhosis

53
Q

What are granulomas?

A

Aggregations of specialised macrophages in response to indigestible substances

54
Q

How do foreign body granulomas arise?

A

They arise in response to endogenous or exogenous materials

55
Q

What are endogenous materials in which foreign body granulomas may arise from?

A

Fragments of bone

56
Q

What are exogenous materials in which foreign body granulomas may arise from?.

A

Silica

57
Q

What are immune granulomas?

A

Localised inflammatory responses to infectious agents like mycobacterium tuberculosis, M leprae, treponema pallidum, schistosoma, eggs

58
Q

What are the infectious agents which can cause immune granulomas and what diseases do they cause?

A 
Mycobacterium tuberculosis - Tuberculosis
M leprae - leprosy 
Treponema pallidum - syphilis
Schistosoma - fluke
Schistosoma eggs - schistosomiasis
59
Q

What are Mtb bacteria entering the lung phagocytosed by?

A

Alveolar macrophages

60
Q

Which Mtb are not killed?

A

Those which block phagosome maturation.

These will proliferate inside macrophages

61
Q

What cellular changes occur in tuberculosis?

A

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

62
Q

Where are immune responses to Mtb centred?

A

On the granulomas

63
Q

What do macrophages transform into after they lose their motility?

A

Epithelioid cells

Which are epithelial like

64
Q

Why do Mtb induce epithelioid cells to develop into lipid storing cells?

A

So that they can provide nourishment for Mtb

65
Q

What may the immune response towards Mtb result in?

A

Sterilisation of MTb or latent infection

66
Q

What may happen with the granulomas?

A

They may be dissolved by proteases and phagocytosis with minimal scarring

67
Q

Name the three mechanisms which may control the MTb infection

A

Macrophage and T cell derived TNF

Development of fibrosis capsule

Caseous necrosis

68
Q

How do macrophages and T cell derived TNF control the infection?

A

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

69
Q

How does development of fibrous capsule control MTb infection?

A

Development of the fibrous tissue (TNF, TGFβ) may contain the infection, but it also excludes lymphocytes and so impedes immunity

70
Q

How does caseous necrosis control the infection?

A

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

71
Q

What happens in a minority of cases.

A

Mtb will not be controlled

72
Q

What can happen if Mtb is not controlled?

A

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

73
Q

What happens when accumulation of fibroblasts and excessive formation of fibrous tissue occur around granuloma?

A

TH2 cytokines and IL-4 and IL-13 are fibrogenic

Fibrosis will damage airways (bronchiectasis)

This will compromise lung function

74
Q

What happens when liquefactive necrosis and cavitation occur?

A

Cytokines like TNF, IL-1β up regulate proteases

Oncotic macrophages release lysosomal proteases

Mtb may produce peptidases

75
Q

Why can’t macrophages survive in necrotic tissue?

A

Macrophages cannot survive with toxic concentrations of fatty acids, like that in necrotic tissue

76
Q

What happens when Mtb is dispersed in aerosols?

A

Coughing can infect other people

77
Q

What are some environmental influences on chronic inflammation?

A

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

78
Q

What are the lifestyle influences which can cause chronic inflammation?

A

Psychological stress,

Lack of exercise

Diet

Obesity

Commensal microbes

79
Q

How does psychological stress influence chronic inflammation?

A

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

80
Q

How can exercise influence chronic inflammation?

A

Exercise suppresses inflammatory cytokines and reduces risk of chronic metabolic and CVD

81
Q

How does diet influence chronic inflammation?

A

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

82
Q

How can obesity influence chronic inflammation?

A

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

83
Q

How do commensal microbes influence chronic inflammation?

A

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

84
Q

How does lipotoxicity affect oxidative stress ?

A

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

NancyMEDSCI203 (12 decks)

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