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MEDSCI 203 > Injury, Inflammation, Repair > Flashcards

Injury, Inflammation, Repair Flashcards

1
Q

Two classes of cell death

A

Accidental or programmed/organised

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2
Q

Accidental cell death

A

Instantaneous injury. Severe physical and chemical insult. Extreme forces. Ruptured cells releases their contents -> leads to inflammation and initiates neighbouring cell death.

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3
Q

What are the 5 types of cell death?

A

Oncosis/Necrosis,
Necroptosis,
Pyroptosis,
Apoptosis,
Autophagic Cell Death

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4
Q

What occurs in oncotic cell death?

A

The cell loses control of the composition of its ions due to trauma resulting in swelling causing lysis and cell death resulting in inflammation

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5
Q

What occurs in Necroptosis?

A

Death ligands (TNF and FasL) activate receptors which turn on protein kinases RIPK 1-3 causing mitochondrial dysfunction leading to a build up in reactive oxygen species resulting in lipase activation and messy cell death

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6
Q

What is tumour necrosis factor?

A

A death ligand.

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7
Q

What is a necrostatin?

A

A competitive inhibitor for RIP 1 protein which can be used to suppress inflammation

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8
Q

What occurs in pyroptosis?

A

Bacterial products activate the inflammasome, which activates the caspase-1 protease resulting in cell lysis and inflammation

pro-IL-1B is cleaved to IL-1B a proinflammatory cytokine.

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9
Q

Gasdermin role in pyroptosis

A

Gasdermin proteins are cleaved to form pores in membranes

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10
Q

What is an inflammasome?

A

An internal danger sensor of cells causing inflammation and cell death

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11
Q

What is the purpose of pyroptosis?

A

To prevent against the intracellular replication of bacteria and to alert the immune system to the presence of invaders

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12
Q

What occurs in apoptosis?

A

This is a more natural and clean way of removing cells that are old and need to be turned over, or if they are in excess to requirements. This is a process which retains an intact cell membrane stopping inflammation provided the budding off apoptopic bodies are phagocytosed before they degrade

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13
Q

What occurs in Autophagic cell death?

A

Double membrane vacuoles enclose cytoplasm or organelles to form autophagosomes, these then fuse with a lysosome to form an autolysosome

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14
Q

What is the normal purpose of autophagy?

A

To remove misfolded proteins and damaged organelles but the process can result in cell death if the cell is placed under too much stress

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15
Q

What are the 5 causes of apoptotic death?

A

Engagement of a death ligand with is receptor,
Damage to DNA,
Absence of required growth factors,
Anoikis,
Oxidative stress (ROS) or ER stress

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16
Q

What is Anoikis?

A

When a cell loses its attachment to the extracellular matrix

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17
Q

What does both DNA damage and death ligands activate?

A

Apoptotic Caspases

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18
Q

What is the effect of an apoptotic caspase?

A

Pores are opened in the outer mitochondrial membrane releasing Cytochrome C, Apoptotic protease activating factor and a caspase cascade

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19
Q

What are Caspases?

A

Proteases activated by oligomerisation and proteolytic cleavage, which cleaves proteins after any aspartate residue resulting in apoptosis

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20
Q

What are the signals that apoptotic cells release?

A

Find me ATP signal and eat me Phosphatidylserine on the outside of the cell

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21
Q

What do phagocytosing cells express after ingesting an apoptotic body and what is its function?

A

Phosphatidylserine which suppresses the release of the inflammatory protein Tumour Necrosis Factor and releases the anti-inflammatory protein transforming growth factor

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22
Q

What can result from a loss of normal apoptosis?

A

Cancers and autoimmune diseases as lymphocytes which target ‘self’ are not removed

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23
Q

What triggers Ferroptosis

A

Triggered by oxidative stress (ROS) when iron is abundant. Generates lipid peroxides which damage the lipids in membranes

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24
Q

What regulates ferroptosis

A

Anti-oxidant glutathione peroxidase-4 which uses glutathione (GSH) as a reducing agent. Stress induced protein p53 protein can induce ferroptosis by suppressing GSH synthesis

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25
Q

What is the result of excessive apopotosis?

A

ischaemic injury, heart failure, neural degeneration, beta pancreatic cells in diabetes, lymphocytes in AIDs

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26
Q

What are four types of necrotic lesions?

A

Coagulative necrosis, Colliquative necrosis, gas gangrene and dry gangrene

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27
Q

What is Coagulative Necrosis?

A

Dead tissue is firm, retain its initial shape until removed by inflammatory cells and replaced with scar tissues. This can result in lesions that persist for years due to inaccessibility

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28
Q

What is Colliquative necrosis?

A

Occurs when a cerebral blood vessel has been blocked, which results in digestion of brain tissue and cyst being formed by glial cells

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29
Q

What is Gas Gangrene?

A

Deep wounds stop blood flow resulting in bacterial growth which releases and alpha toxin destroying an rotting cells while affected tissues turn black as haemoglobin is destroyed to provide iron for bacterial growth

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30
Q

What is the bacteria that grows in gas gangrene?

A

Clostridium perfringens

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31
Q

What is Dry Gangrene?

A

Arteries are slowly narrowed by atherosclerosis leading to tissue death through desiccation and black colour formation due to blood breakdown

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32
Q

What are the two forms of necrosis associated with infection?

A

Suppurative necrosis and Caseous Necrosis

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33
Q

What is suppurative necrosis?

A

Bacterial infections cause necrosis resulting in neutrophils liquefying tissues to from an abscess

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34
Q

What is Caseous necrosis?

A

As seen in tuberculosis, when chronic inflammation has resulted in dead cells forming a cheese like debris rich in lipids and proteins

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35
Q

What occurs in acute haemorrhagic pancreatitis?

A

Fat necrosis resulting in Proteases and phospholipases digest membranes, lipases digest triglycerides causing release of soap

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36
Q

Describe characteristics of Necrosis

A

Energy independent
Membrane permeabilization and cell lysis
Sometimes visible cell swelling (oncosis)
Leakage of intracellular components
Repair of damaged tissue by scarring
Activated by multiple cascade
Messy -> inflammation

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37
Q

What are the four signs of inflammation?

A

Redness, heat, swelling, pain

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38
Q

What is inflammatory exudate?

A

Protein rich fluid leaked out of blood vessels in response to inflammation

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39
Q

What are the 8 effects of inflammation?

A

Delivery of nutrients and Oxygen to infection site
Generation of exudate to transport toxins allowing for an immune response
Generation of exudate to move antibodies and other substances into infection in order to neutralize pathogens
Mobilizes work force to remove dead cells damaged proteins etc
Mobilizes defense force to remove pathogens
Limits the spread of harmful agents
Provides digestive enzymes to remove the exudate when needed
initiates repair

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40
Q

What are the three ‘go’ signals for inflammation?

A

Neuronic release of bioactive peptides
Intracellular molecules are released from broken cells
Microbial products or toxins are recognised

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41
Q

What are DAMPs

A

Danger associated molecular patterns, molecules released when cells undergo lysis

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42
Q

What senses DAMPs?

A

Pattern recognition receptors

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43
Q

What are PAMPs?

A

Pathogen associated molecular patterns, which signal the presence of an infection

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44
Q

What senses PAMPs?

A

Pattern recognition receptors such as soluble complement proteins or cell bound toll-like receptors

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45
Q

What are the first two immune cells to respond to inflammation?

A

Basophils and macrophages

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46
Q

What is the purpose of basophils in inflammation?

A

To initiate an inflammatory response through mediator molecules

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47
Q

What are the mediator molecules released by mast cells?

A

Histamine, tryptases or proteases, lipid derived signals and cytokines

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48
Q

What is the purpose of vasodilatation in inflammation?

A

increased blood flow causes redness and heat

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49
Q

What is the cause of the increase in vascular permeability seen in inflammation?

A

The endothelial cells retract leaving gaps between them in response to inflammatory signals

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50
Q

What is the purpose of the increase in vascular permeability seen in inflammation?

A

To allow proteins to pass through the capillary resulting in the formation of exudate

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51
Q

What do more severe injuries result in with respect to vascular permeability?

A

The endothelial cells detach from the basement membrane resulting in persistent increases in vascular permeability

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52
Q

Why does inflammation lead to swelling?

A

The increased vascular permeability results in a blood pressure drop so less pressure forces the fluid into the vein resulting in a accumulation of fluid causing swelling and pain

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53
Q

What are the chemical mediators linked to swelling and pain in inflammation?

A

Prostoglandin E2 and Bradykinin

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54
Q

What are the four effects of both Vasoactive amines and tryptases?

A

vasopermeability, adhesion for neutrophils, synthesis of lipid mediators leading to vasodilatation, bronchoconstriction

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55
Q

What is the difference between Tryptases and Vasoactive amines?

A

While amines are stored in the granules of mast cells, tryptases cleaves protease activated receptors on mast cells, endothelial cells and neutrophils to cause the same physiological effects

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56
Q

What induces the formation of lipid mediator derivatives?

A

Inflammatory signals use Ca2+ to activate phospholipase A2 which cleaves membrane phospholipids to from the mediators

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57
Q

What is Platelet activating factor derived from?

A

Lysophosphatidylcholine, through the action of phospholipase A2

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58
Q

Sources of platelet activating factor

A

Converted lipids in cell membranes from activated immune cells

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59
Q

Platelet activating factor function

A

Platelet aggregation
Activation (clotting)
Leukocyte Adhesion
Chemotaxis and activation

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60
Q

What are the affects of Platelet activating factor?

A

The same affects as tryptase/vasoactive amines as well as platelet aggregation

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61
Q

What does arachidonic acid do in the inflammation response?

A

Generation of acute phase proteins such as prostaglandins and leukotrienes

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62
Q

How are prostoglandins formed?

A

Arachidonic acid reacts with Cyclooxygenases

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63
Q

How are Leukotrienes formed?

A

Arachidonic acid reacts with 5-Lipoxygenase

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64
Q

What is the function of TXA2?

A

Vasoconstriction and platelet aggregation

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65
Q

What is the function of PCI2?

A

Vasodilation and platelet dissociation

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66
Q

What is the function of PGE2?

A

Vasodilation, pain, fever

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67
Q

What is the function of LTB4?

A

Neutrophil chemotaxis and activation

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68
Q

What are the functions of cysTC4,D4,E4?

A

Vasopermeability and bronchoconstriction

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69
Q

What are the four cascades of inflammation?

A

Coagulation, fibrinolytic, kinin, complement

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70
Q

What activates the coagulation cascade?

A

Tissue factor released from apoptotic endothelial cells and exposed basement membrane

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71
Q

What activates the fibrinolytic and kinin cascade?

A

Hageman factor FXII

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72
Q

What activates the complement cascade?

A

A series of convertases

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73
Q

What is the affect of the coagulation cascade?

A

Activation of thrombin resulting in fibrinogen conversion to fibrin causing clots
Protein activated receptors induce vascular permeability and platelet activating factor release causing its affects

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74
Q

What is the affect of the fibrinolytic cascade?

A

Generation of the protease plasmin degrades fibrin breaking down clots
Cleavage of Extracellular matrix and activation of matrix metalloproteases causing remodeling of the tissue
Activation of the kallikrein protein which activates the kinin system

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75
Q

What is the affect of the kinin cascade?

A

Kallikrein release the bradykinin protein resulting in vascular dilatation, vascular permeability and pain inducing affects

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76
Q

What are the cleavage products in the complement cascade system?

A

C3a, C3B, C5a and components of the membrane attack complex

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77
Q

What is the function of C3a and C5a?

A

Promote mast cell degranulation, vascular permeability and neutrophil chemotaxis

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78
Q

What is the function of C3B?

A

Opsonization

79
Q

What is the function of C5b?

A

Part of the membrane attack complex for bacterial cell lysis

80
Q

What are cytokines?

A

Low molecular weight proteins produced during inflammation to act as chemical attractants

81
Q

What is tumour necrosis factor?

A

Cytokine which up regulates inflammation

82
Q

What is cachexia?

A

Wasting - loss of appetite

83
Q

Why does tumour necrosis factor have limited uses against tumours?

A

Not effective against the most common tumour types ad induces unpleasant flu like symptoms

84
Q

What are the 3 effects of TNF and interleukin1 at low concentrations?

A

Vasodilation
vasopermeability
expression of adhesion molecules on endothelial cells

85
Q

What are the 4 effects of tumour necrosis factor and interleukin1 at high concentrations?

A

Fever, Coagulation cascade, fibrosis, cachexia

86
Q

What is the role of neutrophils?

A

To be rapidly proliferated and to be the initial non specific defence against invaders

87
Q

What is sterile inflammation?

A

Injury without infection

88
Q

What is the function of eosinophils?

A

Anti-parasitic but can cause allergies

89
Q

What are the functions of basophils?

A

Regulation of inflammation but can cause allergies

90
Q

Give 5 examples of DAMPs

A

ECM fragments
intracellular proteins,
DNA and RNA
ATP
Crystals

91
Q

What DAMPs do toll-like receptors bind?

A

ECM fragments,
intracellular proteins,
DNA and RNA

92
Q

What binds to RAGE receptors?

A

intracellular protiens

93
Q

What binds to P2X7 purinergic

A

ATP

94
Q

What receptor binds crystals?

A

Components of inflammasomes

95
Q

What does signalling from TLRs and P2X7Rs do?

A

Activation of inflammasomes resulting in the release of IL-1alpha when cells undergo lysis causing endothelial cells to become adhesive for leukocytes

96
Q

What are the 5 steps of Mobilisation

A
  1. Attraction to sites of injury or infection
  2. Margination
  3. Adhesion
  4. Transmigration
  5. Chemotaxis
97
Q

What occurs in the first step of mobilisation (attraction)

A

DAMPs bind to receptors on macrophages and trigger intracellular signalling cascades. Cytokines IL-1a and B signal to endothelial cells activating them

98
Q

What is margination

A

When activated endothelial cells become adhesive for neutrophils by expressing P and E selectins causing them to stick and roll through interaction with sialyl-Lewis-X.

99
Q

What is the role of P and E selectins?

A

To allow for leukocytes to loosely contact the vessel wall rolling along its surface

100
Q

What causes adhesion flattening of neutrophils?

A

Upregulation of Intracellular adhesion molecule-1 and vascular adhesion molecule 1 as well as leukocyte function associated antigen 1 on neutrophils

101
Q

What is transmigration?

A

Movement of leukocytes through the endothelial cells with use of enzymes to remove the basement membrane

102
Q

What is chemotaxis

A

Neutrophils move towards site of infection. Chemotactic signals are released to recruit more immune cells

103
Q

What are the steps of function (phagocytosis, degranulation)

A
  1. Opsonisation
  2. Adhesion
  3. Phagocytosis
  4. Degranulation
  5. Respiratory Burst
104
Q

What are the chemotatic signals that release leukocytes?

A

Proteins from broken cells like N-Formylated peptides
Chemokines
Leukotriene B4, Complement Products C3a, C5a
Bacterial Products

105
Q

What are the three processes that phagocytes use to kill microbes?

A

Phagocytosis, degranulation and respiratory burst

106
Q

What occurs in opsonization, adhesion and phagocytosis ?

A

Opsonization tags damaged cells and C3B recognition. Phagocytes bind to opsonins.
Becomes phagosomes

107
Q

What happens in degranulation

A

Phagosomes fuse with lysosomes creating phagolysosomes and removes visible lysosomes from cytoplasm

108
Q

What is the process involved in producing a respiratory burst?

A

NADPH oxidase assembles and reduces oxygen to superoxide, this results in rapid entry of K+ counter ion, The super oxides is reduced to hydrogen peroxide by super oxide dismutase, which then reacts with Myeloperoxidase to form hypochlorous acid which kills the pathogen

109
Q

After effects of phagocytosis

A

Damage to surrounding tissues can occur if enzymes leak

If particle is too large to be engulfed, cells release cytotoxins

Macrophages can kill or become antigen presenting cells to T cells

110
Q

What is suppuration?

A

Liquefactive necrosis

111
Q

What is the difference between as an abscess and cellulitis?

A

An abscess is a localized inflammation while cellulitis is a spreading systemic infection

112
Q

What stimulates the acute phase response?

A

Interleukin6

113
Q

What is the acute phase response?

A

When the liver produces many plasma proteins to act as opsonins and coagulation factors

114
Q

What is leukocytosis?

A

An increase in the number of circulating leukocytes

115
Q

What causes fever?

A

Pyrogens TNF, Interleukin1 and Prostaglandin E2

116
Q

Which region of the brain is affected by fever?

A

Hypothalamic thermoregulation

117
Q

What is the difference between sepsis and Systemic inflammatory response syndrome?

A

Sepsis is when there is systemic inflammation with infection, while systemic inflammatory response syndrome is when there is systemic inflammation from a sterile injury

118
Q

What can induce systemic inflammation?

A

Release of DAMPs, Cytokines, increase in the amount of pro-coagulants in relation anti-coagulants, activation of the complement system, generation of reactive oxygen species

119
Q

What are systemic side effects fo inflammation

A

Fever or hypothermia
Heart rate ^
Rapid breathing
Leukocytosis

120
Q

What are the 6 possible outcomes of inflammation

A

Widespread vasodilation and permeability casing a loss of blood volume
Formation of thrombi in small blood vessels
Depletion of clotting factors
Inadequate blood supply to organs
Multi-organ failure
Repair with resolution

121
Q

What occurs to neutrophils during inflammation?

A

Their lifespan is extended through cytokines, growth factors and activated endothelium

122
Q

What turns off the inflammatory reaction?

A

Eliminating the simulating microrganisms or dead cell remains
Negative feedback loops causing anti-inflammatory cytokines, lipid mediators, protease inhibitors

123
Q

What is the difference between regeneration and repair?

A

Regeneration is the replacement of lost cells by those of the same kind while repair requires the use of temporary granulation tissue which will eventually lead to the formation of a scar

124
Q

What type of injuries can be repaired through just regeneration?

A

Injuries which involve loss of the epithelial lining only, if the stromal or parenchymal tissue is lost then a full scale repair mechanism will need to be mounted

125
Q

What causes the regeneration response?

A

Stem cells

126
Q

What are the three types of tissue activity with regards to regeneration and stem cells?

A

Mitotically active tissues which regenerate constantly such as the lining of the gut
Normally quiescent tissues which only undergo regeneration when there is an injury
Terminally differentiated tissues which cannot undergo regeneration

127
Q

Stem cell differentiation signal

A

Generate transit amplifying cells (TAC) which divide asymmetrically.

128
Q

What stimulates regeneration in colon crypts?

A

LPS activates TLR4 on macrophages which activates COX2 Which activates PGE2

129
Q

How do Kupffer cells induce hepatic regeneration?

A

Release of TNF, IL-6, HGF and TGFalpha

130
Q

What are kupffer cells?

A

Macrophages present in the liver

131
Q

What transcription factors can induce terminally differentiated cells to once gain become pulripotent?

A

t4, Sox2, Klf4, Myc

132
Q

M1 macrophages

A

Pro-inflammatory
Respond to IL-6, IL-1, ROS

133
Q

M2 macrophages

A

Wound healing
Respond to PDGF, TGFB, VEGF, TNFa/EGF

134
Q

Pro-resolution Macrophages

A

Remodelling
TGFB, IL-10

135
Q

What are the four phases of repair?

A

Haemostasis, Inflammation, Proliferation, Remodelling

136
Q

What occurs in haemostasis?

A

Platelets aggregate and degranulate at sites of blood vessel damage, conversion of fibrinogen to fibrin with cross linke between fibrin being made by fibronectin and other transglutaminases

137
Q

What is the purpose of haemostasis?

A

To provide temporary mechanical stability, to provide a barrier for invading microorganisms, prevent desiccation and loss of plasma, provides a provisional matrix for repair cells to migrate, generates a matrix rich in cytokines and growth factors (platelet derived growth factor, TGFbeta, Vascular endothelial growth factor)

138
Q

What occurs in the inflammatory response?

A

Removal of necrotic tissue through the actions of both neutrophils and macrophages
These secrete proteases which liquify the necrotic tissue, generate antimicrobial products such as free radicals

139
Q

What actions in the inflammatory response occurs ONLY via macrophage activity?

A

Phagocytosis of dead neutrophils

Secretion of growth factors for fibroblasts and endothelial cells, antigens are processed to activate immunity

140
Q

What occurs in the proliferation response?

A

Stromal and epithelial tissue regrows

Fibroblasts proliferate and form a new matrix out of collagen, fibronectin and glycosaminoglycans

141
Q

What occurs to fibroblasts in the proliferation phase of repair?

A

They differentiate into myofibroblasts when stimulated by Platlet-derived-growth factor and transforming growth factor which interact with ED-A Fibronectin which results in provision of mechanical tension

142
Q

What are the functions of myofibroblasts?

A

Lay down collagen fibers, express alpha smooth muscle actin, smooth muscle myosin and contractile myofilaments
Use focal adhesions to to link stress fibres with extracellular actin
Pull the edges of the wound together through contractile actions
Die by apoptosis at the end of the granulation phase

143
Q

What is the role of endothelial cells in the proliferation phase?

A

New capillaries (angiogenesis) are formed in response to VEGF, pericytes stabilize these in response to PDGF

Endothelial progenitor stem cells from bone marrow can be used to generate new BV (vasculogenesis)

144
Q

What growth factors allow the epithelial lining to regrow in the proliferative phase of repair?

A

Epidermal growth factor or transforming growth factor
These upregulate the EGF receptor, cause integrins to be expressed along the cell margin, activation of proteases (plamin) to break down fibrin via expression of urokinase plasminogen activator, uPA

145
Q

What occurs in the remodelling phase of repair?

A

Granulation tissue is exchanged for scar tissue which lacks cells, collagen III is replaced by parallel collagen, and equilbrium is reached between collagen deposition and MMP degradation, strength of collagen fibres results in crosslinks

146
Q

Excessive scar tissue is damaging, what can cause excessive scar tissue to form?

A

Excessive inflammatory response, excessive production of fibrogenic cytokines (TGFBeta1), prolonged presence of myofibroblasts as a result of their failure to undergo apoptosis

147
Q

What can cause wound repair to develop into fibrosis?

A

Silica or smoke in the lungs, Inability to maintain telomers, hypercholesterolemia resulting in liver damage, alcohol abuse or viruses (HBV, HCV) causing liver damage, obstruction of ureter leading to kidney fibrosis

148
Q

What damaging cycle can fibrosis result in?

A

Fibrosis may suppress blood flow, this can result in cell death due to a lack of oxygen supply which will result in more fibrosis occuring

149
Q

What do the different types of macrophages do?

A

M1 - pro inflammatory
M2 - wound healing
M3 - Remodelling

150
Q

What causes chronic wounds?

A

M1 not switching to M2

151
Q

What causes chronic inflammation?

A

Irritants
Infections
Harmless environmental agents
Commensal microbes
Components of the body
Wound that do not heal
Grafts / Implants

152
Q

What is the role of tH1Cells?

A

Secretion of interferon-gamma which stimulates tH1 development and activates macrophage responses to intracellular pathogens

153
Q

What is the role of tH2 cells?

A

Secretion of IL-4 which stimulates TH2 development and activates eosinophil responses to worms

154
Q

What is the role of tH17 cells?

A

Secretion of IL-17 and IL-21 which stimulates tH17 development and activates epithelial responses to microbes (secretion of antimicrobial substances such as defensins and GM-CSF)

155
Q

What is the role of tReg cells?

A

Secretion of cytokines such as TGFBeta which stimulates Treg development and suppression of inflammation

156
Q

Which T cell types can cause autoimmunity?

A

TH1, TH17

157
Q

Which T cell types can cause allergies?

A

TH2

158
Q

Which T cell type would a deficiency result in damage?

A

Treg as a deficency will result in excessive inflammation

159
Q

Causative lifestyle balance

A

Lead to low grade chronic inflammation
Induction of pro-inflammatory cytokines
(TNF, IL-1B, IL-6)

160
Q

Lifestyle balances contributing to chronic inflammation

A

Psychological stress
Obesity
Microbial balance

161
Q

Pyschological stress

A

Sympathetic system - noradrenalin - influences mood and risk of inflammatory

162
Q

Obesity

A

Hypertrophic adipose tissue releases:
proinflammatory cytokines
Saturated fatty acids
ROS
DAMPS
recruiting TH1 cells

163
Q

Microbial balance

A

Changes microbes associated with our guts and skin due to diet, antibiotics and excessive hygiene. Pathobionts colonise the gut and induce pro-inflammatory cytokines

164
Q

Protective lifestyle balance

A

Can counteract pro-inflammatory factors
Production of Anti-inflammatory cytokines IL-10 and TBFb

165
Q

Microbial balance (Good)

A

Symbionts and probiotics rebalance microbes and promote Treg activity. Fecal balance can rebalance microbes. Helminths (worms) are anti-inflammatory and can be used to treat chronic inflam-gut-diseases like IBD

166
Q

Diet (Good)

A

Diet enriched in short chain FA are produced and bind to GPR43 receptors activating anti-inflam pathways. Omega-3-FA activate GPR120 receptors and regulate metabolism and inflammation

167
Q

Exercise (Good)

A

Suppresses inflam cytokines TNFa. Reduces risk of chronic metabolic and cardiovascular diseases.

168
Q

Acute Inflammation: Innate Immune system

A
  1. Circulating neutrophils
  2. Monocytes -> macrophages
    Recruited to site of damage Phagocytose debris, DAMPs, microbes
    Kill microbes
    Regulate inflam and repair
    Pro-Inflammatory cytokines and chemokines (IL-6, TNF, IL-1B) attract immune cells
    Proteases digest ECM
    ROS
169
Q

Chronic Inflammation: Adaptive Immune System

A
  1. Macrophages acts as Antigen Presenting Cells
    - Phagocytosis of microbes and macromolecules
    -Process into antigens
    -Present to lymphocytes to regulate their activities
  2. Lymphocytes recognize antigen epitopes as foreign by surface receptors.
    T Cells: include killer (CD8) and helper (CD4)
    B Cells: differentiate into plasma cells to produce antibodies
170
Q

Granuloma: TB

A

Progressive lung disease that causes coughing and transmission

Suppression of systemic disease to avoid early death

171
Q

TB immediate host control

A

MTB droplets -> alveoli -> alveolar macrophages phagocytose and bacteria replicate in macrophage endosome. Release of TNF and IL-1 recruit neutrophils. Intracellular bacteria destroyed by autophagy, ROS and anti-microbial peptides. Apoptotic cell death induced by PAMPS releases MTB. Phagocytosis of apoptotic bodies and macrophages switch to anti-inflammatory.

172
Q

TB adaptive immunity and control

A

Phagocytes migrate to lymph nodes as antigen presenting cells to activate TH1 cells. TAKES WEEKS
Release IFNy to activate apoptosis of infected cells. TH17 cells release IL-17 recruiting neutrophils to cause tissue necrosis

173
Q

Escape of MTB and dormancy

A

MTB lipids inhibit M0 activation and generate permissive macrophages that allow intracellular proliferation

Associate into granulomas to impede T cell penetration and antigen presentation

Neutrophil toxins favour macrophage necroptosis freeing intact Mtb which is phagocytosed but no lysis in cell.

Treg suppresses TH1 activity

TH2 release IL-4 to generate fibrosis (scar) to block access of TH1 cells.

Granuloma, caseous necrosis leads to dormancy

174
Q

Reactivation of dormant MTB

A

Cycles of infection, repair and regeneration leading to fibrosis of the lungs

If granuloma reaches capillaries, O2 increases

Induces releases of matrix metalloproteases from the immune cells in the granuloma. MMPs release of MTB into airways.

MTPs can cause infection by travelling through pulmonary veins

175
Q

Chronic inflammation in oesophagus

A

Reflux of stomach acid, Barrett’s metaplasia and Adenocarcinoma

176
Q

Chronic inflammation in colon

A

IBD, ulcerations, fibrosis, stenosis and adenocarcinoma

177
Q

Chronic inflammation in liver

A

HBV, HCV, NAFLD, NASH and cirrhosis and hepatocellular carcinoma

178
Q

What are the symptoms of Gastroesophageal reflux disease?

A

Heartburn, regurgitation of stomach contents, upper abdominal pain

179
Q

What causes Gastroesophageal reflux disease?

A

Regurgitation of stomach acid, which contains acid, proteases such as pepsin and trypsin, bile acids

180
Q

What is the complication that can arise from Gastroesophageal reflux disease?

A

Barrett’s oesophagus where the epithelium of the oesophagus begins to take on the lining of the intestine rather than its typical squamous appearance

181
Q

What condition appears to be linked to barret’s oesophagus?

A

Oesophageal cancer

182
Q

Chronic Oesophagitis: Epithelial and inflammatory cells produce

A

Nox and COX2, generating ROS -> DNA damage, IL6 release
IL6 induces proliferation and suppresses apoptosis
Angiogenic factors
TNF, IL-17 and chemokines to recruit more inflammatory cells
Release of IL4 by TH2 cells induces intestinal transcription factor CDX2

183
Q

What are the symptoms of inflammatory bowel disease?

A

Affected areas will have redness, swelling, pain and leukocyte infiltration
Ulcers form on the epithelial lining
Wall of the bowel undergoes extensive damage and fibrotic thickening
lumen narrows due to obstruction caused by the fibrosis
Fissures in the bowel wall are created
Immune system activated with lymphocytes and granulomas present

184
Q

What is the pathogenesis of chron’s disease?

A

Environmental trigger damages the mucosa invoking an inflammatory response, this may not be able to repair the damage in individuals with a genetic defect resulting in an uncontrolled inflammation response.

185
Q

Causes of Chronic Hepatitis

A

Diet (free fatty acids)
Viral infection (Hepatitis)
Alcohol abuse
Fungal aflatoxins
Poor bile flow
Commonly results in cirrhosis - hepatocyte nodules surrounded by fibrosis.

186
Q

What is Non-alcoholic fatty liver disease?

A

Accumulation of fat in the liver, linked to diabetes, obseity and heart disease

187
Q

What is the progression of NAFLD?

A

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 cirrhosis where liver structure is lost

188
Q

What is lipotoxicity?

A

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 malfunction causing the unfolded protein response

189
Q

What is the mechanism by which fibrotic change occurs in the liver?

A

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

190
Q

What is the normal function of hepatic stellate cells?

A

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

191
Q

What causes hepatic stellate cells to transdifferentiate into myofibrils?

A

Kupffer cells release TGFBeta and PDGF when PAMPs or DAMPs are detected
Myofibrils also produce TGFBeta and Connective tissue growth factor
Release of ROS from neutrophils
Low ration of interferon gamma/IL-4

192
Q

Myofibroblasts

A

Store less lipids
More proliferative
Synthesis of collagen I & III
Express alpha-smooth muscle actin and are contractile
Synthesise tissue inhibitors of MMPs (TIMPS)
Promote fibrosis

193
Q

What are the effects of the portal hypertension seen in cirrhosis?

A

Ascites, Varices (varicose veins) which have weak vessel walls, renal failure

194
Q

What are the effects of liver failure which may be seen in cirrhosis?

A

Hyperbilirubinaemia (excess bilirubin in blood) with jaundice
Loss of blood proteins
Encephalopathy (brain malfunctions due to increased nitrogen compounds like ammonia)

MEDSCI 203 (10 decks)

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