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What are the 3 stages of cellular injury?

1. Aetiology (cause)
2. Pathogenesis
3. Morphology


What are the three types of aetiology?

a) environmental (bacteria, viruses, chemical)
b) genetic (inherited, acquires, auto-immune)
c) physical (mechanical, heat, UV)


What are reversible cellular responses?

- swelling
- cytoplasmic inclusions
- accumulations of pigments
- steatosis (fatty change)


What are irreversible cellular responses?

- abnormal mitochondria
- irregular contours
- eosinophilia
- nuclear deformities


What are two examples of Hydropic Swelling and what do they look like?

- Toxic injury (mostly reversible) - swelling with lipid accumulation
- Adaptive swelling - i.e. blebbing. Cell to cell communication lost


What does hydropic swelling look like?

Cell Sub-structure is dilated, therefore pale and ER is disorganised.


What are three examples of inclusions?

- mallory body in an alcoholic liver. Very pink with weird clumping due to damaged intermediate filaments.
- toxoplasma infection of AIDS
- virus in skin cells - amphiphilic


How are accumulations and pigments categorized?

1. Intracellular or extracellular
2. Endogenous or exogenous

NOTE: endogenous is normally present, but there is an abnormal accumulation, whereas exogenous is not normally there.


Give an example of both intracellular and extracellular accumulations.

Lysosomal Storage Disease (glycogen accumulates in lysosomes)

Amyloid-myocardium = deposits of amyloid (protein stuff)


Give an example of both endogenous and exogenous pigments.

Haemachromatosis (too much stored iron=haemosiderin in liver)

- anthracosis (carbon deposits on lung)
- ferrunginous bodies (asbestos fibbers coated in iron)


What is steatosis?

Steatosis is the infiltration of liver cells with fat, associated with disturbance of the metabolism by, for example, alcoholism, malnutrition, pregnancy, or drug therapy.


What does abnormal mitochondria look like and what could cause it?

Mitochondria is swollen and cristae no longer well organised.

Ischaemic injury


What could cause nuclear deformities?

- Cells arrested at metaphase and therefore separated chromosomes.
Colchine treatment for gout

- Multinucleation
Chemo, HSV infection


What are the potential effects of cell injury?

a) none
b) adaptive response
c) reversible damage
d) irreversible (lethal) damage


What changes occur during necrosis?

1. Initial biochemical damage
2. Delay 4-12 hours
3. Morphological changes


What are the two types (and subtypes) of microscopic changes that occur during necrosis?

1. Non Specific (mainly cytoplasmic) i.e. blabbing, swelling, eosinophilia etc

2. Specific
a) Nuclear Changes
b) Changes resulting from membrane rupture and enzyme release


What nuclear changes can occur during necrosis?

a) Pyknosis - nuclear shrinkage and condensation

b) karyorrhexis - nuclear rupture and fragmentation

c) karyolysis - disappearance


What are the changes resulting from membrane rupture and enzyme release during necrosis?

a) Intracellular:
- Digestion of organelle membranes and contents
- Denaturation of proteins

b) Extracellular:
- digestion of neighbouring cells
- inflammation response


What are macroscopic effects of necrosis?

1. Coagulative
2. Colliquative (liquefactive) necrosis
3. Caseous Necrosis

4. gangrene
5. fat necrosis
6. fibrinoid change
7. autolysis


What is the most common cause of coagulative necrosis?

Ischemia. Resultant lesion is an INFARCT and the process is INFARCTION.


What is the timeline of coagulative necrosis?

- Architecture remains for days/weeks
- increased anaerobic respiration
- denaturation of proteins

- breakdown of cells (some days later)
- inflammatory reaction

- haemorrhagic border
- regeneration or fibrosis


What does coagulative necrosis look like?

- Tissue is softer but still firm.
- Either pale (ischaemic) or red (haemorrhagic).
- Haemorrhagic border.


What are the two types of coagulative necrosis and where do they occur?

1. Ischaemic Necrosis = pale. Blood seeps away from area.
- kidney
- heart
- brain

2. Haemorrhagic infarct = red
- lung
- venous occlusion


What happens during colliquative necrosis?

1. Powerful hydrolytic enzymes are released instead of denatures, so the entire cell dissolves

2. Inflammatory reaction - liquid material removed by ,macrophages, leaving CYSTIC SPACE, often with FIBROUS periphery.


What are the main reasons for colliquative necrosis?

1. Pyogenic organisms (pus forming)

2. Brain Ischaemia


What does caseous necrosis look like and where is it usually seen?




What are the types of gangrene?

1. Wet
2. Dry = 'mummification'
3. Gas (usually due to gram + bacteria)


What causes fat necrosis?

1. enzymatic digestion of fat due to abnormal release of activated pancreatic enzymes. Chalky deposits

2. Traumatic fat necrosis - rupture of fat cells (i.e. boobs, not a problem)


What does fibrinoid necrosis look like?

Pink around blood vessels and protein leaks to damages area.


What is the difference between apoptosis, necrosis, autolysis and autophagy?

Apoptosis - normal cell death activated by caspases

Necrosis - premature death of cells in LIVING tissue

Autolysis - self digestion AFTER DEATH

Autophagy - process for mopping up damaged cell parts. NOT always associated with cell death, i.e. lysosomal vesicles.


What does the outcome of necrosis depend on?

1. Tissue involved (ability to regenerate)
2. Extent of necrosis (intensity and duration)
3. Time elapsed


What are the innate physical barriers?

skin and mucosal surfaces, pH, mucous, flushing


What are the innate cells and their primary functions?

macrophages, DC,
neutrophils, eosinophils, basophils, NK cells.


What are the main professional antigen presenting cells?

- monocytes
- B cells
- macrophages
- DCs


What are professional antigen presenting cells?

Professional APCs specialize in presenting antigen (peptide epitopes) to Th cells with MHC class II.

They have high concentrations of MHC class II on their surface


What is the dual recognition and presentation role of B cells?

They both recognise and act on cells and can present them to Th's.

B cells possess both the BCR (B-cell receptor) – which can bind epitopes on pathogens and then endocytose the bound antigen and then process it (degrade it to peptides) and then present epitopes bound to MHC Class II on their cell surface.

- have both BCR and MHC Class II


How does the innate differ from the adaptive immune system?

- rapid
- lacks specificity
- usually does not have an immunological memory


What are PAMPS? Give two examples

Pathogen-Associate Molecular Patterns (now MAMP - 'microbe')

- Bacterial endotoxins
- bacterial flagellin


What are DAMPS? Give two examples

Damage/Danger Associate Molecular Patterns

- DNA or RNA anywhere other than the nucleus or mitochondria
- Uric Acid

Arise during infection due to tissue damage


What is the function of C reactive protein?

C-reactive protein (CRP) is a substance produced by the liver in response to inflammation.

CRP binds to the surface of dead or dying cells and some bacteria. This activates the complement system, promoting phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria.


Name two pro-inflammatory cytokines



What is an inflammasome?

Thing inside cell with receptors that trigger pro-inflammatory cytokines


What is the difference between necrosis and apoptosis?



What are the 5 cardinal signs of inflammation?

1. Calor (heat)
2. Rubor (redness)
3. Tumor (Swelling)
4. Dolor (pain)
5. Loss of function (sometimes)

Cats Run To Da Lake


What are the causes of inflammation?

1. Infections
2. Trauma
3. Physical and chemical agents
4. Tissue necrosis
5. Foreign bodies
6. Immune reactions


What causes edema in inflammation?

Edema = swelling
vasodilation leads to increased vascular permeability and therefore outpouring of fluid carrying proteins and cells


What are the interacting molecules involved in leukocyte rolling and adhesion?

P and E Selectin bind to Sialyl-LewisX
P Selecting - Rolling
E - Rolling and adhesion

ICAM-1 causes adhesion, arrest and transmigration


What are the mediators of leukocyte adhesion/transmigration etc?

- Histamine and thrombin - more P selectin to surface.
-TNF and IL-1 cause gene expression of adhesion molecules on endothelium
- chemokines


What is the process of chemotaxis?

- movement along chemical gradient
- 7TM-GPCRs receptor
- chemoattractants induce actin-polymerisation at leading edge of cell, and the reorganisation of the rear edge leads to movement.


What is the process of phagocytosis?

1. Microbe binds to manose receptor
2. MAC-1 integrin and scavenger receptor leads to engulfment. Forms pseudopod around organism.
3. phagosome
4. phagosome + lysosome = phagolysosome
5. killed and degranulation

- binding improved by opsonins


What are the two types of inflammation mediators?

1. Cell derived
2. Plasma mediators


What are the types and subtypes of cell-derived mediators in inflammation?

1. Preformed mediators in secretory granules
a) vasoactive amines
i) Histamine (mainly from masts)
- arteriole dilation and increased permeability
ii) Serotonin (platelets)
- increased permeability

b) Lysosomal enzymes (froms ns and monos)
i) specific granules (small) - need low {antagonist] and are released extracellularly
ii) Azurophil granules (large) - need high {antagonist] and are released into phagosome

2. Newly synthesised mediators
a) arachidonic metabolites
i) produced by cyclooxygenases:
- prostaglandins
- thromboxanes
ii) produced by lipoxygenases:
- leukotrienes
- lipoxines
EFFECTS - chemotaxis, vasodilation, increased permeability.

b) cytokines
IL and Lymphokines.
IL-1 and TNF important in inflam
- cause endothelial activation
- cause systemic acute phase response

c) chemokines
- receptors = 7-TMGPCRs
i) CXC
ii) CC
iii) C
iv) CX3C


What systems do plasma mediators effect in inflammation

- complement cascade
- coagulation cascade
- kinin system
- fibrinolytic system


What are the pathways of the complement cascade and what do they result in?

1. Alternative pathway
Stimulator: microbial surface

2. Classic pathway
Stimulator: immune complex

3. Lectin pathway
Stimulator: manose-binding lectin on microbial surfaces

Critical event = generation and deposition of C3b on organism surface which leads to:
- recruitment for inflammation (C3a)
- opsoniation
- Assembly of MAC (lysis)



What are the pathways of the coagulation cascade and what do they result in?

1. Intrinsic pathway - Hagmann factor (XII) in circulation
2. Extrinsic - tissue damage

Activates thrombin and causes fibrin formation

Factor I - Factor XII


What is the kinin system?

Pro-inflammatory, generates vasoactive peptides.
Results in bradykinin.

- also triggers fibrinolytic system and complement


What is the fibrinolytic system?

Works in opposition to clotting cascase


What are the possible outcomes and consequences of acute inflammation?

- resolution
- abscess
- fibrosis
- chronic inflammation


How is acute inflammation terminated?

a) short half lives of mediators
b) active terminators


What is required for resolution of inflammation?

1. return to normal permeability (vasoconstriction)
2. drainage of fluid and proteins to lymph
3. Macros take up fluid and proteins
4. Phag of apoptopic neuthrophils
5. phag of necrotic debris
6. disposal of macros

Macros are the link between inflam and healing


What is fibrinous inflammation?

Severe injury - greater vascular permeability. Too much fibrinogen enters tissues and is cleaved to form fibrin.

If fibrin used in resolution is not all removed, you get scarring.


What is Serous inflammation?

thin fluid, i.e. blisters


What is ulcerous inflammation?

- shedding of necrotic inflammatory tissue


What can initiate chronic inflammation?

a) endogenous causes - acute inflammatory reaction that doesn't resolve
b) exogenous:
- persistent infections (i.e. TB)
- prolonged exposure to toxic agents
- autoimmunity


Examples of chronic inflammation

- arthritis
- asthma (can be acute)
- chronic lung disease


What is purulent inflammation?

pus = dead white cells/bacteria

Characterised by:
- large amounts of pus
- large amounts of neutrophils, necrotic cells, edema fluid

Abscesses are a collection of purulent inflammatory tissue in a confined space (or deep within tissues)


What are the morphological features of an abscess?

- central region with mass of necrotic cells
- preserved zone of neutrophils
- vascular dilation and fibroblast proliferation - repair?
- maybe fibrotic wall - attempt to wall it off


Morphologically, what are the differences between acute and chronic inflammation?

Primarily vascular changes, edema, and neutrophil infiltration

- infiltration by mononuclear cells
- tissue destruction
- repair


What is the role of monocytes/macrophages in chronic inflammation?

In acute, they die off when irritant is removed.

If not removed they cause tissue injury or fibrosis.


What are the effects of macrophage derived factors?

- chemotaxis
- elimination of injurious agents (ROI and NOI[anti-inflam?])
- initiation of repair
- tissue injury - proteases
- collateral damage


What is the ongoing cycle of T-cells in chronic inflammation?

- T cells activated - mp acts as APC.

- activated T cell releases TNF and other inflammatory mediators and IFN-y

- IFN-y stimulated mps

- mps release TNF, cytokines, IL-1 and other inflammatory mediators contributing to inflammation

- mps also present antigen to more T cells and their cytokines activate them.


What is granulomatous inflammation?

- focal accumulations of activated mps
- epithelioid appearance

- granuloma = focus of chronic inflammation containing transformed, aggregated, epithelia's mps surrounded by a collar of leukocytes.

- central necrosis (no nuclei)
- giant cells
- black dots (leukocytes) surrounding it


What are giant cells?

- fused epithelioid cells
- found in periphery of some granulomas
- 40-50 um in diameter
- large cytoplasmic mass - 20 or more small nuclei


What are some diseases with granulomatous inflammation?

- TB
- leprosy
- syphilis
- cat-scratch disease


What are the types of granulomas?

- foreign body granulomas
- immune granulomas - insoluble particles inducing reaction
- defective inflammation, i.e. delayed wound healing and repair
- excessive inflammation - i.e. excessive tissue damage


what could be the three outcomes from injruy

healing, regeneration and fibrosis



growth of cells to replace lost structures - restitution of normal structure



formation of scar tissue



formation of excessive fibrous tissue


what are the 4 ECM proteins

collagen, elastic fibres, adhesion proteins and proteoglycans


when can granulation tissue start to form

24 hours after injury


what are the major source of ECM components



degradation of ECM is performed by what



describe healing by first intention

- narrow incision with blood cells and fibrin,
- neutrophils appear at margin with 24 hours,
- neutrophils are replaced by macrophages by 3 days and the space is filled with granulation tissue,
- vertical collagen fibres not organised,
- vascularisation proceeds and collagen becomes reorganised, scarring is minimal


describe healing by second intention

more cellular loss, edges not opposed,
- more abundant granulation tissue,
- more necrosis debris and exudate,
- wound contraction reduces size of scar,
- myofibroblasts contains actin filaments cause contraction,
- dermis is thinned


what are the factors that affect healing

injury related (nature of tissue), inflammatory factors (foreign bodies), host factors (age, anaemia)


what are the complications to healing

- deficient scar formation (mechanical stress or inadequate vascularisation),

- excessive formation of repair components (excess collagen causes raised scars such as hypertrophic, scar beyond origins boundaries is keloid),

- contractures (too much deforms the surrounding tissue)


*Give an overview of healing

Fibroproliferative response that patches areas of damaged tissue

1. Inflammation to remove damaged and dead tissue
2. Entry and proliferation of parenchymal cells and production of new connective tissue
3. Formation of new blood vessels
4. Synthesis of new ECM proteins
5. Tissue remodelling
6. Wound contraction
7. Acquisition of wound strength