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22 Cards in this Set

  • Front
  • Back
Define necrosis
- Pathological cell death
- The series of structural changes that dead cells go through due to impairment of key cellular systems
- Enzymatic cell digestion involved
- Cell contents leak out e.g. proteins
- Usually multiple cells
Define apoptosis
- Programmed cell death
- May be pathological or physiological
- Internally controlled
- Nuclear dissolution but no cell leakage
- Usually single cells
Describe 7 causes of cell injury
1. Hypoxia
- Ischaemia
• Lack of O2 and nutrients to tissue
• May be local e.g. due to an embolus (blockage)
• May be systemic e.g. cardiac failure (blood not pumped around sufficiently)
- Hypoxaemia
• Decreased partial pressure of oxygen in blood
• May be caused by oxygen problems e.g. altitude
• May be caused by haemoglobin problems e.g. anaemia
- Oxidative phosphorylation
• Oxygen metabolism in mitochondria
• May be inhibited e.g. by cyanide poisoning

2. Chemical
- Poisons
• E.g. arsenic, cyanide, mercury
• Interfere with cellular metabolism
• If ATP levels drop below critical levels, affected cells will die
• Most medications toxic. Some act directly, but most have their effect through breakdown metabolites

3. Infections
- Caused from everything from helminths to prions (pieces of proteins)
- Particularly fungi, rickettsiae, bacteria and viruses
- E.g. viruses can take over protein translation and subvert it entirely to the production of new virions → all cellular energy is focused on this causing cell stress and eventual death

4. Trauma
- Direct physical effects
- Exposure of tissues to extreme heat or cold results in direct injury that is often irreversible, resulting in a pattern of coagulative necrosis

5. Immune
- Double-edged sword = fights infection but can turn on itself
- Inflammatory mediators e.g. interferons and interleukins
• Can alter both gene expression and cellular metabolism
• Effects are designed to help cells combat an infectious precess, but the resulting stress to the cells can be highly injurious and sometimes deadly
- Activation of complement can resulting in direct attack on a cell's surface membrane
- Cytotoxic T-cells and NK cells can mediate a direct atack on target cells and initiate a self-destruct cascade within the target cell

6. Nutrition
- Dietary insufficiency
• Proteins, vitamins and/or mineral can lead to injury at the cellular level
• Due to interference in normal metabolic pathways
- Dietary excess
• Can also lead to cellular and tissue alterations that are detrimental
• E.g. fat is the biggest offender → in liver tissue 'holes' are left because of fat, that means that cells cannot carry out their normal actions, leading to stress and injury

7. Radiation
- Can cause alterations in DNA, causing abnormal proteins which can prevent the cell functioning properly
What are the 4 primary structural targets for cell damage?
1. Cell membrane
- Plasma membrane
- Organelle membrane
2. DNA
3. Proteins
- Structural (cytoskeleton)
- Enzymes
4. Mitochondria
- Oxidative phosphorylation
Describe the general pathogenesis of cell injury
1. Reduced ATP synthesis / mitochondrial damage
• If cells become too hypoxic or mitochondria are directly damaged, they cannot produce enough ATP
• Causes failure of many membrane pumps (e.g. Na/K) and biosynthetic processes
2. Loss of calcium homeostasis
• Calcium usually removed from the cytosol by ATP-dependent Ca pumps.
• Damage to membranes of storage vesicles and lack of ATP → increase of Ca concentration that can't be buffered or pumped out
• Free calcium used to activate a variety of cytosolic enzymes
→ protein kinases = phosphorylation of other proteins
→ phopholipids = attack membrane lipids
→ Calpain = protease which causes disassembly of cytoskeleton proteins
3. Disrupted membrane permeability
• Often immune-mediated e.g. when complement activation leads to the formation of membrane attack complex
• In energy-depleted cells, failure of biosynthesis of new membrane phospholipids
• Free calcium causes activation of phospholipases
4. Free radicals
• Perioxidation of lipids in cell membranes → membrane permeability
• Attacks thiol groups in proteins e.g. Na/K-ATPase pump
• Fragments DNA strands
• May also cause the proudction of reactive intermediates e.g. glutathione from glutathione peroxidase, used as a radical scavenger
5. Metabolic derangements
• E.g. cyanide prevents mitochondria working so inhibits ATP synthesis
Describe the pathogenesis of reversible cell injury
- Loss of ATP
• Failure of Na/K pump
• Influx of Ca, K, H2O and Na
- Anaerobic metabolism
• Increased lactic acid and phosphate
- Reduced protein synthesis
Describe the pathogenesis of irreversible cell injury
- Massive intra-cytoplasmic calcium accumulation
- Enzyme activation
Describe the morphological differences between reversible and irreversible cell injury
Reversible = cell membrane intact
Irreversible = contents spill out
Describe the propagation and destruction of free radicals
- Highly reactive, unstable chemical
- Single unpaired electron, outer orbital
- Associated with cell injury
• Chemical/drugs
• Reperfusion injury
• Inflammation
• Irradiation
• Oxygen toxicity
• Carcinogenesis
- Free radical generation occurs by:
• Absorption of irradiation e.g. OH• and H•
• Endogenous normal metabolic reactions e.g. O2-• and H2O2
• Transition metals e.g. Fe+++
- Free radical generation occurs by
• nitric oxide = an important paracrine-type mediator that helps regulate vascular pressure
• Toxins e.g. carbon tetrachloride
- Free radicals are removed by
• spontaneous decay
• Anti-oxidants e.g. vitamin E, vitamin A, ascorbic acid, gluthione
• Storage proteins e.g. transferrin, ferritin, ceruloplasmin
• Enzymes e.g. catalase, SOD, glutathione peroxidase
- Injure cells by
• Membrane lipid peroxidation = autocatalytic chain reaction
• Interaction with protein = protein fragmentation and protein-protein cross-linkage → can't function
• DNA damage = single strand breaks (genomic and mitochondrial)
Describe the general protective mechanisms of cells
- Heat shock response genes
• Comprise of a large group of genes
• Expression is up-regulated in the face of cell stressors and serves to protect from stress-related damage
• Clean-up damaged proteins from the cell
- Many tissues and organs can survive significant injury if they are 'pre-stressed'
Define necrosis
Death of groups of contiguous cells in tissue or organ
May be:
- Coagulative
- Liquefactive
- Casseous
- Fat necrosis
- Gangrene (clinical term)
- Infarct = red or white (clinical term)
What is coagulative necrosis?
- Cells have died but the basic shape and architecture of the tissue endures
- Most common manifestation of ischaemic necrosis in tissues.
- Affected tissue maintains solid consistency.
- In most cases the necrotic cells are ultimately removed by inflammatory cells.
- The dead cells may be replaced by regeneration from neighbouring cells, or by scar (fibrosis).
Describe liquefactive necrosis
- Complete dissolution of necrotic tissue.
- Most commonly due to massive infiltration by neutrophils (abscess formation).
- Release of reactive oxygen species and proteases
- Liquefaction is also characteristic of ischaemic necrosis in the brain and other tissues that contain a large lysosomal content.
Describe the features of caseous necrosis
Accumulation of amorphous (no structure) debris within an area of necrosis.
Tissue architecture is abolished and viable cells are no longer recognizable.
Characteristically associated with the granulomatous inflammation of tuberculosis. Also seen in some fungal infections.
Describe the features of fat necrosis
- Results from the action of lipases released into adipose tissue.
• pancreatitis, trauma.
- Free fatty acids accumulate and precipitate as calcium soaps (saponification).
• These precipitates are grossly visible as pale yellow/white nodules
- Microscopically, the digested fat loses its cellular outlines. There is often local inflammation
What is gangrene?
- Not a separate kind of necrosis at all, but a term for necrosis that is advanced and visible grossly.
- If there's mostly coagulation necrosis, (i.e., the typical blackening, desiccating foot which dried up before the bacteria could overgrow), we call it dry gangrene.
- If there's mostly liquefactive necrosis (i.e., the typical foul-smelling, oozing foot infected with several different kinds of bacteria), or if it's in a wet body cavity, we call it wet gangrene.
What is infarction?
- An area of ischaemic necrosis in a tissue or organ
- May be:
• White
→ caused by arterial occlusion in most solid tissues
• Red/haemorrhagic
→ caused by venous occlusion = too much blood due to lack of drainage
→Found in:
Loose tissues
Dual blood supply e.g. lungs
Previously congested
Describe the structural changes associated with necrosis and apoptosis
- pathological response to cellular injury.
- Chromatin clumps
- mitochondria swell and rupture
- membrane lyses
- cell contents spill
- inflammatory response triggered

- A distinct reaction pathway which represents programmed cell death = cells expend energy in order to die
- May occur during normal physiology, or may be pathological e.g. Graft-versus-host disease in colonic mucosa following bone marrow transplant
- DNA cleaved at specific sites - 200 bp fragments.
- Cytoplasm shrinks without membrane rupture
- Blebbing of plasma and nuclear membranes
- Cell contents in membrane bounded bodies, no inflammation
Describe the triggers of apoptosis
1. Withdrawal of growth stimuli e.g. growth factors → proteins can no longer function
2. Death signals e.g. TNF and Fas via an extrinsic receptor
3. DNA damage = p53 plays an important role by detecting irreversible DNA damage
Describe mechanisms of apoptosis
- Extrinsic factors e.g. by members of the TNF family
- Intrinsic mechanisms e.g. hormone withdrawal
Describe the histological and biochemical consequences of chronic, excessive alcohol intake
- Excessive alcohol consumption is associated with several distinct pathological changes in the liver. It should be understood however that in many instances the pathology is mixed and all these changes may be seen
1. Fatty liver
- Due to changes in the metabolic activity of hepatocytes
- Occurs following even a single episode of excessive alcohol intake
- The liver is enlarged and in gross cases has a yellow colour
- The accumulation of fat in the liver cells is due to diversion of hepatic enzymes to metabolise the alcohol causing a deficiency and resulting in interference with fat and carbohydrate metabolism
- Continued alcohol abuse induces further hepatic changes, part adaptive, part impairment, to cope with the excess alcohol e.g. increase in certain enzymes. This may have side-effects e.g. increased catabolism of drugs and steroids (so are less effective and may lead to feminisation in males) and the convesion of potential hepatotoxins to active metabolites, causing further damage to the liver

2. Alcoholic hepatitis
- Fatty change is reversible but in a small proportion of cases alcoholic hepatitis is superimposed
- Causes hepatocellular degeneration and necrosis
- A abnormal protein - Mallory's hyaline, accumulates in some of the cells near the hepatic venule
- Many cells are ballooned and fatty change is present
- Foci of necrotic cells induces an acute immune response

3, Alcoholic fibrosis
- Focal fibrosis occurs are a result of alcoholic hepatitis
- Spurs of fibrous tissue develop around the portal tracts producing a stellate pattern and enlarging them

4. Cirrhosis
- Caused by progressive alcoholic fibrosis, most apt to happen if there are attack of alcoholic hepatitis
- 3 types
• Micronodular = liver normal sized and surface has fine granular appearance formed from small nodules
• Macronodular = liver size varies and surface shows coarse nodularity. Often no hepatic venule can be seen in a lobule
• Mixed nodule = most common
- 4 Mechanisms are involved in the production of cirrohisis:
• Hepatocellular necrosis
• Replacement fibrosis and inflammation
• Vascular derangement (causing portal hypertension and interference with hepatic function)
• Hyperplasia of surviving liver tissue to form nodules (which further distort vascular distribution)
- Cirrhosis is usually slow but progressive due to continued action of the damaging factor causing necrosis, and the development of cytotoxic immune reaction to proteins set free by damaged hepatic cells, causing fibrosis, vascular damage, and therefore also necrosis
Describe the histological and biochemical consequences of aspirin and paracetamol overdose
- Paracetamol (PCM) is usually conjugated in the liver by sulphate gluconiside
- In overdose, this route is overwhelmed and detoxification is pushed to the oxidase P450 route, making NABQI which is bound to glutathione and excreted.
- However, NABQI is very reactive and toxic and a build up will cause coagulative necrosis
- Build-ups are more likely to occur e.g. in malnourished individuals, who have a smaller reserve of glutathione in their hepatocytes
- Necrosis usually occurs in the centrilobular region, although in most other toxins necrosis may occur in the periportal region

- Aspirin has a number of toxic effects, inculding directly stimulating the respiratory centres
- In the liver causes accelerated activity of the glycolytic and lipolytic pathway, causing depletion of hepatic glycogen and eventual necrosis of cells due to lack of nutrients and metabolic acidosis