Session 1 Flashcards
What does the degree of cell injury depend on?
- Duration of injury
- Severity of injury
- Type of injury
- Type of tissue
What can cause cell injury?
- Hypoxia
- Toxins
- Physical agents (eg. direct trauma, changes in temperature like burns, changes in pressure)
- Microorganisms
- Radiation (internal organ injury)
- Dietary insufficiencies
- Immune mechanisms (eg. autoimmune, allergy)
What is the difference between hypoxia and ischaemia?
- Hypoxia: reduced oxygen supply.
- Ischaemia: loss of the blood supply into an area and therefore reduced delivery of O2 and nutrients
What can cause ischaemia?
- Arterial occlusion
- Global hypotension (sepsis)
What is hypoxaemic hypoxia?
Low arterial content of oxygen
What are the causes of hypoxaemic hypoxia?
- Reduced O2 partial pressures at altitude
- Reduced O2 absorption (lung disease, poor O2 exchange)
What is anaemic hypoxia?
Decreased ability of haemoglobin to carry oxygen
What are causes of anaemic hypoxia?
- Anaemia
- CO poisoning
What is ischaemic hypoxia?
Interruption to the blood supply (most important clinically!)
What are the causes of ischaemic hypoxia?
- Blockage of a vessel
- Heart failure
What is histiocytic hypoxia?
Inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes (when tissue cells are poisoned and can’t use O2)
What can cause histiocytic hypoxia?
Cyanide poisoning
Why can the brain not survive without oxygen for too long?
- Neurones have a higher and quicker demand for O2
- Other cells (eg. fibroblasts) can survive for longer
How can the immune system damage cells in the body?
- Hypersensitivity: overly vigorous immune reactions
- Autoimmune reactions: failure to distinguish self from non-self
Which cell components are most susceptible to injury?
- Plasma/organelle membranes
- Nucleus (DNA)
- Proteins (structural, metabolic enzymes)
- Mitochondria (oxidative phosphorylation)
What happens in hypoxia when the injury is reversible (short term)?*
- Oxidative phosphorylation can’t function, so less ATP is produced
- Less ATP means reduced function of sodium pump which causes an increase in Ca2+, Na+ and H2O, K+ efflux
- Causes oncosis, blebs, ER swelling, myelin figures
- Less ATP means increased glycolysis, causing lower pH and therefore chromatin clumping
- Lower ATP causes less protein synthesis leading to lipid deposition
What happens in prolonged hypoxia?*
- Increased Ca2+ inhibits: ATPase: reduced ATP Phospholipase: decreased phospholipids Protease: disruption of protein Endonuclease: nuclear chromatin damage
What are free radicals?
Reactive oxygen species which have a single unpaired electron in the outer orbit and therefore have an unstable configuration that can react with other molecules and produce further free radicals.
What are the 3 significant free radicals that can cause damage?
- Hydroxyl
- Superoxide
- Hydrogen peroxide
When are free radicals produced?
- Oxidative phosphorylation (can escape the electron transport chain)
- Oxidative burst of neutrophils (inflammation)
- Radiation causing lysis of H2O
- Contact with unbound metals within body (Fenton reaction)
- Drug metabolism
How does the body control free radicals?
- Antioxidant scavengers that donate electrons to free radicals (Vit. A, C, E)
- Metal carrier and storage proteins (transferrin, ceruloplasmin) that make metals unavailable for reactions
- Enzymes that neutralise free radicals
Which enzymes neutralise free radicals?
- Superoxide dismutase
- Glutathione peroxidase
- Catalase
How do free radicals injure cells?
- Cause lipid peroxidation in the lipids in cell membranes
- Generates further radicals and creates a chain reaction
How do free radicals affect DNA?
- Can oxidise proteins, carbohydrates and DNA
- Molecules can become broken or crosslinked
- Made mutagenic and therefore carcinogenic
What are heat shock proteins?*
A response that ‘mends’ misfolded proteins to maintain cell viability. They are unfoldases and chaperonins.
What is an example of a heat shock protein?
Ubiquitin
What do injured cells look like under microscope?*
- Oncosis
- Paler cytoplasm
What do dead cells look like under the microscope?*
- PYKNOSIS - pink cytoplasm that shrinks, is darker
- KARYORRHEXIS - breakdown of the nucleus
- KARYOLYSIS - dissolved nucleus
What are the general features of injured and dying cells?
- Cytoplasmic changes
- Nuclear changes
- Abnormal cellular accumulations
How do dead/dying cells look under the electron microscope?*
Look at diagram, page 20! :)
What can accumulate in cells?
- Water and electrolytes
- Lipids
- Carbohydrates
- Proteins
- Pigments
Why do abnormal cellular accumulations occur?
When metabolic processes become deranged, especially with sublethal or chronic injury.
When can fluid accumulate in the cell?
- During hypoxia
- Sodium and water enter the cell
- Big problem in the brain
- Indicates severe cellular distress
How to see swelling in a brain?*
Less defined gyri and sulci.
What is steatosis?
Accumulation of triglycerides that is mainly seen in liver.
What are the causes of steatosis?
- Alcohol
- Diabetes
- Obesity
- Toxins
What does steatosis look like?
IRL: Liver yellow due to fat accumulation, will cause dysfunction.
Microscope: Many adipocytes present.
When does cholesterol accumulate in cells?
- Excess that is not eliminated by conjugation with albumin and removal through liver is stored in cell in vesiclees
- Accumulation = foam cells
- Present in macrophages, skin and tendons of people ith hyperlipidaemias (xanthomas)
What does accumulation of cholesterol look like?*
Slide 28! :)
What do proteins look like when they accumulate in cells?
- Eosinophilic droplets
- Aggregations in cytoplasm
What is Mallory’s hyaline and how does it cause protein accumulation?*
- Damaged intermediate filaments within hepatocytes
- In people with alcoholic liver disease
- Highly eosinophilic, appear pink on H&E
How does alpha 1-antitrypsin deficiency cause protein accumulation?
- Liver produces incorrectly folded alpha 1-antitrypsin
- Cannot be packaged or secreted so accumulates in the ER
How does alpha 1-antitrypsin cause systemic deficiencies?
Proteases in the lungs act unchecked and therefore result in emphysema as the alveoli become destroyed.
When do pigments accumulate in cells?
Air pollution particles (eg. carbon/soot)
- When they are phagocytosed by macrophages
Tattooing when pigment enters skin
- Phagocytosed in dermis where it remains but also can reach the lymph nodes
What does accumulation of pigment look like?*
- Anthracosis (accumulation of carbon in lungs)
- Blackened lung, blackened peribronchial lymph nodes
Is anthracosis harmful?
No, unless in large amounts, where they can cause fibrosis and emphysema
What are endogenous pigments that can accumulate in cells?
Haemosiderin (an iron storage molecule), derivative of Hb (yellow/brown)
When is haemosiderin found in cells?
When there is a systemic (disease) or local (bruise) overload of iron.
What can cause accumulation of haemosiderin?
- Hereditary haemochromatosis
- Haemolytic anaemias (iron released)
- Blood transfusion (no mechanism to remove iron)
What is hereditary haemochromatosis and what does it look like?*
- Inherited disorder
- Increased dietary absorption of iron
- Deposited in skin and organs (cirrhosis associated)
What are the symptoms of hereditary haemochromatosis?
- Liver damage
- Heart dysfunction
- Endocrine failures (pancreas)
All associated with iron overload in cells.
What is the treatment for hereditary haemochromatosis?
Repeated bleeding to remove blood and therefore extra iron.
What is jaundice and what does it look like?*
Jaundice is yellowing of the skin due to buildup of bilirubin, which is bright yellow
Why can jaundice happen?
- Bile flow obstructed
- Increased bile production
All leads to deposition extracellularly or in macrophages
What is bilirubin?
Breakdown product of heme, broken porphyrin rings (released heme)
Where is bilirubin formed and how is it removed from the body?
- Formed in all cells
- Eliminated in bile
- Taken from tissue by albumin to liver, conjugated and then excreted in bile
What does pleural fluid look like when jaundiced?
Yellow-tinged.
What happens when molecules leak out of membranes?
- Local inflammation
- General toxic effects
- High concentrations in blood = diagnosis?
How do intracellular accumulations occur? List 4 ways.*
1) Abnormal metabolism (eg. overproduction)
2) Alterations in protein folding and transport
3) Deficiency of critical enzymes
4) Inability to degrade phagocytosed particles
What is dystrophic calcification of tissue?
Abnormalities/degeneration of tissue leading to mineral calcium depositions even though levels in blood remain normal.
What are examples of dystrophic tissue calcification?
- Area of dying tissue
- Calcification of valve leaflets
- Atherosclerotic plaques
- Malignancies
What does calcification look like?*
See slides. :) (80/88)
Why can dystrophic calcification occur?
- Local disturbance that favours nucleation of hydroxyapatite crystals
What can be the consequences of dystrophic calcification?
Organ dysfunction (atherosclerosis, heart valve calcification)
What is metastatic calcification and why does it occur?
- Deposition of calcium salts in otherwise normal tissue.
- Caused by hypercalcaemia secondary to disturbances in calcium metabolism.
- Hydroxyapatite crystals deposited throughout body
- Usually asymptomatic
Can metastatic calcification be cured?
Yes, if cause of hypercalcaemia is corrected.
What causes hypercalcaemia?
- Increased secretion of PTH resulting in bone resorption
- Destruction of bone tissue
What is primary, secondary and ectopic bone resorption?
- Primary: parathyroid tumour/hyperplassia
- Secondary: renal failure and retention of phosphate
- Ectopic: PTH related proteins secreted by malignant tumours (rectified by surgery)
Why can bone tissue be destroyed?
- Tumours of bone marrow
- Skeletal metastases
- Accelerated bone turnover (Paget’s disease)
What is the definition of oncosis?
Cell death with swelling; changes that occur in injured cells prior to death.
What is the definition of necrosis?
Morphologic changes in a living organism that occur after a cell has been dead for 12-24+ hours
What are the 4 types of necrosis?
- Coagulative
- Liquefactive (2 main)
- Caseous
- Fat necrosis (2 special types)
What is coagulative necrosis?
- Necrosis caused by the ischaemia of solid organs (eg. heart, kidneys)
- Caused by protein denaturation & hypoxia
What is liquefactive necrosis?
- Necrosis caused by ischaemia in loose tissues (eg. brain, lung)
- Identified by presence of many neutrophils
- Protease release
What does coagulative necrosis look like?*
- Pyknosis
- Cell architecture preserved (Ghost outline)
- Maintained integrity
- Denaturation of proteins dominates over protease release
- Pale to naked eye
- Many neutrophils
What does liquefactive necrosis look like?*
- Cells fall apart
- Eosinophilic pink debris left over
- Enzymatic digestion of tissue (greater than denaturation)
- Many neutrophils deposited
What is caseous necrosis?
- Structureless debris
- Associated with infections (eg. TB)
What does caseous necrosis look like?*
- Stains pink/purple
- ‘Cottage cheese’ appearance before staining
- Often has granulomatous inflammation
What is fat necrosis?*
- Adipose tissue (after injury)
- Fatty acids and calcium deposit in tissue
When does fat necrosis occur?
eg. Acute pancreatitis
What is the definition of gangrene?*
Necrosis visible to the naked eye
What is the definition of infarction?
Necrosis caused by reduction in arterial blood flow (cause of necrosis and can cause gangrene)
What is an infarct?
An area of necrotic tissue which is the result of loss of the arterial blood supply
Why are some infarcts white and some red?
- White: poor blood supply. Will occur in solid organs after occlusion of an end artery. (coagulative)
- Red: extensive haemorrhage into dead tissue, dual blood supply, reperfusion (liquefactive)
What is dry gangrene?*
- Modified by exposure to air (coagulative necrosis)
What is wet gangrene?
- Necrosis modified by infection (liquefactive necrosis)
What is gas gangrene?
Wet gangrene where the tissue became infected with anaerobic bacteria that produce palpable bubbles of gas in tissues.
What are the most common causes of infarcts?
- Emboli that break off and occlude a blood supply somewhere else.
- Intestines twisting and occluding blood supply.
- Testicular torsion
What are the consequences of infarction?
Dependent on:
- If there’s an alternative blood supply
- Tissue involved
- Blood O2 content
- Ischaemia speed (collateral arteries develop)
What is ischaemia-reperfusion injury?
Return of blood flow causing further damage
- Increased production of radicals
- Increased number of neutrophils = more inflammation
- Complement pathway
What leaks out of the cell when it is damaged?
- Potassium
- Enzymes (can indicate what organ is involved, eg. troponin)
- Myoglobin (dead myocardium and striated muscle)
Why is the release of myoglobin dangerous?
- Can block kidney and cause renal failure
- Leads to rhabdomyolysis
What is cell apoptosis?*
Programmed cell death with shrinkage, when the cell activates enzymes that degrade its own proteins and nuclear DNA. Does not elicit an inflammatory response.
What do apoptotic cells look like under the microscope?*
- Shrunken
- Eosinophilic
- Chromatin condensation, karyorrhexis and pyknosis seen
- Apoptotic bodies phagocytosis so no leakage out of cell and inflammation
What are some features of apoptosis?*
- Maintained membrane integrity
- No lysosomal enzymes
- Quick
- Opposite to mitosis
When does apoptosis occur physiologically?
- Embryogenesis (eg. phalanges) - Hox genes
- Maintaining a steady state
When does apoptosis occur pathologically?*
- When DNA in cell damaged
- Killing of infected cells by cytotoxic T cells
What are the key phases of apoptosis?*
- Initiation
- Execution
- Fragmentation
- Phagocytosis (express proteins recognised by phagocytes)
What is the initiation &execution phase?
Activation of caspases - enzymes that cause cleavage of DNA and proteins in cytoskeleton
What is the intrinsic pathway of initiation?*
Signal from within cell.
- p53 protein activated
- mitochondrial membrane becomes leaky
- cytochrome C release causes caspase activation
What is the extrinsic pathway of initiation?*
Signal by cells that are a danger (eg. cancer)
- TNF alpha secreted by cytotoxic T cells
- Binds to ‘death receptor’ on cell membrane
- Activates caspase cascade
What is different in apoptosis compared to oncosis?*
- Shrinking not swelling
- Cell budding not blebbing
- No inflammation
Compare apoptosis, necrosis and oncosis.
Slide 71! :)
Why do cells die?
- Accumulate damage to DNA
- Reach senescence
- Cell can no longer divide when telomeres reach critical length
Why can stem cells continue to replicate?
Contain an enzyme (telomerase) that maintains the original length of telomeres
Why do cancer cells multiply so much?
They produce telomerase.
