S1) Cell Injury Flashcards
How do cells respond to environmental changes?
- Cells can maintain homeostasis during mild environmental changes
- During severe changes, cells undergo physiological and morphological adaptations to remain viable
What happens when cells reach the limits of their adaptive response?
- Reversible cell injury
- Irreversible cell injury and death
Identify 4 factors which affect the extent of cell damage
- Type of injury
- Duration of injury
- Severity of injury
- Type of tissue
Identify 7 agents by which cells can be damaged
- Hypoxia
- Physical agents
- Chemical agents and drugs
- Micro-organisms
- Immune mechanisms
- Dietary imbalances
- Genetic abnormalities
What is hypoxia and how does it cause cell injury?
- Hypoxia is oxygen deprivation and if persistent causes cell adaptation, injury or death
- Very common
Identify 5 physical agents which can cause cell injury
- Direct trauma
- Extremes of temperature (burns and severe cold)
- Sudden changes in atmospheric pressure
- Electric currents
- Radiation
Identify 5 chemical agents/drugs which can cause cell injury
- Oxygen in high concentrations
- Poisons
- Alcohol
- Illicit drugs
- Therapeutic drugs
Identify 4 micro-organisms which can cause cell injury
- Viruses
- Bacteria
- Fungi
- Parasites
Identify 3 types dietary imbalances which can cause cell damage
- Dietary insufficiency
- Dietary deficiencies
- Dietary excess
Provide and example of a genetic abnormality which can cause cell damage
Inborn errors of metabolism
Identify 4 types of hypoxia
- Hypoxaemic
- Anaemic
- Ischaemic
- Histiocytic
What are the targets of cell injury?
- Cell membranes
- Nucleus
- Proteins (structural proteins & enzymes)
- Mitochondria
Provide a 10-point summary of reversible hypoxic cell injury
- Cell is deprived of oxygen
- Mitochondria stops ATP production & membrane ionic pumps stop
- Na+ and H20 seep into the cell
- Cell swells and initiates a heat-shock response (stress)
- Glycolysis keeps cell alive but pH drops as lactic acid accumulates
- Calcium enters the cell & activates: phospholipases, proteases, ATPase and endonucleases
- ER and other organelles swell
- Enzymes leak out of lysosomes and attack cell contents
- Cell membrane is damaged (show blebbing)
- Cell dies – burst of a bleb
Describe the effect of the following enzymes in causing cell injury:
- Phospholipases
- Protease
- ATPases
- Endonucleases
- Phospholipases – cause cell membranes to lose phospholipids
- Proteases – damage cytoskeletal structures and attack membrane proteins
- ATPases – cause more loss of ATP
- Endonucleases – cause nuclear chromatin to clump
What is Ischaemia-Reperfusion Injury?
Ischaemia-reperfusion injury is the injury that occurs when blood flow is returned to a tissue that has undergone ischaemia but not necrosis
What causes Ischamia-Reperfusion injury?
- Increased production of oxygen free radicals with reoxygenation
- Delivery of complement proteins activates the complement pathway
- Increased neutrophils with returned blood flow results in inflammation and increased tissue injury
What are free radicals and what do they do?
- Free radicals are reactive oxygen species and have a single unpaired electron in an outer orbit
- This is an unstable configuration and hence, they react with other molecules often producing more free radicals
What do free radicals do in Ischaemic reperfusion injury?
- Attack lipids in cell membranes and cause lipid peroxidation
- Damage proteins, carbohydrates and nucleic acids
Identify 3 free radicals of particular biological significance in cells
- OH• (hydroxyl)
- 02- (superoxide)
- H202 (hydrogen peroxide)
What causes cell injury, in terms of free radicals?
- Cell injury is caused by an imbalance between free radical production and free radical scavenging
- Free radicals accumulate and the cell / tissue is said to be in oxidative stress
What is the anti-oxidant system?
The anti-oxidant system is the body’s defence system to prevent injury caused by free radicals
Identify and describe the components of the antioxidant system
- Superoxide dismutase catalyse the reaction production of H2O2 (less toxic) from O2-
- Catalases and peroxidases catalyse the production of H2O and O2 from H2O2
- Free radical scavengers neutralise free radicals
- Storage proteins that sequester transition metals in the extracellular matrix
Identify some free radical scavengers
- Vitamin A
- Vitamin C
- Vitamin E
- Glutathione
Identify two storage proteins involved in the antioxidant system
- Transferrin
- Ceruloplasmin
What are heat shock proteins?
Heat shock proteins are proteins triggered by any form of cell injury to protect the body in the stress response
Provide 3 examples of heat shock proteins
- Stress proteins
- Unfoldases
- Chaperonins
How do cells respond to the heat shock response?
- Decrease usual protein synthesis
- Increase synthesis of HSPs
What are the main cell alterations that can be seen under a light microscope?
- Cytoplasmic changes
- Nuclear changes
- Abnormal intracellular accumulations
Identify 4 reversible changes involved in cell injury as seen in electron microscopy
- Swelling of cell & organelles
- Cytoplasmic blebs
- Clumped chromatin
- Ribosome separation from the rER
Identify 5 irreversible changes involved in cell injury as seen in electron microscopy.
- Nuclear changes
- Swelling and rupture of lysosomes
- Membrane defects
- The appearance of myelin figures
- Lysis of the ER
Identify and describe the three types of nuclear changes that can occur in cell injury
Define apoptosis
Apoptosis is cell death with shrinkage, induced by a regulated intracellular program where a cell activates enzymes that degrade its own nuclear DNA and proteins
Define oncosis
Oncosis is cell death with swelling and the spectrum of changes that occur prior to death in injured cells
Define necrosis
- Necrosis is the morphologic changes that occur after a cell has been dead some time e.g. 4-24 hours
- It is not a type of cell death, i.e. it is an appearance and not a process
Why is inflammation often accompanied with necrosis?
- Cell membranes are damaged (plasma and organelle)
- Lysosomal enzymes are released into the cytoplasm and digest the cell
- Cell contents leak out of the cell and cause inflammation
How is necrotic tissue removed?
- Necrotic tissue is removed by enzymatic degradation and phagocytosis by white cells
- If some remains it may calcify (dystrophic calcification)
Coagulative necrosis is a type of necrosis.
Outline this process
- Proteins of dying cells denature and tend to coagulate
- Denaturation dominates over release of active proteases
- Cellular architecture is preserved (ghost outline)
Liquefactive necrosis is a type of necrosis.
Outline this process
- Proteins of dying cells undergo autolysis where they are dissolved by the cell’s own enzymes
- Enzyme degradation dominates over denaturation
- Leads to liquefaction of tissues
Caseous necrosis is a type of necrosis.
Outline this process
- Contains amorphous (structureless) debris
- Associated with infections e.g. TB
Fat necrosis is a type of necrosis.
Outline this process
- Lipase releases fatty acids from triglycerides which then complex with calcium to form soaps
- Soaps appear as white chalky deposits
- Associated with pancreas, breast and the salivary glands
What is gangrene?
Gangrene is not a type of necrosis, it is a clinical term used to describe necrosis that is visible to the naked eye
Classify the different types of gangrene
- Dry gangrene – necrosis is modified by exposure to air (coagulative necrosis)
- Wet gangrene – necrosis is modified by infection with a mixed bacterial culture (liquefactive necrosis)
What is gas gangrene?
- Gas gangrene is wet gangrene where the tissue has become infected with anaerobic bacteria
- It produces visible and palpable bubbles of gas within the tissues
What is infarction?
Infarction refers to a cause of necrosis, namely ischaemia (reduced blood supply)
Identify the 2 most common causes of infarction
- Thrombosis
- Embolism
Explain how infarcts can be described by their colour
- Infarcts can be white / red
- It indicates how much haemorrhage there is into the infarct
Where are white infarcts found?
A white (anaemic) infarct occurs in ‘solid’ organs after occlusion of an “end” artery
Where are red infarcts found?
A red (haemorrhagic) infarct occurs where there is extensive haemorrhage into dead tissue due to:
- Loose tissue
- A dual blood supply
- Numerous anastomoses
Identify 4 consequences of infarction
- Local irritation
- Local inflammation
- General toxic effects on the body
- Substances appear in high concentrations in the blood
Identify 3 types of molecules released from an infarction
- Potassium
- Enzymes e.g. Creatine Kinase, AST, troponin
- Myoglobin
Why does apoptosis not induce inflammation?
- Apoptotic bodies are removed by macrophage phagocytosis
- No leakage of cell contents occurs
What does apoptosis look like under a light microscope?
- Apoptotic cells are shrunken and appear intensely eosinophilic
- Pyknosis and karyorrhexis are seen
What does apoptosis look like under an electron microscope?
- Cells show cytoplasmic budding (not blebbing as is seen in oncosis)
- This progresses to fragmentation into membrane-bound apoptotic bodies
Why are apoptotic bodies phagocytosed?
The apoptotic bodies express proteins on their surface which are recognised by phagocytes or neighbouring cells
Compare and contrast the structural changes in oncosis/necrosis and apoptosis in terms of:
- Pattern
- Cell size
- Nucleus
- Plasma membrane
- Cellular contents
- Adjacent inflammation
When and why do abnormal cell accumulations occur?
- Occurs when cell cannot metabolise something
- Occurs with sub-lethal or chronic injury
- Can be reversible / harmless / toxic
Where are abnormal cell accumulations derived from?
- Cell’s own metabolism
- The extracellular space e.g. spilled blood
- The outer environment e.g. dust
What are the five main groups of intracellular accumulations?
- Carbohydrates
- Water and electrolytes
- Lipids (triglycerides and cholesterol)
- Proteins
- Pigments (exogenous and endogenous)
Hydropic swelling is a type of abnormal cellular accumulation.
What occurs?
- Indicates severe cellular distress
- Na+ and H2O flood into the cell
When and where does hydropic swelling occur?
- Occurs when energy supplies are cut off e.g. hypoxia
- Particularly occurs in the brain
What is steatosis?
- Steatosis is the accumulation of triglycerides
- If mild, it is asymptomatic
What is the most common site of steatosis?
Liver (major organ of fat metabolism)
Identify 4 causes of steatosis
- Alcohol
- Diabetes mellitus
- Obesity
- Toxins
Outline the metabolism of cholesterol
- Cannot be broken down and is insoluble
- Can only be eliminated through the liver
- Excess stored in cell in vesicles
How are foam cells formed?
Foam cells are formed from cholesterol accumulating in the smooth muscle cells and macrophages of atherosclerotic plaques
Where are xanthomas found?
Xanthomas are present in macrophages in skin and tendons of people with hereditary hyperlipidaemias
How do protein accumulations appear?
- Look like eosinophilic droplets
- Look like aggregations in the cytoplasm
Outline abnormal protein accumulations as seen in α1-antitrypsin deficiency
- Liver produces incorrectly folded α1-antitrypsin protein
- Protein cannot be packaged by ER, accumulates and is not secreted
- Systemic deficiency results (emphysema)
Describe the effect of accumulations of exogenous pigments (tattoos)
- Phagocytosed by macrophages in dermis and remains there
- Some pigment will reach draining lymph nodes
Explain how coal, dust or soot (endogenous pigments) accumulate in the body
- Pigment inhaled and phagocytosed by alveolar macrophages
- Anthracosis and blackened peribronchial lymph nodes
- Harmless unless in large amounts (fibrosis/emphysema)
What is pathological calcification?
Pathological calcification is the abnormal deposition of calcium salts within tissues
What are the 2 types of pathological calcification?
- Dystrophic calcification (local – more common)
- Metastatic calcification (general)
What is dystrophic calcification?
- Dystrophic calcification is when a local change or disturbance in the tissue favours the nucleation of hydroxyapatite crystals
- No abnormality in calcium metabolism
Identify 4 locations where dystrophic calcification occurs
- An area of dying tissue
- Atherosclerotic plaques
- Aging or damaged heart valves
- Tuberculous lymph nodes
What is metastatic calcification?
Metastatic calcification is when hydroxyapatite crystals are deposited in normal tissues throughout the body due to hypercalcaemia secondary to disturbances in calcium metabolism
Distinguish between the acute and chronic liver disease
- Acute liver disease is when damage to the liver develops over a few months
- Chronic liver disease is when damage to the liver occurs over a number of years
Identify 2 effects of chronic excessive alcohol intake on the liver
- Oxidative stress – liver tries to break down alcohol and the resulting chemical reaction damages its cells, leading to inflammation and scarring
- Toxins – alcohol damages our intestine which releases toxins from gut bacteria into the liver, leading to inflammation and scarring
What causes jaundice?
Accumulation of bilirubin
What is bilirubin?
Bilirubin is a breakdown product of heme, formed in all cells of body and excreted in bile
How does jaundice arise?
- Bile flow is obstructed or overwhelmed
- Bilirubin in blood rises and is deposited in tissues extracellularly or in macrophages
What is chronic hepatitis?
Chronic hepatitis is defined as over 6 months history with histology of inflammation and necrosis in the liver
Identify 4 laboratory features of hepatitis
- Raised serum ALT, AST and LDH
- Raised bilirubin
- Decreased albumin
- Raised PT
- Raised ammonia
Identify 3 laboratory features of alcoholic liver disease
- Raised bilirubin
- Raised alkaline phosphatase
- Raised gamma GT (glutamyl transpeptidase)
What are the clinical and laboratory features of acute pancreatitis?
- Raised serum amylase in first 24 hours
- Raised serum lipase from 72-96 hours
- Glycosuria (10%)
- Hypocalcaemia possible
How do we take measurements to identify myocardial infarctions?
Measure blood levels of intracellular macromolecules that leak out of injured myocardial cells through damaged cell membranes
Identify 5 substances which indicate the occurrence of a myocardial infarction
- Troponin T (TnT)
- Troponin I (TnI)
- Creatine kinase (CK)
- Lactate dehydrogenase (LDH)
- Myoglobin
