Cell Injury

Question 1

Define hypoxia

Answer 1

Decreased oxygen supply to cells or tissues

Question 2

Define ischaemia

Answer 2

Decreased oxygen supply to cells or tissues due to decreased blood supply

Question 3

Explain ischaemia reperfusion injury

Answer 3

If blood flow is returned to a damaged but not yet necrotic tissue, damage sustained can be worse than if blood flow had not been returned
Caused by increased production of oxygen free radicals with reoxygenation
Increased number of neutrophils resulting in more inflammation and increased tissue injury
Delivery of complement proteins and activation of the complement pathway

Question 4

State the causes of hypoxia

Answer 4

Hypoxaemic hypoxia - arterial content of oxygen is low
Anaemia hypoxia - decreased ability of haemoglobin to carry oxygen
Ischaemic hypoxia - interruption to blood supply (blockage of vessel or heart failure)
Histotoxic hypoxia - inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes

Question 5

Discuss the causes of cell injury and cell death

Answer 5

Hypoxia
Physical agents, e.g., trauma, heat, cold, radiation, changes in pressure, electric currents
Chemical agents and drugs, e.g., poisons, alcohol, therapeutic drugs, toxins
Microorganisms
Immune mechanisms
Hypersensitivity reactions - host tissue is injured secondary to an overly vigorous immune reaction
Latex glove allergy
Autoimmune reactions - immune system fails to distinguish self from non-self
Dietary insufficiency and dietary excess
Genetic abnormalities, e.g., inborn errors of metabolism

Question 6

What cell components are most susceptible to injury

Answer 6

Cell membranes - plasma membrane, organellar membranes
Nucleus - DNA
Proteins - structural, enzymes
Mitochondria - oxidative phosphorylation

Question 7

What is reversible hypoxic injury

Answer 7

Low levels of ATP means the sodium potassium pump stops working
Leads to build up of sodium and water into the cell, leading to cell swelling
Calcium also begins to enter the cytoplasm from outside and ER
Cell relies on anaerobic respiration/glycolysis which decreases pH
Ribosomes fall off of ER so protein synthesis decreases leading to lipid deposition

Question 8

What is irreversible hypoxic injury

Answer 8

In prolonged hypoxia, large increases in calcium in cell activates many pathways include ATPase and phospholipases which attack cell membrane, attack protease which activates destructive enzymes to the cytoskeleton

Question 9

What are free radicals and state common examples

Answer 9

Reactive oxygen species
Single unpaired electron in an outer orbit - unstable configuration hence react with other molecules, often producing further free radicals
OH• (hydroxyl), O2- (superoxide) , H2O2

Question 10

How are free radicals produced

Answer 10

Produced in normal metabolic reactions eg. Oxidative phosphorylation
Kept in mitochondria and locked away
Inflammation - oxidative burst of neutrophils
Radiation - H2O -> OH•
Contact with unbound metals within the body - iron and copper
Free radicals damage occurs in haemachromatosis and Wilson’s disease
Drugs and chemicals - in the liver during metabolism of paracetamol or carbon tetrachloride by P450 system

Question 11

How are free radicals controlled

Answer 11

Anti-oxidant system - donate electrons to the free radical - vitamins A,C and E
Metal carrier and storage proteins sequeste iron and copper
Enzymes that neutralise free radicals

Question 12

Explain how free radicals can cause cell injury

Answer 12

Free radicals injure cells if number of free radicals overwhelm the antioxidant system = oxidative imbalance
Primarily damage lipids in cell membranes
Lipid peroxidation - takes an electron from other molecules and so on, leading to a chain reaction producing further free radicals
Oxidise proteins, carbohydrates and DNA
These molecules become bent, broken or cross-linked
Mutagenic and therefore carcinogenic

Question 13

Discuss heat shock proteins

Answer 13

Heat shock proteins - in cell injury, heat shock response aims to mend misfolded proteins and maintain cell viability
Unfoldases or chaperonins
Eg. Ubiquitin

Question 14

Discuss the appearance of dead cells under a microscope

Answer 14

In hypoxia, cells begin to look pale as they swell when injured
When cells are dead - become pink as proteins become denatured and strongly pick up eosin stain
Under a light microscope - cytoplasmic, nuclear changes, abnormal intracellular accumulations
Under an electron microscope - blebs seen as cell membrane lose strength and become leaky
Eventually, lysosomes and enzymes will rupture and may leave cell (irreversible)

Question 15

Define oncosis

Answer 15

Cell death with swelling, the spectrum of changes that occur in injured cells prior to death

Question 16

Define necrosis

Answer 16

In a living organism the morphologic changes that occur after a cell has been dead some time

Question 17

Discuss the differences between the four types of necrosis

Answer 17

Coagulative - lots of protein denaturation leading to pink clumping of cells
Organ or tissue with lots of solid support - lots of connective tissue
Denaturation of proteins dominates over release of active proteases
Cellular architecture somewhat preserved, creating a ‘ghost outline’ of cells
Liquefactive - enzyme release results in liquid like cells
Organ or tissue with loose tissues - eg. Brain
Or presence of many neutrophils - lots of inflammation
Enzyme degradation is substantially greater than denaturation
Leads to enzymatic digestion of tissue
Caseous necrosis - contains structureless debris but no ghost outline like in coagulation necrosis
Associated with infections, especially tuberculosis
Fat necrosis - pancreatitis - enzymes leak out into abdominal cavity and breakdown triglycerides in cell membrane into fatty acids
Areas of calcification in fat necrosis
Test for serum amylase, lipase and proteases are also released by pancreas

Question 18

Define apoptosis

Answer 18

Cell death with shrinkage, induced by a regulated intracellular program where a cell activates enzymes that degrade its own nuclear DNA and proteins
Programmed cell death

Question 19

Explain when apoptosis occurs physiologically and pathologically

Answer 19

Occurs physiologically when in order to maintain a steady state - maintain the size of tissue
Hormone controlled involution
Embryogenesis - when the webbing cells between digits are destroyed (sculpting)
Metamorphosis
Occurs pathologically when virus or tumour cells that are a danger to the body
Occurs when DNA is damaged
Graft versus host disease - own white blood cells are cancerous
Inject bone marrow from donor but may be recognised as foreign

Question 20

Explain the intrinsic and extrinsic pathway of apoptosis

Answer 20

Both result in activation of caspases - enzymes that control and mediate apoptosis
Caspase 3 most important in apoptosis
Cause cleavage of DNA and proteins of the cytoskeleton
Chromatin within nucleus begins to breakdown and clumps
Intrinsic - signal from within cell triggers when damage to DNA that cannot be repaired or withdrawal of growth factors needed for survival
P53 protein becomes activated and makes outer mitochondrial membrane leaky
Cytochrome C is released from mitochondria and causes activation of caspases
Extrinsic - initiated by extracellular signals and triggers when cells are a danger eg tumour cells, virus infected cells
One of the signals is TNFα
Secreted by T killer cells
Binds to cell membrane receptors (death receptor)
Results in activation of caspases

Question 21

Discuss the stages of apoptosis

Answer 21

Normal cell
Condensation
Fragmentation
Apoptic bodies -
Apoptotic bodies are then phagocytosed
Both intrinsic and extrinsic pathways caused cells to fragment and bud off into apoptotic bodies
Apoptotic bodies express proteins on their surface which are recognized by phagocytes

Question 22

Discuss the differences between apoptosis and necrosis

Answer 22

Necrosis occurs for groups of cell, apoptosis targets individual cells
Necrosis leads to swelling, apoptosis leads to shrinking
Necrosis disrupts plasma membrane, apoptosis doesnt
Necrosis causes cellular contents to leak out, apoptosis doesnt
Necrosis causes inflammation, apoptosis doesnt

Question 23

Define gangrene

Answer 23

Necrosis visible to the naked eye

Question 24

Distinguish between the 3 types of gangrene

Answer 24

Dry gangrene - necrosis modified by exposure to air (coagulative necrosis) eg. Frostbite
Wet gangrene - necrosis modified by infection (liquefactive necrosis)
Gas gangrene - wet gangrene where the infection is with anaerobic bacteria that produce gas

Question 25

Define infarction

Answer 25

Necrosis caused by reduction in arterial blood flow

Question 26

Define infarct

Answer 26

An area of necrotic tissue caused by reduction in arterial blood supply

Question 27

Distinguish between the two types of infarct

Answer 27

White infarcts - solid organs, occlusion of an end artery (sole arterial support for an organ segment) Eg. heart, kidney, spleen etc Red infarcts - loose tissue, dual blood supply (lungs), leak from vessels and bleed into area, collateral blood supply (bowel), prior congestion, reperfusion

Question 28

What are examples of molecules leaking out in cell injury

Answer 28

Potassium mainly leaks out - burns means potassium moves into tissues and cause cardiac arrest Enzymes leak out - troponin, CK in myocardial infarction Myoglobin leaks out and causes renal failure Happens in massive trauma or dehydration

Question 29

What can accumulate within cells after cell injury

Answer 29

Water and electrolytes, lipids, carbohydrates, proteins, pigments

Question 30

When does water accumulate in cells

Answer 30

Hydropic swelling Occurs when energy supplies are cut off Indicates sever cellular distress Particular problem in the brain - no where to enlarge meaning key parts of the brain are compressed leading to vessels being narrowed

Question 31

What is steatosis

Answer 31

Often seen in liver (hepatic steatosis) If mild - asymptomatic Causes - alcohol, diabetes, obesity, toxins No ATP, ribosomes dislodged Entire organ swells up and becomes a yellow colour - grease on knife if cut Becomes heavier

Question 32

Why does cholesterol accumulate in the liver

Answer 32

Cannot be broken down and is insoluble Can only be eliminated through the liver Excess stored in cell in vesicles Accumulates in smooth muscle cells and macrophages in atherosclerotic plaques Present in macrophages in skin and tendons of people with hereditary hyperlipidaemias = xanthomas

Question 33

In what conditions does protein accumulation occur

Answer 33

Seen as eosinophilia droplets or aggregations in the cytoplasm Alcoholic liver disease - Mallory's hyaline (damaged keratin filaments) α1-antitrypsin deficiency Liver produces incorrectly folded α1 antitrypsin protein Cannot be packaged by ER, accumulates within ER and is not secreted Systemic deficiency - proteases in lung act unchecked resulting in emphysema

Question 34

When do exogenous pigments accumulate in cells

Answer 34

Carbon/coal dust/soot - urban air pollutant Inhaled and phagocytosis by alveolar macrophages Anthracosis (accumulation of carbon dust in lungs) and blackened peribronchial lymph nodes Usually harmless, unless in large amounts = fibrosis and emphysema = coal workers pneumoconiosis Tattooing - pigments pricked into skin Phagocytosed by macrophages in dermis and remains there Some pigment will reach draining lymph node

Question 35

When do endogenous pigments accumulate in cells

Answer 35

Haemosiderin - iron storage molecule Derived from haemoglobin, yellow/brown Forms when there is a systemic or local excess of iron eg bruise With systemic overload of iron, haemosiderin is deposited in many organs = haemosiderosis Seen in haemolytic anaemia, blood transfusions and hereditary haemocrhomatosis Hereditary haemochromatosis - body takes in more iron than needed in intestines Iron deposited in skin, liver, pancreas, heart and endocrine organs - often associated with scarring in liver and pancreas Symptoms include liver damage, heart dysfunction and multiple endocrine failures, especially of the pancreas Repeatedly take blood from patients to treat

Question 36

How does jaundice accumulate in cells

Answer 36

Accumulation of bilirubin - bright yellow Breakdown product of heme from red blood cells, stacks of broken porphyria rings Formed in all cells of body but must be eliminated in bile Taken from tissue by albumin to liver, conjugated with bilirubin and excreted in bile If bile flow is obstructed or overwhelmed, bilirubin in blood rises and jaundice results Yellow sclera

Question 37

Discuss the types of pathological calcification

Answer 37

Dystrophic - much more common than metastatic Occurs in an area of dying tissue, atherosclerotic plaques, ageing or damaged heart valves, in tuberculous lymph nodes No abnormality in calcium metabolism, or serum calcium phosphate concentrations Local change/disturbance favours nucleation of hydroxyapatite crystals Can cause organ dysfunction eg. Atherosclerosis, calcified heart valves Metastatic - disturbance is body-wide Due to hypercalcaemia secondary to disturbances in calcium metabolism Hydroxyapatite crystals are deposited in normal tissues throughout the body Usually asymptomatic but can be lethal

Question 38

What causes hypercalcaemia

Answer 38

Increased secretion of parathyroid hormone resulting in bone resorption Primary - due to parathyroid hyperplasia or tumour Secondary - due to renal failure and the retention of phosphate Ectopic - secretion of PTH-related protein by malignant tumours Destruction of bone tissue Primary tumours of bone marrow eg. Leukaemia, multiple myeloma Diffuse skeletal metastases Paget's disease of bone - when accelerated bone turnover occurs Immobilization

Question 39

Discuss cellular ageing

Answer 39

As cells age, they accumulate damage to cellular constituents and DNA After a certain number of divisions, they reach replicative senescence - related to the length of chromosomes Ends of chromosomes are called telomeres, with every replication the telomere is shortened When the telomeres reach a critical length, the cell can no longer divide Germ cells and stem cells contain telomerase enzyme - maintains the original length of telomeres Many cancer cells produce telomerase and so have the ability to replicate multiple times

Question 40

Discuss the effects on the liver of chronic excessive alcohol intake

Answer 40

Fatty change - steatosis (accumulation of fat) Acute alcoholic hepatitis - inflammation of liver due to excessive alcohol intake Cirrhosis - impairment of liver leading to scarring and liver failure

Question 41

What is the lab results of acute pancreatitis

Answer 41

Increase in serum amylase and serum lipase (acute pancreatitis only)

Question 42

What is haemochromatosis, presentation, complication and treatment

Answer 42

Body takes in more iron than needed in intestines Iron deposited in skin, liver, pancreas, heart and endocrine organs - often associated with scarring in liver and pancreas Bronzing of the skin Symptoms include liver damage, heart dysfunction and multiple endocrine failures, especially of the pancreas Repeatedly take blood from patients to treat

Question 43

What is alpha-1 antitrypsin, pathophysiology, presentation and complication

Answer 43

Liver produces incorrectly folded α1 antitrypsin protein Cannot be packaged by ER, accumulates within ER and is not secreted Protein accumulation - alpha-1 antitrypsin deactivates enzymes released from neutrophils during inflammation Systemic deficiency - proteases in lung act unchecked resulting in emphysema Presents with coughing and wheezing

Question 44

What is coalworker's pneumoconiosis, presentation and complication

Answer 44

Carbon/coal dust/soot - urban air pollutant Inhaled and phagocytosis by alveolar macrophages Anthracosis (accumulation of carbon dust in lungs) and blackened peribronchial lymph nodes Usually harmless, unless in large amounts = fibrosis and emphysema = coal workers pneumoconiosis