5.1

Question 1

Define disease.

Answer 1

Condition in which the presence of abnormality causes loss of normal STRUCTURE and FUNCTION. Consequently affects health.

Question 2

What are the three types of changes that cause disease?

Answer 2

1. Biochemical changes to cells.
2. Structural changes to tissues.
3. Functional changes to organs.

Question 3

There is a scope for pathology. Define the three different types of pathology.

Answer 3

1. General = study of disease processes that occur in ALL body systems (e.g. cell apoptosis and inflammation.
2. Systemic =study of diseases found within an organ system.
3. experimental = investigation and manipulation of animal and cell culture models of disease/patient observations and investigation.

Question 4

What are the 7 terms and characteristics of disease?

Answer 4

1. Aetiology = cause of disease (SMOKING).
2. Pathogenesis = mechanism causing disease (GENETIC ALTERATION).
3. Pathology = molecular and morphologic changes to cells/tissues (LUNG TUMOUR).
4. Clinical manifestations = functional consequences (signs and symptoms) (BREATHLESSNESS).
5. Complications = secondary, systemic, or remote consequences of the disease (METASTASIS).
6. Prognosis = anticipated course of disease (DEATH/REMISSION).
7. Epidemiology = incidence, prevalence, and distribution (RISK - gender, age, etc).

Question 5

What does stress/increased demand cause a normal cell to do/become?

Answer 5

Undergoes adaption.

Question 6

What happens when an injury-inducing stimulus is applied to a normal cell? What does this mean?

Answer 6

Cell becomes injured.
THIS MEANS that cell loses its function (can be reversible or irreversible).

Question 7

What happens to a cell if it fails to adapt?

Answer 7

1. does not go back to normal cell homeostasis.
2. failure to adapt = cell injury occurs.

Question 8

What are the two broad categories of adaption?

Answer 8

1. Physiological –> cell response to normal stimulation (e.g. hormones, endogenous chemicals).
2. Pathological –> cell response to stimulation (stimuli/stress) that is abnormal (secondary to underlying disease/avoid injury) by modulation/altering the cell’s structure and/or function.

Question 9

What are the four types of adaption?

Answer 9

1. Hypertrophy –> increased cell size and therefore organ size.
2. Hyperplasia –> increased cell number and therefore increased organ size.
3. Atrophy –> decrease in cell size/number and decrease in organ size.
4. Metaplasia –> cell types changes in response to stimulus

Question 10

What is hypertrophy?

Question 11

What is hyperplasia?

Question 12

What is atrophy?

Question 13

What is metaplasia?

Question 14

What are injury inducing stimuli?

Answer 14

1. Chemical agents
2. Infectious agents
3. Immunologic reactions
4. Genetic defects
5. Nutritional imbalance
6. Physical agents
7. Aging

Question 15

Explain how chemical agents act as an injury inducing stimulus.

Answer 15

• Poisons = all substances are poisons, the right dose separates a poison from a remedy
• Tobacco
• Alcohol
• Therapeutic and non-therapeutic drugs
• Glucose and salt alter osmotic balance
• O2 (too much)
• Environmental agents (pollution, lead, mercury)

Question 16

Explain how infectious agents act as injury inducing stimuli.

Answer 16

• bacteria, viruses, fungi, parasites.
• prions –> small proteinaceous infectious particles which are resistant to inactivation by most procedures that modify nucleic acids.

Question 17

Explain how immunological reactions act as injury-inducing stimuli.

Answer 17

• Immune imbalance
• Autoimmunity (e.g. rheumatoid arthritis)
• Hypersensitivities
• Graft rejection
• Immune deficiency

Question 18

Explain how genetic defects act as injury-inducing stimuli. Provide an example.

Answer 18

• Congenital malformations (down syndrome).
• Single base mutations –> causing functional deficiency or protein misfolding
• E.g. Tay-Sachs disease- accumulation of gangliosides - mutation in an
  enzyme.

Question 19

Explain how nutritional imbalances act as injury-inducing stimuli. Provide an example.

Answer 19

• Deficiency: malnutrition, vitamins (A and D)
• Excess: obesity, type 2 diabetes, hypertension, hyperglyceridemia
• E.g. Ricketts disease: vitamin D deficiency leading to improper bone
  formation

Question 20

Explain how physical agents act as injury-inducing stimuli. Explain the example of hypoxia.

Answer 20

• Mechanical trauma (abrasion, contusions, lacerations)
• Thermal injury (burns, hyperthermia, hypothermia)
• Electrical injury
• Ionizing radiation
• Atmosphere (pressure)

Hypoxia:
- Oxygen deficiency
- Interferes with aerobic oxidative respiration
- Arises from: pneumonia (inflammation of alveolae)= inadequate oxygenation, blood loss anaemia, carbon monoxide poisoning,
ischemia = loss of blood supply to the tissue

Question 21

Explain how aging acts as an injury inducing stimulus.

Answer 21

• Progressive decline in cellular function and viability.
• Genetic factors and exogenous influences.

Question 22

Define the term adaption.

Answer 22

Response to stress/increased demand that maintains the steady-state of the cell without compromising cellular function.

Question 23

Explain what reversible (sublethal) injury is. Provide an example.

Answer 23

Response to stress/stimuli that temporarily COMPRIMISES cellular function. Not severe enough to cause permanent damage or cell death. If the harmful stimulus is removed or adequately managed, the cells can recover and return to their normal functioning.

An example of reversible injury = is cardiomyocytes.
- Reversible injury may compromise organ function.
- Transient ischemia occurs when there is a temporary reduction in blood flow to the tissue, depriving the myocytes of necessary oxygen and nutrients.
- During the ischemic period, the myocytes may become non-contractile, meaning they temporarily lose their ability to contract effectively.
- Once the blood flow is restored and oxygen supply is normalized, the affected myocytes can regain their contractility.
- This recovery restores the normal function of the heart.

Question 24

Explain what Irreversible injury is.

Answer 24

Response to stress/stimuli that COMPROMISES cellular function to the point that it CANNOT recover.

Question 25

What are the two types of cell death?

Answer 25

1. Apoptosis = programmed cell death by the immune system. It is a controlled process that the cell initiates in response to internal cues or external signals. It is a necessary aspect of development and cellular turnover.
2. Necrosis = cell death caused by TRAUMA –> external factors such as injury, infection, or toxins, leading to the uncontrolled destruction of cell structures.

Question 26

How does apoptosis and necrosis differ?

Answer 26

1. Morphologically:
   - Apoptosis = cells shrink, condense, and their parts are neatly packaged into vesicles called apoptotic bodies. Apoptotic bodies
   are phagocytosed by other cells therefore = preventing inflammation.
   - Necrosis = cells swell, burst, and release their contents into the surrounding tissue therefore = cause inflammation.
2. Roles in disease:
   - Apoptosis = plays critical roles in both normal physiological processes (e.g. embryonic development and immune function) and disease (e.g. cancer, where its dysregulation can lead to uncontrolled cell growth).
   - Necrosis = is associated with diseases where damage and inflammation are prevalent. e.g. heart attacks (myocardial infarction) and strokes.

Question 27

When does injury cause irreversible damage to cells?

Answer 27

Occurs when the extent, type or duration of the stress or injury surpasses the cell’s ability to adapt and recover.

Question 28

What two factors can irreversibility be influenced by?

Answer 28

1. Cell-related factors (factors intrinsic to the cell):
   - Genetics –> variations in the cytochrome P450 enzymes, can affect how cells respond to toxins, potentially making some cells more susceptible to damage.
   - Adaptability –> cells’ ability to adapt to stress through mechanisms like upregulating stress responses or repair pathways influences their survival.
   - Cell types –> different types of cells have varying tolerances to ischemia (oxygen deprivation). Skeletal muscle cells can withstand 2-3 hours of ischemia, cardiac muscle cells around 20-30 minutes, and neurons only 3-5 minutes.
   - State –> metabolic state of the cell, such as its glycogen stores, can affect its ability to undergo anaerobic glycolysis and survive during periods of low oxygen.
2. Injury-related factors (nature of the injury itself):
   - Type of injury –> chemical, physical, or biological = all have diff effects.
   - Duration –> longer exposure time = increases likelihood of irreversible damage.
   - Severity –> more severe injuries = overwhelm defensive/repair systems.
   - Exposure –> short, low dose VS long, high dose to toxins or hypoxia.

Question 29

Define the role of morphology.

Answer 29

The study of the structure, shape, and appearance of cells and tissues to assess their health, function, and response to various conditions including disease and injury.

Question 30

Morphology: Observation and Diagnosis.

Answer 30

• Allows scientists and medical professionals to observe and diagnose diseases/damage in cells and tissues.
• By examining the gross/microscopic appearance of cells and tissues = pathologists can infer the physiological and pathological conditions affecting the tissues.

Question 31

Morphology: Staining Techniques.

Answer 31

• Most cells = are naturally transparent.
• Staining procedures make cells visible under a microscope.
• Haematoxylin and eosin (H&E) staining:
• Haematoxylin stains acidic or basophilic structures, including nucleic acids, giving the nucleus a purplish-blue colour. Eosin stains basic or acidophilic structures, such as most proteins, pink or red, enhancing contrast and detail in cytoplasmic components.

Question 32

MORE MORPHOLOGY ….

Question 33

Irreversible injury….

Question 34

Explain the process/mechanism of Injury.

Answer 34

1. reduction in the conc of O2 to the mitochondria (hypoxia).
2. decreased ATP production –> bc mitochondria require O2 to produce ATP efficiently, therefore, decreased O2 = decreased ATP production. ATP = essential for the synthetic (building up) and degradative (breakdown) metabolic processes.
3. damage to mitochondria –> ongoing hypoxia and reduced ATP production = stress mitochondria and lead to structural and functional damage. Damaged mitochondria = less efficient at producing ATP (EXACERBATING ENERGY CRISIS WITHIN CELLS).
4. Influx of Ca^2+ –> Ca2+ levels = tightly regulated bc Ca2+ ions play a crucial role in activating various cellular enzymes. Disruptions in energy production = impair the cell’s ability to regulate Ca2+ –> leads to an influx. High intracellular Ca2+ levels = activate enzymes that DEGRADE cellular components (further damaging the cell!!).
5. Accumulation of reactive oxygen species (ROS) –> ROS = by products of normal cellular metabolism (mostly aerobic respiration). Under normal conditions = cells have mechanisms to scavenge these molecules and prevent DAMAGE. HOWEVER, in stressed/damage = increased ROS = overwhelm these mechanisms –> leading to oxidative stress and damage to macromolecules (e.g. lipids, proteins, nucleic acids).
6. Membrane damage –> accumulation of ROS (and other stressors like high Ca2+ levels) = damage to various cellular membranes - including mitochondrial membrane, plasma membrane, and lysosomal membranes. DAMAGE = impairs func and integrity of these membranes, disrupting cellular homeostasis and leading to cell death if severe.
7. DNA and Protein Damage –> damaged membranes and oxidative stress = lead to direct damage of DNA and proteins. When DNA and proteins = damaged beyond repair –> triggers programmed cell death mechanisms (apoptosis)/lead to necrotic cell death if the damage is extensive/sudden.

Question 35

Explain the mechanism of injury and why cells become inflamed (briefly).

Answer 35

Mechanism of injury involving the retention of H2O = typically relates to disruptions in ATP-dependent ion channels.
- ATP-dependent Ion Channels = use ATP to actively transport ions (e.g. Sodium and Potassium) across the cell membrane. This maintains osmotic balance and cellular volume. REDUCTION IN ATP DUE TO DAMAGE = malfunctioning of these ion channels - therefore, results in the inability to properly regulate ion gradients across the cell membrane.
- Water retention = occurs because of ion pump failure. Sodium accumulates in the cell, therefore, water travels down the concentration gradient to try and balance, therefore leads to cell swelling/bursting.
- Ca2+ ion homeostasis = in normal cells, Ca2+ play NB role in numerous cellular processes: signalling, muscle contraction, and enzyme activity. Proper regulation of Ca2+ levels w/in cells = essential for cellular health and function. DISRUPTION = seen when cell injury affects Ca2+ channels or pumps - lead to an overload of Ca2+ in cells. Overload of Ca2+ = activate destructive enzymes –> further damaging cellular structures and exacerbating cell injury. NOTE: excessive Ca2+ interferes with with ETC (which is crucial with ATP production). When ETC effected by Ca2+ interference - therefore it begins to leak e- –> leaked e- can react with oxygen to form ROS.

Question 36

Explain the process of ischemia.

Answer 36

1. Reduced Oxygen/Nutrients to the mitochondria cause damage. Additionally, toxins (e.g. cyanide) inhibit the ETC.
2. Decreased ATP production bc of mitochondrial damage - ATP = critical fro numerous cell funcs including energy for active transport mechanisms.
3. Ion channel dysfunction = ATP-dependent ion channels fail without sufficient ATP - disrupting the ion balance across the cell membrane.
4. Ion imbalance = Ca2+ and Na+ accumulate inside the cell, while K+ exits the cell. This solute imbalance attracts water into the cell osmotically.
5. Cell and ER swelling = influx of H2O causes cell and the ER to swell. This can lead to the membrane ‘blebbing’/forming blisters.
6. Anaerobic glycolysis = in response to hypoxia, hepatocytes increase anaerobic glycolysis –> leading to rapid glycogen depletion and lactic acid build up.
7. Acidic intracellular Environment - accumulation of lactic acid lowers the intracellular pH, one of the 1st morphological changes visible under a microscope as nuclear chromatin clumping (???).
8. Protein synthesis disruption = lower pH and cell stress = leads to ribosomes detaching from the rough ER - THEREFORE, reducing protein synthesis, and potentially leading to further blebbing.

Question 37

What does damage to the mitochondria cause?

Answer 37

Disrupt cellular function in several critical ways.
1. Opening of the mitochondrial permeability transition pore (MPTP) –> allows solutes to move freely across the mitochondrial membrane (disrupting mito membrane potential and impairing the mitochondria’s ability to generate ATP).
2. Decreased efficiency of aerobic respiration –> reduces ATP production and also lead to increased production of ROS. ROS = damaging to cellular components and can exacerbate mito damage.
3. Release of cytochrome C from the inner membrane space into the cytoplasm can occur if mito damaged. Once in cytoplasm, CC-C = activate pathways that lead to apoptosis/programmed cell death.

Question 38

Explain why the influx of Calcium Ions is a bad thing.

Answer 38

• Ca2+ = deliberately kept low inside of the cell.
• This is maintained using ATP-dependent transport (channels, pumps, etc).
• Ca2+ = can activate phospholipases, proteases, endonucleases and ATPases.
• As a consequence, when Ca2+ conc increases in the cell –> membrane and nuclear damage occurs.
• Ca2+ can also activate caspases which can induce APOPTOSIS.

Question 39

Explain why the accumulation of ROS is a bad thing.

Answer 39

• ROS = oxygen-derived free radicals (have unpaired e- in outer orbital, unstable, and reactive, and attack nucleic acids, proteins, and lipids).
• ROS = by-product of respiration and produced by phagocytic leukocytes. Removed by scavengers (catalase).
• If cell makes an increased number of ROS/scavengers aren’t working –> ROS increases and cell = under oxidative stress.

EFFECTS OF ROS:
- Peroxidation of lipids (plasma membrane and organelle membranes).
- Oxidative modification of proteins - change the active site of enzymes, change protein structure, or increase proteasomal degradation of damaged proteins.
- Lesions in DNA - causes cross-linking and strand breaks.
All of the above = moving towards membrane damage.

Question 40

Explain what causes and occurs during protein and DNA damage.

Answer 40

• DNA damage can be caused by drugs, radiation, or oxidative stress (ROS)
• Protein damage/misfolding can be caused by inherited mutations and external triggers. Initiates suicide program if it cannot be repaired (apoptosis)

Question 41

What is hypoxia?

Answer 41

• Oxygen deficiency
• Interferes with aerobic oxidative respiration
• Caused by ischemia (loss of blood supply to tissue), pneumonia (inadequate oxygenation), blood loss/anaemia, CO poisoning.

Question 42

Explain what occurs when hypoxia occurs in the heart, and how this can be morphologically represented.

Answer 42

Increased Staining with Eosin (Eosinophilia): In hypoxic conditions, heart cells (cardiomyocytes) undergo protein denaturation and digestion of RNA. Normally, RNA stains blue with hematoxylin due to its basophilic properties, but loss of RNA leads to less blue staining. The denatured proteins stain more intensely with eosin, making the cytoplasm appear more pink—a condition known as eosinophilia.

Reduced Nuclei (Less Haematoxylin Staining): The nuclei may appear less prominent or reduced in number, which can be detected by lighter staining with hematoxylin. This change indicates potential nuclear degradation or damage, common in dying cells.

Oedema (Swelling): Hypoxia can cause fluid accumulation in tissues (oedema), which leads to swelling. In the heart, this results in increased gaps between cardiomyocytes, observable in histological samples.

Inflammatory Cells (Purple Staining): The presence of inflammation in response to tissue injury is marked by the infiltration of inflammatory cells, which are stained purple with hematoxylin. This is a typical response to cellular damage and necrosis.

Intracellular Proteins Leak Through Damaged Cell Membrane: Due to the compromised integrity of the plasma membrane under hypoxic stress, intracellular proteins can leak out of the cardiomyocytes.

Cardiac Specific Enzymes: The leakage of specific cardiac enzymes like the cardiac isoform of creatine kinase (CK-MB) and troponin into the bloodstream is a key marker used clinically to diagnose cardiac injury. These proteins are normally found within the cells, and their presence in blood typically indicates damage to the heart muscle.

Serum Levels Reflect Tissue Injury:
Myocardial Infarction: In cases of myocardial infarction, an irreversible injury, there is significant damage to the cardiac tissue, leading to loss of plasma membrane integrity. This allows cardiac enzymes to enter the bloodstream, where their levels can be measured.
Angina: In contrast, angina is typically considered a reversible injury where the plasma membrane remains intact. However, severe or prolonged angina can stress cardiomyocytes enough to cause mild enzyme leakage, detectable in some cases.

Question 43

What are intracellular accumulations? Why/when do they occur?

Answer 43

Accumulations within cells occur when a cell is unable to metabolize a substance - causing it to accumulate within the cytoplasm, organelles, or nucleus of the cell.

When do they occur?
1. Normal endogenous substance is produced at a normal/increased rate, but the rate of metabolism is inadequate to remove it.
2. Accumulation due to defects in folding, packaging, or degradation, typically due to mutation.
3. Failure to degrade due to enzyme deficiency (mutation).
4. Deposition of exogenous substance.

Question 44

What are the different types of accumulation?

Answer 44

• Water accumulation in cells when the cell membrane permeability is
  increased, or ion pumps fail- Hydropic swelling (pale vacuolated
  cytoplasm)
• Injury to cells involves fat metabolism can lead to accumulation of
  triglycerides- Steatosis or fatty change (accumulation of lipids
  displaces the nucleus)
• The accumulation of cholesterol and cholesterol esters in
  macrophages and smooth muscle cells in the intimal layer of blood
  vessels gives these cells a foamy appearance (foam cells) aggregates
  of foam cells form atherosclerotic plaques
• Exogenous pigments such as carbon found in air pollution are taken
  up by alveolar macrophages- the accumulation of carbon in tissue is
  known as anthracosis
• Endogenous pigments include lipofuscin (polymers of lipids/
  phospholipids/ proteins) a sign of free radical injury and lipid
  peroxidation
• Endogenous pigments include hemosiderin, a major storage form of
  iron that accumulates in tissue when iron is in excess- accumulates as
  golden-brown granules (haemochromatosis)
• Intracellular accumulation of proteins gives a homogenous, glassy
  pink appearance under H&E staining described as hyaline changeaggregation
  of specific proteins is associated with specific diseases
  and called proteinopathies of protein-aggregation diseases