Session 1 Flashcards
1
Q
What does Diagnostic Pathology involve and why is it important?
A
- Studying the structural and functioal alterations in cells and tissues e.g. by microscopy, in order to arrive at a diagnosis
- The MORPHOLOGICAL changes in cell and tissues and their distribution within an organ results in the symptoms and signs of disease
- All disease starts with molecular or structural alterations in cels
2
Q
How can Disease be Considered?
A
- As a conseqence of failed homeostasis with consequent morphological and function disturbances
- Cells are to maintain homeostasis when subjeced to MILD changsin environmental conditions. BUT when changes are more SEVERE cells undergo physiological and miorphological adaptations in an attempt to remain viable.
- When cells reach the limits of their adaptive response, they may show evidence of reversible or irreversible injury and death.
- The degree of injury depends on the type, duration and severity of an injury and the type of tissue involve.
3
Q
List the Various Causes of Cell Injury and Death
A
- Hypoxia
- Physical agents e.g. direct trauma, extremes of temperature (burns and severe cold), sudden changes in atmospheric pressure, electric currents and radiation
- Chemical agents and drugs e.g. glucose or salt in hypertonic solutions, oxygen in high concentrations, poisons, insecticides, herbicides, asbestos, alcohol and illicit drugs, therapeutic drugs
- Micro-organisms e.g. viruses, bacteria, fungi, parasites
- Immune mechanisms: hypersensitivity and autoimmune reactions
- Dietary insufficiencies and deficiencies and dietary excess
- Genetic abormalities e.g. inborn errors of metabolism.
4
Q
Explain about Hypoxia
A
- Oxygen deprivation results in decreased aerobic oxidative respiration which if persistent will cause cell adaptation (e.g. atrophy), cell injury or cell death.
- The length of time a cell can tolerate hypoxia varies: neurones can only tolerate a few minutes while dermal fibroblasts can tolerate a number of hours.
5
Q
What are the causes of hypoxia?
A
- Hypoaxaemic: arterial content of oxygen is low e.g. reduced inspired pO2 at altitude
- Anaemic: decreased ability of haemoglobin to carry oxygen e.g. anaemia, carbon monoxide poisoning
- Ischaemic: interruption to blood supply e.g. blockage of a vessel, heart failure
- Histiocytic: inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzyme (cyanide poisoning)
6
Q
What is Ischaemia?
A
- Loss of blood supply due to reduced arterial supply eg. obstruction of an artery, hypotension, OR reduced venous drainage
- This causes a reduced supply of oxygen and metabolic substrates e.g. glucose for glycolyis and the resultant injury therefore occurs more rapidly and is more severe than that seen with hypoxia.
7
Q
Explain how immune mechnisms can cause injury
A
Principally by two mechanisms:
- Hypersensitivity reactions: the host tissue is injured secondary to an overly vigorous immune reaction e.g. urticaria (hives)
- Autoimmune reactin: immune system fails to distinguish self from non-self e.g. Grave’s
8
Q
What are the principal targets of cell injury?
A
- Cell membrane: the plasma membrane plays a vital role in homeostasis and the organellar membranes whch compartmentalise organelles such as Lysosomes (particularly important as they contain enzymes which cause cell damage)
- Nucleus (contains genetic material of the cell)
- Proteins (structural proteins forming the cytoskeleton and the enzymes involved in the metabolic processes of the cell)
- Mitochondra where oxidative phosphorylation and production of ATP occurs.
9
Q
Describe Reversible Hypoxic Injury
A
- Oxygen deprivation leads to decreased production of ATP in mitochonria. When the levels of ATP drop to less than 5-10% of normal concentrations, vital cellular functions become compromised.
- Loss of activity of the Sodium Pump (ATP-dependent). As the intracellular concentrations of Na+ rises, water enters the cell and the cell and its organelles swell up. Ca2+ also enters causing damage to cell components.
- The cell switches to the glycolytic pathway of ATP prodution leading to accumulation of lactic acid, lowering the pH inside the cell. Low pH affects the activity of many enzymes within the cell. Chromtin clumping occurs.
- Ribosomes detach from the ER and protein synthesis is disrupted. This can result in intracellular accumulations of substances such as fat and denatured proteins.
10
Q
What does Irreversible Hypoxic Injury mean and when does it occur?
A
- Not well understood but at some point, injury becomes irreversile and cell eventually dies
- Usually appers as necrosis
- Develomentof profound disturbances in membrane integrity and the associated massive cytosolc accumulation of Ca2+ is a key even
11
Q
What happens when Ca2+ enters the cell across the damaged plasma membrane and is released from intracellular stores in severely damaged cells?
A
Activate an array of potent enzymes:
- ATPases (decrease [ATP} even further)
- Phospholipases (causes further embrane damage)
- Proteases (break down membranes and cytoskeletal proteins)
- Endonucleases (damage DNA)
When Ca2+ enters cells whose membranes are irreversibly damaged, intracellular substances leak into the circulation. These can be detected in blood samples and particular substances can be indicative of location of cellular damage e.g if liver cells are injured, transminases will be detected in the blood.
12
Q
What happens when lysosomal membranesare damaged?
A
Lysosomal hydrolases leak into the cytoplasm further damaging the cell
13
Q
Describe an Ischaemia-Reperfusion Injury
A
- This is when blood is returned to a tissue which has been subject to ischaemia but isn’t yet necrotic.
- Sometimes the injury that is then sustained is worse than if blood flow was not restored
- This may be due to:
- increased production of oxgen free radicals with reoxygenation
- Increased number of neutrophils following reinstatement of blood suppy resulting in more inflammation and increased tissue injury
- Delivery of complement proteins and activation of the complement pathway
14
Q
What are free radicals and how can they cause cell damage?
A
- Single unpaired electron (unstable configuration) so they react with other molecules, often producing further free radicals (autocatalytc chain reaction)
- Produced particularly in chemical and radiation injury, ischaemia-reperfusion injury, cellular aging and at high oxygen concentrations.
- They attack lipids in membranes and cause lipid peroxidation.
- They aso damage proteins, carbohydrates and nucleic acids - molecules become bent - deformed, broken or cross-linked.
- Known to be mutagenic
15
Q
What important roles do free radicals have in the body?
A
- Leukocytes produce free radials - used for bacteria killing ‘oxidative burst’
- Also used in cell signalling
16
Q
What are three main radicals and how can they be produced?
A
- Three free radicals: OH● (hydroxyl, most dangerous), O2- (superoxide) and H2O2 (hydrogen peroxide).
- Hydroxyl can be formed in a number of ways
- Radiation can directly lyse water → OH●
- The Fenton and Haber-Weiss reactions produce OH●. NB: H2O2 and O2- are substrates for these reactions which is one reason why it is important to rapidly remove hydrogen peroxide and superoxide so that the more dangerous OH● can’t be generated.
- Generation of H2O2 and O2- occurs in normal metabolic reactions in cytoplasm and mitochondria.
17
Q
What is meant by Oxidative Stress
A
When there is an imbalance between free radical production and free radical scavenging so free radicals accumulate in the cell/tissue causing cell injury.
