PATHOLOGY- Essentials of general pathology- cell injury and cell death Flashcards
What are the 3 responses to cellular stress
Adaptation
Reversible cell injury
Irreversible cell injury/death
What are some causes of cell injury and death
- Oxygen deprivation/deficiency (hypoxia)
- Physical/environmental
- Chemical agents/toxins/drugs
- Infectious agents
- Immunologic reactions
- Genetic derangements
- Nutritional imbalances
- Ageing
Cellular response to injury depends on what 3 things
Type
Duration
Severity of the insult
What happens when an injurious agent causes cell injury
Simultaneously triggers multiple interconnected mechanisms
Cell injury can result due to which 5 cellular processes being disrupted
- ATP production (via effects on mitochondrial aerobic respiration)
- Mitochondrial integrity (independent of ATP)
- Plasma membrane integrity
- Protein synthesis, folding, degradation and re-folding
- Genetic (DNA) integrity
How many mechanisms is there responsible for cell injury
6
What are the 6 mechanisms of cell injury
- ATP depletion
- Mitochondrial damage
- Increased intra-cellular calcium
- ROS/ free radical damage
- Membrane damage
- DNA damage and protein mis-folding
What 3 energy dependent functions is ATP required for
- Membrane transport
- Maintenance of ionic gradients (e.g. Na, K, and Ca2+)
- Protein, DNA & RNA synthesis
What does the efficient production of ATP require
Oxygen
ATP depletion can occur due to what 2 things
Hypoxia/toxins
Mitochondrial damage
What % reduction in ATP levels can cause critical cellular damage
5%-10%
What negative affect does ATP depletion have on pumps, what does this lead to?
Failure of Na* / K+ ATPase pumps
Failure of ionic gradients
What affect can ATP depletion have on Na
- failure of Na+/K+ ATPase pumps
- failure of ionic gradients (increase influx of Ca++, H2O and Na+ and increased effluent of K+)
-ER swelling, cellular swelling, loss of microvilli
What does hypoxia (insufficient oxygen) cause
Anaerobic respiration
What affect does ATP depletion have on anaerobic glycolysis
- anaerobic glycolysis increases
- glycogen decreases as its converted to lactic acid through glycolysis
- increase is lactic acid causes lower pH
- drop in pH causes acidosis
- results in clumping of nuclear chromatin
What other effects does ATP depletion have
- Enzyme failure
- Disruption of protein synthesis / folding
- Irreversible damage to membranes
- Formation of reactive oxygen species (ROS)
What are the 2 types of damage to the mitochondria
Direct
Indirect
3 examples that cause direct damage to the mitochondria
hypoxia, toxins, radiation
3 examples that cause indirect damage to the mitochondria
Increase in Ca?+ / oxidative stress / phospholipid breakdown
What type of damage to the mitochondria is reversible
Early damage
What is the MPTP
Membrane permeability transition pore
What is created when there is sustained damage to the mitochondria
MPTP
Why is MPTP an issue
- MPTP impairs oxidative phosphorylation which lowers ATP
- Reactive oxygen species formation increases
- leads to multiple cellular abnormalities
- leading to necrosis
What can specific damage of the mitochondria lead to
Leakage of mitochondrial proteins leading to apoptosis
How abundant is cytosolic calcium usually
Normally low
How is increased intra-cellular calcium caused by hypoxia/toxins
- Hypoxia/toxins lead to pump failure
- increase in Ca2+ causes release of Ca2+ from motichondria/ER
- increase in Ca2+ causes increase in membrane permeability, causing further increase in Ca2+
Why is increased calcium harmful to cells
- Increase in Ca2+ activates harmful intracellular enzymes
- ATPases / phospholipases / endonucleases
- Leads to decrease in ATP / cell membrane / DNA damage
What are free radicals
Single unpaired electron
What are reactive oxygen species
oxygen-derived free radical that is highly reactive
How do free radicals come about
How abundant are they
What do cells have to counteract the free radicals
- Normal by-products of cellular respiration (mitochondria)
- Limited amounts, limited life due to reactivity
- Mechanisms to counteract - enzymes e.g. SOD (super oxide dismutase) / anti-oxidants
What can increased pathological ROS production result in
Oxidative stress
What 4 things can cause oxidative stress
- lonising radiation / chemicals
- Ischaemia-reperfusion injury
- Metals (iron / copper) or chemicals (CCI4)
- Nitric oxide - inflammation
What are the cellular effects of free radical damage
Damage cell membrane/ lipids / nucleic acid breaks / protein oxidation & fragmentation
What is common in most forms of cellular injury
Early loss of selective membrane permeability, especially in oxygen deprivation
3 examples of direct damage to the membrane of the cell
Bacterial
Viral
Immune proteins
3 examples of indirect damage to the membrane of the cell
Increase in ca2+
Decrease in ATP
ROS formation
What affect does membrane damage have on cells
Increase permeability
What is lysosomal membrane damage
Intra-cellular lysosomes release digestive enzymes
Leads to auto digestion of the cell
What can DNA damage often lead to
Apoptosis
When there is an excess of misfolded proteins, what is caused
ER stress
What is ER stress
When the protein folding demand is higher than the protein folding capacity
What 2 things can ER stress lead to
Failure of adaptation
Apoptosis
Why is it difficult to assign a dominant mechanism to a specific injury
All mechanisms are generally inter-related
What is a reversible cell injury
Mechanisms that can be offset if insult to cell is mild/transient
What are morphological features of reversible cell injury
Functional / structural alterations occurring in mild and/or early injury that reverse upon removal of the damaging stimulus.
What are the 2 microscopic features of reversible cell injury
cellular swelling
Fatty change
What are the 4 ultra structural features of reversible cell injury
- Plasma membrane blebbing
- Mitochondrial swelling
- ER dilation
- Chromatin clumping
What are the 2 main forms of cell death
Apoptosis
Necrosis
What is the difference between apoptosis and necrosis generally
In apoptosis, cell contents contained and not released
In necrosis, the membrane is broken down and there’s leakage of cell contents into tissues (inflammation)
Difference between cell size in necrosis and apoptosis
Necrosis- increased cell size (cell swollen)
Apoptosis- reduced cell size (cell shrunken)
Difference between nucleus in necrosis and apoptosis
Necrosis- fragmentation
Apoptosis- fragmentation and condensation
Difference between plasma membrane in necrosis and apoptosis
Necrosis- disrupted (spilling of contents)
Apoptosis- intact
Difference between nearby inflammation in necrosis and apoptosis
Necrosis - almost always
Apoptosis - never
Difference between physiological/pathological in necrosis and apoptosis
Necrosis- pathpological
Apoptosis- physiological but may be pathological
What is coagulative necrosis
necrosis in tissue with connective tissue
Connective tissue allows the shape/structure to be preserved
What is colliquative necrosis
Tissue with minimal connective tissue
This causes the tissue to liquify
What is caseous necrosis
‘Cheese’-like necrotic debris held within a defined border
What is gangrene necrosis
Coagulative necrosis of a limb (dry)
With infection (wet)
What is fat necrosis
focal necrosis in fat due to action of lipases (also trauma)
What is fibrinoid necrosis
what does it cause
Occurs when there is damage to blood vessel walls
Causes pink material to be deposited in the vessel walls (fibrin-like)
What is apoptosis
Programmed cell death (cellular suicide)
3 features of apoptosis
Tightly regulated
Removed unwanted cells without damaging surrounding tissues
Can be physiological or pathological
Physiological examples of apoptosis
-embryogenesis
-involution of hormone-dependent tissues
-control cell turnover in proliferating cells populations
-elimination of potentially harmful self-reactive lymphocytes
-death of host cells after immune response
What is embryogenesis
Removal of unwanted/excessive cells during development
What is involution of hormone-dependent tissues
apoptosis on hormone withdrawal
Pathological examples of apoptosis
- DNA damage
- Accumulation of misfolded proteins
- Infections
- Pathological atrophy
Why is apoptosis important in DNA damage
- Radiation / drugs, direct or indirect via free radicals
- Important as prevents propagation of cells with DNA damage resulting in carcinogens
What are the 2 main pathways for apoptosis
Mitochondrial (intrinsic) pathway
Death receptor (extrinsic) pathway
What happens in the mitochondrial (intrinsic) pathway
- Loss of survival signals, DNA damage etc.
- Leakage of pro-apoptotic proteins (mitochondria)
- Activates caspases
What happens in the death receptor (extrinsic) pathway
- Binding of ligand to a cell surface receptor
- Activates caspases
What is common in both the pathways of apoptosis?
What does this lead to?
Caspase activation
Fragmentation of DNA / nuclei
Formation of “Apoptotic body” - cell fragments for phagocyte absorption
6 morphological features of apoptosis
- Cell shrinkage
- Chromatin condensation
- Cytoplasmic blebs
- Apopototic bodies (AB)
- Phagocytosis of Abs
- No surrounding damage
What the main differences between necrosis and apoptosis
Necrosis
- increased cell size
- nucleus pyknosis (going), karyohexis (going), karyolysis (gone)
-plasma membrane distrupted (spilling of contents)
- almost always has nearby inflammation
-pathological
Apoptosis
- reduced cell size
- nucleus fragmentation/condensation
-plasma membrane intact
- never has nearby inflammation
- physiological but may be pathological
How does cell death lead to clinical diagnosis in myocardial infarction
Necrosis occurs
Myocardial enzymes released into blood
Troponin detected in blood
How does cell death lead to clinical diagnosis in pancreatitis
-Necrosis occurs
-Pancreatic enzymes released into blood
-Amylase increases which can be detected
-Lipase increases leading to fat necrosis, this leads to saponification and Ca2+ in the blood decreases
How can apoptosis directly help with clinical diagnosis
Can be seen microscopically in specific conditions e.g liver disease/GVHD
What is cellular adaption
Reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment
What is hypertrophy
An increase in the size of cells resulting in an increase of organ size
- No new cells, just larger
- Synthesis of more structural components of the cells
An example of hypertrophy being physiological
bodybuilding
- increases muscle fibre size
- results of increasing load stress
An example of pathological hypertrophy
Cardiac hypertrophy
Increase in myocyte size
Result of circulatory stress and hypertension
What is hyperplasia
An increase in the number of cells in an organ or tissue usually resulting in increased mass of the organ or tissue
- Usually in response to hormones / growth factors in tissues with dividing cells
Example of physiological hyperplasia
Hormonal (e.g. breast in pregnancy)
Example of pathological hyperplasia
Benign prostatic hyperplasia
Although hyperplasia is not the same as neoplasia, what can happen
give example
Neoplastic change can occur in hyperplastic tissues
E.g. endometrial hyperplasia
What is atrophy
Reduced size of an organ or tissue resulting from a decrease in cell size and number
Example of physiological atrophy
- embryology, postpartum uterus
Examples of pathological atrophy
- Decreased workload
- Denervation
- Diminished blood supply
- Inadequate nutrition
- Loss of endocrine stimulation
- Pressure
What is metaplasia
Change in which one differentiated cell type is replaced by another cell type
- Adaptive substitution of cells that are sensitive to stress by cell types better able to withstand adverse environment (usually inflammatory)
Examples of metaplasia
- Oesophagus
Acid reflux -> squamous cells -> gastric-like columnar epithelium (Barrett’s) - Lungs
Cigarette smoke -> respiratory-type columnar cells -> squamous cells - Cervix
Vaginal pH decreases -> columnar cells (endocervix) -> squamous cells (ectocervix)
