Cell Degeneration, Injury and Death Flashcards
What is Atrophy?
Decrease in size/number of cells after the end of normal development.
What is involution?
Give three examples.
Physiological Atrophy
- The uterus after parturition
- Thymus after puberty
- Senile atrophy
Give examples of pathological atrophy.
- Disuse atrophy
- Nerve damage
- Decreased perfusion
- Pressure atrophy
- Loss of endocrine stimuli
- Senile
What is this? It is an example of which degenerative cell process?
Hydrocephalus.
Pressure atrophy.
What is this? It is an example of which cell degenerative process?
Hydronephrosis.
Pressure atrophy
Neutering an animal can cause atrophy of which organ? Why?
The prostate gland, due to a loss of endocrine stimuli.
What is this histological feature called? Explain its presence.
Found in atrophic cells, filled with small degenerating organelles.
An increase in size of a cell/organ.
What causes this?
Hypertrophy
Increased functional demand on the cell.
Give examples of pathological and physiological hypertrophy.
Pathological - Genetic, Obstruction, pressure overload, tumour
Physiological - Muscle training, pregnant uterus
Name this gross pathological feature.
Right ventricular hypertrophic myopathy. Caused by haemodynamic overload.
Name this gross pathological feature.
Explain.
Adenocarcinoma obstructing the small intestine. Obstruction increases force of peristalsis contraction leading to hypertrophy.
Name this gross pathological feature.
Explain.
Severe diffuse hypertrophy (X-linked dystrophin deficiency), caused by congenital deficiency of dystrophin.
Altered number of cells.
______Plasia
Outline two examples of physiological hyperplasia.
- Hormonal hyperplasia
- mammary epithelium during pregnancy
- uterine epithelium during pregnancy
- Compensatory hyperplasia
- Partial loss of parenchyma (eg. partial hepatectomy)
- Symmetrical organs, with functional loss of one organ (eg. kidneys)
Explain this gross pathological feature.
Unilateral hypo/aplasia of one kidney with contralateral hyperplasia of the other.
If one kidney is absent or not fully developed, the controlateral one is required to work more it therefore increases its dimension by the means of increasing number of functional cell.
Give examples of pathological hyperplasia and briefly explain each.
- Excessive hormonal stimulation or growth factors
- Cystic endometrial hyperplasia (dog)
- Proud flesh
- Regeneration
- Nodular hyperplasia with age
- Viral
- Papilloma
Which organs can be see in this image?
What can cause this?
Parathyroid and thyroid gland (hyperplasia)
Caused by chronic renal failure and abnormal calcium handling.
What organ can be seen in this image?
Name the gross pathological feature seen.
Pancreas
Nodular hyperplasia which occurs in old age.
Metaplasia
Exchange of one adult cell type with another adult cell type.
True or False.
Metaplasia is an example of a reversible cellular change.
True.
Once the cellular stimuli is removed the original cell type will return.
Give an example of a tissue which can undergo metaplasia and name two causes.
The respiratory tract, replacement of respiratory epithelium by squamous epithelium due to chronic irritation or vitamin A deficiency.
Name and give example of the three categories of intracellular accumulations.
- Normal cellular constituents - water, lipid, protein, carbohydrates
- Abnormal substance
- Exogenous: mineral, products of infectious agents
- Endogenous: due to abnormal synthesis/ metabolism
- Pigment
Steatosis. State causes.
Intracellular accumulation of triglycerides.
Causes:
- Toxic injury
- Dibetes mellitus
- Hypoxia
- Elevated fat intake
Describe this pathological histology feature.
Steatosis. Large white vacuoles can be seen within cells, these contained triglycerides before processing.
Describe this gross pathological feature.
Severe diffuse lipidosis of the liver. The tissue would also be greasy to the touch.
Which stain can be used to identify lipidosis in cells?
Oil-red O
What can cause abnormal protein accumulation within cells?
- Protein folding disorders - prions, genetic, age, amyloidosis
- Excess protein presented to cells - glomerular damage
- Excess protein synthesis - Russell bodies
Name this histological feature. Describe its aetiology.
Hyaline droplets in the kidney tubules. These are caused by poor protein filtration in the glomerulus leading to proteinuria. Since a higher concentration of protein is presented to tubule cells glassy vaculoes filled with protein appear in the cell cytoplasm.
Name this hitological feature.
Hyaline droplets (also may have a glassy appearance). Appear eosinophilic (red)
Outline the pathogenesis of protein storage disorders. Hint - prions
Which type of abnormal proteins cause these protein folding disorders?
- Alzheimer`s disease
- Pancreatic islet amyloidosis
- Reactive amyloidosis
- Transmissible spongiform encephalopathies
- Alzheimer`s disease - amyloid-b
- Pancreatic islet amyloidosis - amylin
- Reactive amyloidosis - serum amyloid-A
- Transmissible spongiform encephalopathies - PrP
What can cause abnormal accumulation of glycogen within the cell?
- Hyperglycemia - DM
- Glycogen storage disease
- Drug/steroid overuse
Name and describe this histological feature.
Glycogen accumulation. Cloudy vacuoles found within cell cytoplasm.
Anthracosis
Abnormal build up of carbon compounds within cells.
What is shown in this histological slide?
Build up of lipofuscin within cells.
Name and describe two endogenous pigments which can accumulate within cells.
- Lipofuscin
- insoluble
- yellow-brown
- Melanin
- brown-black, in melanocytes
- non-haemoglobin-derived
- Haemosiderin
- haemoglobin-derived, gold yellow to brown
- storage form of iron
- Bile pigments - biliverdin and bilirubin
Which type of stain is used to identify haemosiderin within cells?
Perl’s stain
What are the products of haemoglobin breakdown?
- Haem -> Haemosiderin
- Biliverdin -> Bilirubin -> conjugation with glucoronic acid
How is haemorrhage resolved? What feature does this result in?
Macrophage - dependant phagocytosis of extravasated erythrocytes.
A bruise forms - goes through multiple colour changes before resolving.
Name this pathological finding. What is it caused by?
Jaundice, caused by high levels of bilirubin within the blood.
What componants make up bile?
a) water
b) cholesterol
c) bile salts
Na and K salts of bile acids
d) bile pigments (bilirubin) from haemoglobin
globin = re-useable protein
haem = broken down into iron and bilirubin
Name and describe this pathological feature.
Dystrophic calcification
Depositation of calcium in non-viable or dying tissues despite normal serum calcium
What occurs in i) initiation and ii) propagation of dystrophic calcification?
- Initiation
- Intracellular: Ca2+ accumulates in mitochondria of dying cells
- Extracellular: Inititated by phospholipids in membrane-bound vesicles of dying cells
- Propagation
- Ca2+ binds membrane phospholipids and form groups in membranes. This leads to Ca deposits near membrane which form microcrystals and perforate the cell membrane.
What type of calcification is shown in this image?
In what pathological state would this occur?
This image shows metastatic calcification which occurs in normal tissues with hypercalcaemia.
Hypercalcaemia can occur with:
- Increased PTH
- Bones catabolism
- Vit D excess
- Renal failure (secondary hyperthyroidism)
What does this histo slide show?
Metastatic calcification of the gastric wall
Where in tissue would you find amyloid deposits?
Between cells
What is amyloid?
What is it made up of?
Pathological proteinaceous substance
Name amyloid as its reaction with Lugol’s iodine is “starch like”
- 95% Fibril protein
- 5% P component and other glycoproteins
What pathological accumulation is shown in this image?
Glomerular amyloidosis
Describe the four components of Amyloid.
- AA (amyloid-associated):
- synthesised in liver [hepatocytes]
- AL (amyloid light chain):
- derived from plasma cells, contains Ig light chains
- with monoclonal B cell proliferation
- b-amyloid protein:
- deposited in spongiform encephalopathies
- islet amyloid polypeptide [IAPP; amylin]
- deposited in pancreatic islets
Which Amyloid molecule is indicative of chronic inflammation?
AA or AL
AA
AL is found in myeloma tumours in humans.
This amyloid protein is deposited in spongiform encephalopathies.
Name a condition in which this occurs.
Beta-amyloid protein
Alzheimer’s
What six terms are used to classify amyloidosis?
Briefly describe each.
- Sytemic - In several organs
- Localised
- Primary - due to immunocytic disorders
- Secondary - a complication of chronic inflammation
- Hereditary
- Endocrine - eg islet amyloidosis
“Programmed cell death”
Apoptosis
Outline the morphological features of apoptosis.
- Cell Shrinkage
- Chromatin condenses
- Membrane blebbing
- Nuclear collapse
- Apoptotic bodies form
- AB’s lysed or phagocytosed
What molecules stimulate the intrinsic and extrinsic pathways of Apoptosis?
Intrinsic - Growth factors or hormones
Extrinsic - FAS or TNF
What are the biochemical features of the Apoptosis pathway?
- Protein cleavage
- Protein cross-linking
- DNA breakdown
- Phagocytosis recognition
What is the common molecular goal of the intrinsic and extrinsic pathways of Apoptosis?
What phase does this molecule stimulate and what occurs?
Caspase 3
Caspase 3 begins the execution phase in which endonuclease destroys DNA, the cytoskeleton is cleaved and mitochondria breakdown.
Apoptosis occurs without inflammation.
True or False
True Apoptotic bodies are phagocytosed unlike in necrosis when cells are lysed and leak intracellular substances into surrounding tissues.
Outline examples of Apoptosis.
- Uterine involution
- Embryogenesis
- cell turnover
- atrophy
- Tc cell induced
- virus clearance
This molecule is expressed by apoptotic bodies and signals their phagocytosis.
Phosphotidylserine
Absence of growth factors stimulate the intrinsic pathway. What series of events does this stimulate which lead to the production of caspse 3.
Removal of GF/H causes cytochrom c release from mitochondria, this causes the release of casepase 9, triggering the caspase cascade.
TNF or FAS trigger which events leading to the generation of caspase 3 for Apoptosis?
FAS or TNF trigger adapter proteins which signal the release of caspase 8 leading to the generation of caspase 9.
“Irreversible exogenous injury”
Necrosis
Pyknosis
Nuclear shrinkage and chromatin condensation
Karyohexis
Fragmentation of the nucleus
Karyolysis
Nuclear lysis
The six characteristic morphological features of necrosis.
- Cell swelling
- Eosinophilia
- Pyknosis
- Karyohexis
- Karyolysis
- Membrane fragmentation and cell lysis
Which two processes cause necrosis?
- Enzymatic digestion
- Protein denaturation
Two types of enzyme cause cell lysis with necrosis, name them and the type of lysis they stimulate.
- Lysosomal enzymes - autolysis
- Leukocyte enzymes - heterolysis
Caseous Necrosis
- Granular friable mass
- Cheese-like
This slide represents which type of necrosis?
Caseous
Depletion of ATP which occurs with cell injury leads to which biochemical effects?
- Na+/K+ ATPase quits - Na+ & Ca2+ accumulates, water influx and cell swelling and ER dilation. K+ accumulates extracellularly.
- Anaerobic glycolysis, decreased glycogen, lactic acid accumulates, decreased pH and decreased activity of cellular enzymes
- Failure of the Ca2+ pump increased Ca2+ - damages cell
- Structural disruption of the protein synthetic apparatus leading to decreased protein synthesis
Describe the pathological condition seen in this image.
What type of stain has been used?
Glomerular amyloidosis
Lugol’s iodine
What is meant by “cell injury”?
Reversible and irreversible?
When the limits of adaptive capability are exceeded or when adaptation is not possible.
Irreversible - Persistent or severe stimuli where the cell reaches the point of no return
Which intracellular systems are vunerable to cell injury?
- Cell membranes
- Aerobic apparatus
- Protein synthesis
- Genetic apparatus
Differenciate between reversible and irreversible cell injury.
Irreversible cell damage occurs with persistent or severe stimuli, cells go past the “point of no return” and undergo cell death.
What are the five biochemical methods of cell injury?
- ATP depletion
- Mitochondrial damage
- Membrane damage
- Altered calcium homeostasis
- Oxygen free radical damage (oxidative stress)
Outline the mechanism of ischemic cell injury.
Reduced O2 delivered to the cell, decreased intracellular O2 tension, this lead to reduced oxidative phosphorylation within mitochondria.
This leads to a number of
What are the consequences of ischemia/ hypoxia?
- Decreased sodium pump activity - Na+, H2O and Ca2+ influx, K+ efflux
- Decreased microvilli
- Cells swells
- Membrane blebbing
- Increased anaerobic glycolysis - decreased glycogen stores and pH
- Protein sysnthesis disrupted - Ribosomes detached, decreased protein synthesis
- Lipid depositation
Describe the characteristic features of irreversible ischemic damage.
- Lysosomal swelling
- Mitochondrial vacuoles and calcification
- Ca2+ influx on reperfusion
- Plasma membrane damage
- Lipid products act as detergents
- Free radical damage
- Cytoskeletal abnormalities
- PLA activated - loss of phospholipids
What are the consequences of reperfusion injury?
Free radical production and release of cytokines and adhesion molecules from hypoxic cells which leads to inflammation.
Define Free Radical.
An extremely unstable, highly reactive chemical species with a single unpaired electron in its outer orbit.
Name three free radical species and three potential sources.
OH*, H*, O2*-
- Ionised radiation
- Redox reactions
- Exogenous chemicals
What happens in free radical mediated cell injury?
- DNA lesions as FRs react with thymine causing single strand breaks
- Lipid peroxidation - FR attack double bonds of unsaturated FA’s
- Enzymic degradation of protein cross-links
Name three antioxidants.
Vitamin A,E and K
What two ways can chemicals work to cause cell damage?
- Direct binding to molecules in cell - eg mercuride, cyanide, anti-neoplastic drugs
- Metabolite causes problem - CCl4
Which enzymes are activated with loss of calcium homeostasis?
What effect do these enzymes have on the cell?
- ATPase - decreased ATP
- Protease - disrupts membrane and cytoskeleton
- Phospholipase - decreased phospholipids
- Endonuclease - nuclear chromatin damage
Membrane damage can result from which mediators of cell injury?
- decreased O2 - decreased membrane molecule synthesis
- increased Ca2+ - increased enzyme activity
Coagulative Necrosis
Morphology.
- Pale pink cells - denatured proteins
- Cell Outline still present
- Hypoxic cell death - Infarcts
- Eosinophilic cytoplasm
- Damaged/ dense clumping nucleus
Liquifactive Necrosis
Morphology
- Enzymatic Digestion
- Complete loss of cellular architecture
- Focal bacterial/fungal infection
- PMNs seen = PUS
Caseous Necrosis
Morphology
- Combination of coagulative and liquifactive
- Obliteration of architecture surrounded by inflammatory cells
Fat Necrosis
- Focal destruction of adipose tissue
- Chalky white gross appearance
- Cytoplasm is pink mass of amorphous tissue
- Loss of peripheral nuclei
Pyknosis
Shrinking and condensing of cell nuclei
Karyohexis
Nuclear Fragmentation
Karyolysis
Lysis of the nucleus
Describe the morphological changes undergone by a dying cell.
- Cell swelling and eosinophilia
- Nuclear changes - Pyknosis, Karyohexis, Karyolysis
- Membrane fragmentation and lysis - Enzyme digestion or protein denaturation
Describe the morphology of apoptosis.
Cell shrinks, chromatin condenses, membrane blebbing, nuclear collapse, apoptotic bodies form, cell lyses and is phagocytosed.
What biochemical changes occur during apoptosis?
- Protein cleavage
- Protein cross links
- DNA breakdown & nuclear collapse
- Phygocytic recognition
Describe the intrinsic and extrinsic causes of the caspase cascade.
- Intrinsic - growth factor/ growth hormone stimulated
- Cytochrome C released from mitochondria
- Causes caspase 9 release
- Extrinsic - FAS/ TNF stimulated
- Adapter proteins cause the release of caspase 8
What is the common molecular goal of the caspase cascade?
Caspase 3
Caspase three stimulates which processes/ molecules of apoptosis?
- Exectution
- Mitochondrial breakdown
- Endonuclease
- Cytoskeleton cleavage
- This further leads to Phosphotidylserine expression by apoptotic bodies which causes phagocytosis
