Cell Injury and Death Flashcards
What are the principle adaptations to stress?
- Atrophy
- Hypertrophy
- Hyperplasia
- Metaplasia (Conversion)
What is the morphology, function and cause of atrophy?
Morphology:
- Shrinkage of cell size by the loss of substance
- organ shrinkage
- Often in combination with autophagy
Function: Gradually decline in effectiveness due to underuse
Cause: Decreased protein synthesis, increased protein degradation
What is the morphology, function and cause of hypertrophy?
Morphology:
- Increase in cell size beyond what is normal for that cell
- more cellular organelles and cytoplasm
- enlarged organ = hypertrophic organ
Function: Overuse, increased burden cannot be compensated for
Causes:
- Physiologic or pathologic
- Increased functional demand
- Growth factor stimulation
- Hormonal simulation
Examples:
- Working muscles at gym. Muscles increase in size due to hypertrophy. Reversible as muscles can return to normal size when not used
- Enlarged organs
- Most often occurs in cells that cant make more of themselves. Eg. Cardiac muscle, doesn’t produce much of itself.s
What is the morphology, function and cause of hyperplasia?
Morphology:
- Enlargement of an organ or tissue
- Caused by an increase in the reproduction rate of its cells
Causes (Physiologic or Pathologic):
- Increased functional demand
- Development and maturation (bone growth)
- Growth factor stimulation
- Hormonal simulation
- Pathologicalhyperplasia-> significant abnormalities in organisation and cytomorphology
- Hypertrophy and hyperplasia often happen at the same time.
- Cancers undergo hyperplasia
What is the morphology, function and cause of metaplasia (conversion)?
Morphology:
- Adult cell type replaced by another cell type
- New function dependent on cell type
Cause: differentiation of stem cells along a new pathway
Metaplasia is a double edged sword:
- initially beneficial as defence but other properties are lost
- if persistent may predispose to malignant transformation of the epithelium
- Cells cant change into other cell types.
- In early stages metaplasia is reversible
Describe the morphology of cell injury
- All stresses & injuries exert their effects first at the molecular or biochemical level
- Cellular function may be long lost before cell death occurs
Morphologic changes lag far behind both
- Ultrastructural (EM): minutes -> hours
- Light Microscope: hours -> days
What are the types of morphologic changes in cell injury, and when do they occur?
- Biochemical Changes
- Ultrastructural Changes
(minutes -> hours) - Light Micrographic Changes
(hours->days)
What are ultrastructural changes in cell injury?
Ultrastructural Changes:
- Alterations of cell membrane
- Swelling of RER and detachment of ribosomes
- Swelling of, and presence of small phospholipid-rich amorphous deposits in mitochondria
- Nuclear alterations with clumping of chromatin
Viewable under an electron microscope
What are light micrographic changes in cell injury and their causes?
Light Micrograph changes:
- Cell swelling
- Fatty change
Cell Swelling Morphology:
- Increase in cell size by increased fluid
- Often seen as hydropic change = vacuoles fail to stain
- Entire organ can be affected
Cell Swelling Cause:
- Loss of function of cell membrane Na-K pump
- inability to maintain ionic and fluid homeostasis
Fatty change
Morphology:
- Presence of lipid vacuoles in cytoplasm
- Often in cells involved in fat metabolism
- Cell nucleus displaced to periphery of cell
- Injured cells often increased eosinophilic staining
Fatty Change Cause: hypoxic, toxic or metabolic injury
Viewable under a light microscope
Identify morphologic changes of cell injury in this image.
Rat on normal diet (A) and iron deficient diet B
Hint: Electron Microscope image
Ultrastructural changes:
- B: degenerated mitochondria with membrane loss
- Cell changed as wasn’t getting enough oxygen due to iron deficiency to maintain current shape
What are the biomechanical mechanisms (biochemical alterations) of cell injury?
- ATP Depletion
- Damage to Mitochondria
- Loss of Calcium Homeostasis
- Free Radical Formation and Oxidative Stress
- Defects in Membrane Permeability
- Damage to DNA and Proteins
Multiple mechanisms normally contribute to cell injury
Describe ATP Depletion in cell injury
ATP produced by mitochondria
- +O2: oxidative phosphorylation of ADP
- -O2: glycolysis
Causes of ATP depletion:
- Inadequate O2 supply|
- Inadequate nutrient supply
- Mitochondrial damage
- Chemical (toxic) injury
- Ineffective ATP dependant pumps
Describe Damage to Mitochondria in cell injury
Causes of mitochondrial damage:
- Hypoxia
- Toxins
- Radiation
Result:
Abnormal oxidative phosphorylation
- Depletion of ATP
- Formation of reactive oxygen species (ROS)
- Formation of mitochondrial permeability transition pore
- Leakage of mitochondrial proteins in cytosol
Describe Loss of Calcium Homeostasis in cell injury
Ca2+ within cytosol about 10000 x lower than extracellular or Ca2+ within mitochondria or ER controlled by ATP dependant Ca2+ transporters
Ischemia and toxins can lead to increased cytosolic Ca2+
Increased cytosolic Ca2+ activates enzymes
- Membrane damage
- Nuclear damage
Describe free radical formation and how it can lead to cell injury
Free Radical Formation:
Excessive accumulation of highly reactive oxygen -derived free radicals e.g. ROS, NO
- Free radicals have single unpaired electron -> extremely unstable
- Attack nucleic acids, proteins and lipids
A) Superoxide generated by electron transport chain and converted to H2O2and the hydroxyl (-OH) free radical or to peroxynitrite (ONOO−)
B) Phagocyte oxidase enzyme in phagosomes of leukocytes generates superoxide
Describe oxidative stress
- Lipid peroxidation of membranes = oxidative degradation oflipids
- Cross-linking and changes in proteins
- DNA damage
Describe defects in membrane permeability
Causes:
- Ischemia
- Free radicals
- Cytosolic Ca2+
Direct damage to plasma membrane
- microbial toxins
- viral protein
- complement components
- chemicals
Mitochondrial membrane damage
Plasma membrane damage
Lysosome membrane damage
Differentiate Apoptosis form Necrosis
Apoptosis: Programmed Cell Death
- Targeted cause of cellular death
- Pathway that enzymatically degrades DNA and proteins
- Fragmentation of cell into smaller bodies
- Intact plasma membrane
- No inflammatory response
Necrosis: Premature Cell Death
- Caused by external factors, such as infection, toxins, or trauma
- Severe Injury causes cellular stress response
- Cell initially swells
- Loss of cell membrane integrity
- Cell Lysis
- Inflammation of tissue
List and describe the nuclear changes during cell death
What are the morphological characteristics of Apoptosis?
- Cell shrinkage = pyknosis
- Depolymerization of cytoskeleton
- Condensation of nucleus (chromatin condensation, nuclear fragmentation)
- Blebbing of plasma membrane without loss of integrity
- Formation of membrane bound vesicles = apoptotic bodies
- Cellular fragmentation into smaller bodies
For example: Fatty Liver
- Caused e.g. by diabetes, alcoholism
What is phagocytosis and why is it necessary?
- Usually very limited host reaction as dead are cleared quickly
- Prevents further tissue damage by stimulating production of anti-inflammatory cytokines and chemokines
- Recruitment of macrophages for phagocytosis (cells capable of engulfment digest dead cells)
What are the two Apoptotic signal transduction pathways?
- Mitochondrial (Intrinsic) Pathway
- Death Receptor (Extrinsic) Pathway
What is the Caspase cascade for apoptotic cell death?
- Caspases: = Cysteine Aspertate proteases
Describe the Mitochondrial (Intrinsic) Pathway of Apoptotic signal transduction
- Mitochondrial damage and leakage of cytochrome c
- Activation of caspase 9
Describe the Death Receptor (Extrinsic) Pathway of Apoptotic signal transduction
- Activation of transmembrane death receptors (cell mediated)
- Activation of caspase 8
Describe coagulative necrosis and provide examples
- Most common form
- Cell is dead but basic tissue architecture is initially preserved
- Tissues exhibit firm texture
- Leukocytes recruited into area
- Homogeneous, glassy eosinophilic appearance due to loss of cytoplasmic RNA and glycogen - Characteristic of hypoxic death of cells (infarcts) in all solid organs except the brain
- Nucleus may show karyopyknosis, karyolysis or karyorrhexis
Describe liquefactive necrosis and provide examples
- Liquid - fluid
- Loss of organ cellular architecture
- Hallmark = enzymatic breakdown of tissue = complete cell digestion
- In tissues with focal bacterial or fungal infection e.g. renal abscess - Hypoxic death of cells within the CNS evokes liquefactive necrosis
- If initially inflammation creamy yellow = pus
Describe fibrinoid necrosis and provide examples
- Caused by immune reactions
- Complexes of antigens and antibodies deposited in arterial walls
- Fibrin leaks out of vessels
- Complexes react with fibrin and form eosinophilic (bright pink) areas = fibrinoid (e.g. polyadarteritis nodosa)
Describe enzymatic fat necrosis and provide examples
- Focal areas of fat destruction
- Release of activated lipases on fat cells - Often seen in the pancreas
- Usually due to trauma
- Fatty acids released via hydrolysis react with calcium to form chalky white areas -> “fat saponification”
Describe caseuos necrosis and provide examples
- ‘Caseous’ in gross anatomy (white-yellow)
- Loss of organ cellular architecture
- Rim of inflammatory cells = granuloma
- No visible cell outlines – tissue architecture is obliterated - Usually seen in infections
- Encountered most often in foci of tuberculous infection
Describe gangrenous necrosis and provide examples
- Most often seen on extremities
- Most due to lack of blood flow, “ischemic” necrosis or are due to trauma or physical injury
“Dry” gangrene:
- No bacterial superinfection
- Tissue appears dry (“black and dead”)
“Wet” gangrene:
- Bacterial superinfection has occurred
- Tissue looks wet and liquefactive
