Download Cell injury, death and adaptation yemen

Cell injury, death and adaptation
Yemen University
Lectures 1 and 2
Dr Heyam Awad
FRCPath
Coordinator : Dr Heyam Awad
• Email: [email protected]
• Lectures will be available on my university
website www.ju.edu.jo
• Office hours: Monday and Wednesday 10-12 ..
Office in hospital 3rd floor.
Lecture distribution
•
•
•
•
•
•
Cell injury 4+lab
Inflammation 6 +2labs
Repair 3 +lab
Haemodynamic diseases 5+lab
Neoplasia 8 +2 labs
Genetic diseases 8 + 2 labs
EVALUATION
• 1 EXAM
• THEORY AND PRACTICAL.
• mock
What is pathology?
• Patho… disease
• Logy… study
• Pathology = study of disease
involves: causes of disease.. Etiology
: mechanisms.. pathogenesis
:morphological changes.
• Etiology: Origin of disease , underlying
causes.
• Pathogenesis: steps in the development
of disease…… cellular and molecular
changes .
• Morphology: macroscopic and
microscopic changes.
Why to study pathology???
Cellular adaptations and cell injury
• Cells maintain a steady state.. Homeostasis.
• Stresses .. Adaptation….. New homeostatic state
with preservation of function.
• Stress beyond capability of adaptation.. Cell
injury.
• Cell injury… reversible within certain limits
• Then .. Irreversible…. Ends in cell death.
• Two types of cell death: necrosis and apoptosis.
Adaptation
•
•
•
•
Hyertrophy
Hyperplasia
Atrophy
metaplasia
Adaptation
• Adaptive changes are reversible.
• Can be physiologic or pathologic.
• Hypertrophy: Increased cell size.
• Hyperplasia: increased number of cells.. Cell
division.
• Metaplasia: change from one adult cell type
to another
• Atrophy: decreased size.
Hypertrophy versus hyperplasia
Hypertrophy
• Increased cell size.
• Due to increased organelles and proteins.
• Increased intracellular synthesis..
Caused by: increased demands, hormones or
growth factors.
Physiologic hypertrophy
• Uterus during pregnancy… due to estrogen
• Skeletal muscle… due to increased demand
Physiologic hypertrophy
Pathologic hypertrophy
• Cardiac.. Hypertensive heart disease
• Pathogenesis.. Two types of signals:
mechanical: stretch and trophic: growth
factors and androgenic hormones
Pathologic hypertrophy
Pathologic hypertrophy
hyperplasia
• Only in tissues that can replicate.
• Can be physiologic or pathologic.
Physiologic hyperplasia
• Hormonal: uterus, breast.
• Compensatory: after removal or loss of part of
tissue.
Pathologic hyperplasia
• Due to excess in hormones or growth factors.
• E:g endometrial hyperplasia.
• Controlled.. Responds to decreased
stimulation. This differentiates it from cancer
Normal endometrium
Endometrial hyperplasia
atrophy
• Shrinkage in cell size due to loss of cell
substance.
Causes
• decreased work load.
• Loss of innervation
• Loss of endocrine stimulation.
• Aging
Atrophy
• Physiologic: endometrial atrophy during
menopause
• Pathologic: loss of innervation.
atrophy
Mechanisms:
• Decreased protein synthesis.
• Degradation of cellular proteins.
• Autophagy…. Literally means self eating.
Brain atrophy
Muscle atrophy
metaplasia
• Adult cell type replaced by another adult cell
type.
• Arise in reprogrammed stem cells to
differentiate along a new pathway.
Epithelial metaplasia
• Respiratory epithelium to squamous.
• Barrett's mucosa.. Esophegeal squamous to
columnar
Barrett’s mucosa
Normal esophegeal mucosa
Metaplastic, Barrett’s mucosa
Metaplasia in mesenchymal tissue
• Usually pathologic
• Ossification of soft tissue due to injury.
Cell injury
Causes of cell injury/ 1
•
•
•
•
•
•
•
Chemical agents
Infections.
Immunologic
Genetic factors
Nutritional imbalances
Physical agents
Aging.
Causes of cell injury/ 2
Oxygen deprivation.. Hypoxia and ischemia.
Hypoxia= oxygen deficiency
Ischemia = loss of blood supply due to impaired arterial
flow or reduced venous return.
-Ischemia is the most common cause of hypoxia.
-Other causes of hypoxia:
*reduced oxygen carrying capacity in anemia or carbon
monoxide deficiency.
*inadequate oxygenation of the blood as in pnumonia.
Rules and principles/ 1
• Cell response to injurious stimuli depend on
type, duration and severity of the injury.
• Example: low dose of a toxin can cause
reversible injury whereas larger dosed can
cause cell death.
• Short-lived ischemia.. Reversible
• Ischemia of long duration… death
Rules and principles/ 2
• Response to injury also depends on type, status,
adaptability and genetic makeup of the injured
cell.
• Example: skeletal muscle cells can stand 2-3
hours of ischemia without irreversible injury but
cardiac muscles die in 20-30 minutes .
• Glycogen content in hepatocytes can determine
their response to injury.. How?
• Genetic polymorphism in cytochrome P-450
influences response to toxins.
Rules and principles/ 3
Cell injury results from functional and
biochemical changes in essential cellular
components, mainly:
• Mitochondrial function
• Calcium homeostasis
• Cell and organelle membranes
• DNA
• Protein synthesis and folding.
Rules and principles/ 4
• All injurious stimuli first affect the molecular
or biochemical level.
• Cellular functions lost before cell death
occurs.
• The morphologic changes of cell injury (or cell
death) occur very late.
Rules/4 example
• Ischemia of the heart… coronary artery
occlusion.
• Myocardial cells loose function ( become noncontractile) after 1-2 minutes of ischemia.
• They die 20-30 minutes after ischemia.
• It takes 2-3 hours to recognise ultrastructural
changes of death (EM)
• 6-12 hours by light microscope to appear
dead.
Morphology of reversible cell injury
• Cellular swelling : due to failure of energydependent ion pumps in the plasma
membrane causing inability to maintain ion
and fluid homeostasis.
• Fatty change : small or large lipid vacuoles
(hepatocytes and myocardial cells)
Cell swelling
• The first manifestation of almost all forms of
cell injury.
• Reversible.
• Grossly: organ affected becomes pale and
gains weight.
• Micro: small clear cytoplasmic vacuoles …
which are distended endoplasmic reticulum.
Cell swelling
Fatty change
• In cells participating in fat metabolism:
hepatocytes and myocardial cells)
• Reversible
• Fat droplets.
Ultrastructural changes of reversible
injury (EM)
• (1) plasma membrane changes such as blebbing,
blunting or distortion of microvilli, and loosening
of intercellular attachments.
• (2) mitochondrial changes such as swelling and
the appearance of phospholipid-rich amorphous
densities.
• (3) dilation of the ER with detachment of
ribosomes and dissociation of polysomes.
• (4) nuclear alterations, with clumping of
chromatin.
EM changes
Morphology of irreversible injury
Necrosis
• Necrosis = Morphologic changes that follow
cell death in living tissues.
NECROSIS
• Denaturation of intracellular proteins.
• Digestion of cells by lysosomal enzymes of
dying cells ( autolysis) and leukocytes
(heterolysis).
Protein denaturation
denaturation
LM changes
1) Increased cytoplasmic eosinophilia. Cause?
2) Vacoulation of cytoplasm, moth eaten.
Cause?
3) Nuclear changes
4) Calcification
Nuclear changes
one of three patterns
1. karyolysis: decreased chromatin basophilia
secondary to deoxyribonuclease (DNAase)
activity.
2. pyknosis: nuclear shrinkage and increased
basophilia (DNA condenses into a solid shrunken
mass.
3. karyorrhexis, fragmentation then
disappearance of nucleus.
EM changes
1)Discontinuities in plasma and organelle
membranes.
2) Marked dilation of mitochondria and large
amorphous densities.
3)Disruption of lysosomes.
4) Intracytoplasmic myelin figures
Myelin figures
• Myelin figures: aggregates of damaged cell
membranes (phospholipids).
Fate of Myelin figures:
• phagocytosed by other cells or further
degraded
• into fatty acids and calcify
Patterns of necrosis
• Denaturation of protein predominates….
Coagulative necrosis.
• Enzymatic digestion predominates…
liquefactive necrosis.
• Special circumstances: caseous necrosis and
fat necrosis.
Coagulative necrosis
• preserved architecture of dead tissue .
• Denaturation of structural proteins and
enzymes… so no cellular proteolysis.
• Eosiniphilic anucleated cells
• Cells are removed by inflammatory cells.
• Ischemia in all solid organs except the brain
may lead to coagulative necrosis.
Coagulative necrosis
Liquifactive necrosis
• digestion of the dead cells resulting into a
liquid jelly-like mass.
• In focal bacterial or fungal infections and in
hypoxic death in central nervous system.
Caseous necrosis
• White cheese like friable necrosis.
• Prototype: Tuberculosis
• Typical finding is granuloma :Collection of
fragmented or lysed cells with amorphous
granular eosinophilic debris surrounded by
macrophages.
Caseous necrosis
• White cheese like friable necrosis.
• Prototype: Tuberculosis
• Typical finding is granuloma :Collection of
fragmented or lysed cells with amorphous
granular eosinophilic debris surrounded by
macrophages.
Fat necrosis
• used as a clinical terms and not a specific
type.
• Necrosis of fat.
• Typical example: pancreatic enzymes (lipases)
release in acute pancreatitis.
Fate of necrotic tissue
•
•
•
•
Phagocytosis.
Replacement by scar.
Regeneration.
Calcification.
Mechanisms of cell injury
•
•
•
•
•
•
ATP depletion
Mitochondrial damage
Calcium influx
Oxygen derived free radicals
membrane defects
Damage to DNA and protein
ATP depletion
•
•
•
•
ATP.. Importance?
Sources of ATP?
Causes of depletion?
Effects of ATP depletion?
Effects of ATP depletion
• Membrane permeability affected due to
effects on Na- K pump.
• Increased acidity due to increased non
oxidative phosphorylation.
• Failure of calcium pump.. Increased
intracellular calcium.
• Structural disruption in protein synthesis
apparatus.. Detacment of ribosomes and
dissociation of polysomes
Mitochondrial damage
• Failure of oxidative phosphrylation.. ATP
depletion.
• Abnormal oxidative phosphorylation.. ROS
• Mitochondrial permeability transition pores..
Loss of membrane potentional and pH change
• Release of proteins that initiate apoptosis
Calcium influx
• Activates enzymes… phospholipases,
proteases, endonucleases, ATPases… so cell
destruction.
• Calcium can directly activate caspases…
apoptosis
Oxygen free radicals
• Lipid peroxidation
• Cross linking of proteins
• DNA damage
Membrane permeability defects
Caused by:
Decreased phospholipid synthesis due to ATP
depletion.
Increased phospholipid breakdown .. Due to
increased calcium
ROS. .
Lipid breakdown products
DNA damage
• Initiates apoptosis
mechanisms