Transcript 2-Cell Injury L1, 2008

CONCEPT OF INJURY AND
CELLULAR RESPONSE TO INJURY
Cells are constantly exposed to a variety of stresses.
When too severe, INJURY results.
Injury alters the preceding normal steady state of the cell.
What hurts cells?
Causes of Cell Injury/Lesions
1.
2.
3.
4.
5.
6.
7.
8.
oxygen deprivation (anoxia)
physical agents
chemical agents
infections agents
immunologic reactions
genetic defects
Nutritional imbalances
Aging
This is a lesion
caused by
infectious agent
This is a lesion
caused by
oxygen deprivation
Hepatic necrosis (patient poisoned by carbon tetrachloride)
This is a lesion
caused by
chemical agent
This is a lesion
caused by
infectious agent
This is a lesion
caused by
physical agent
The “boutonnière” (buttonhole) deformity
This is a lesion
caused by
intrinsic factors
(auto aggression)
This is a lesion
caused by
infectious agent
(chemical:alcohol,
genetic:a1-AT
deficiency)
This is a lesion
caused by HBV
infectious agent
(chemical:alcohol,
genetic:a1AT
deficiency)
General principles:
The cellular response to injurious stimuli depends on
1. type of injury
2. Its duration
3. Severity
-
The consequences depend on
the type, status, adaptability, and genetic
makeup of the injured cell.
-
The structural and biochemical components of a cell
are so integrally connected that multiple
secondary effects rapidly occur
-
Cellular function is lost far before cell death occurs
Etiologic agents
1.
2.
3.
4.
5.
6.
7.
EXCESS or DEFICIENCY OF OXYGEN
PHYSICAL AGENTS
CHEMICAL AGENTS
INFECTION
IMUNOLOGICAL REACTIONS
GENETIC DERANGEMENTS
NUTRITIONAL IMBALANCE
CONCEPT OF INJURY AND
CELLULAR RESPONSE TO INJURY
•
one of two things can happen to the cell:
1. It can survive in a damaged state and adapt to the injury
(REVERSIBLE INJURY) or
2. It can die (IRREVERSIBLE INJURY) or cell death.
•
Injury of a CHRONIC nature: the cell may be able to adapt
to it, resulting in a variety of cellular changes known as
ADAPTATIONS
16
Environment – ECM – other cells
Signals/injury
No change
No adaptation
Adjustment
No adjustment
Adaptation
Change
1. Atrophy 2. Metaplasia 3. Hypertrophy 4. Hyperplasia 5. Dysplasia
Cellular adaptations include:
1. Atrophy - shrinkage of cells
2. Hypertrophy - increase in the size of cells which results in
enlargement of the organs
3. Hyperplasia - increased number of cells in an organ or tissue
4. Metaplasia - transformation or replacement of one adult cell
type with another
Signals/injury
Hypoplasia:
Atrophy
•Developmental failure
•Atrophy of organ
•Failure in morphogenesis
Reversible
Decrease in size of cell (-s) previously of normal size
Physiologic
•Morphogenetic (apoptosis)
•Thymus
Branchial clefts
•Ductus arteriosus
Notochord
•Uterus
Mullerian ducts
Wolffian ducts
•Bones
Pathologic
•Decreased function
•Loss of innervation
•Pressure (“bed soars”)
•Malnutrition/cahexia/cancerTNF
•Loss of endocrine stimulation
•Aging
Net results: tissue /organ smaller than normal
Normal
Atrophy - testis
Small intestine
Normal
Atrophy
Alzheimer disease – brain atrophy
Hypertrophy – cell or organ
Signals/injury
Reversible
Increase in size of cell (-s) in response to increased functional
demand (-s) and/or in response to H/GF stimulation
Physiologic
•Cardiac muscle
•Athletes muscle
•Uterine muscle
•Prostatic tissue (elderly)
Pathologic
•Cardiac muscle
•Thyroid
•Arterial smooth muscle
•Cushing syndrome
Net effect: increase in size/volume/weight of tissue / organ
24
Hyperplasia – cell or organ
Signals/injury
Reversible
Increase in number of cell (-s) in response to increased
functional demand (-s) and/or in response to H/GF stimulation
Physiologic
•Lactating breast
•Uterine muscle
•Prostatic tissue (elderly)
Pathologic
•Thyroid
•Arterial smooth muscle
•Breast , fibrocystic disease
•Focal nodular hyperplasia (liver)
Net effect :increase in size/volume/weight of tissue / organ
Polipoid endometrium
Endometrial carcinoma and endometrial hyperplasia
Signals/injury
Metaplasia
Reversible
But not always
Substitution of mature (differentiated) cell for another mature cell
Physiologic
(metaplastic tissue/organs)
•cervical canal
Pathologic
(metaplastic tissue/organs)
•Gastric/duodenal metaplasia
•Squamous metaplasia-cervix
•Ciliated to squamous
•Osseous metaplasia
•Barret’s oesophagus
•Myeloid metaplasia
Net effect: another cell/tissue - protective – changes in function
Metaplasia
Metaplasia
Ciliated
Squamous
Metaplasia

Overview of Cell Injury and Cell Death
◦ Reversible cell injury ( nonlethal hit)
◦ Irreversible injury and cell death ( lethal hit)
Mechanisms of Cell Injury
 Free radical injury
 Necrosis
 Apoptosis

 Overview
of Cell Injury and Cell Death
◦ Reversible cell injury (nonlethal hit)
◦ Irreversible injury and cell death ( lethal hit)
Mechanisms of Cell Injury
 Free radical injury
 Necrosis
 Apoptosis

Causes of Cell Injury/Lesions
1.
2.
3.
4.
5.
6.
7.
8.
oxygen deprivation (anoxia, hypoxia)
physical agents
chemical agents
infections agents
immunologic reactions
genetic defects
Nutritional imbalances
Aging
Nature and Severity of Injurious
Stimulus
Cellular Response
Altered physiologic stimuli:
Cellular adaptations:
Increased demand, increased
trophic stimulation (e.g. growth
factors, hormones)
Decreased nutrients, stimulation
Chronic irritation (chemical or
physical)
Hyperplasia, hypertrophy
Atrophy
Metaplasia
Nature and Severity of Injurious Cellular Response
Stimulus
Reduced oxygen supply;
chemical injury; microbial
infection
Acute and self-limited
Progessive and severe
(including DNA damage)
Mild chronic injury
Cell injury:
Acute reversible injury
Irreversible injury → cell
death
Necrosis
Apoptosis
Subcellular alterations in
various organelles
Metabolic alterations,
genetic or acquired
Intracellular accumulations;
calcifications
Prolonged life span with
cumulative sublethal injury
Cellular aging
MECHANISMS OF CELL INJURY

The most important targets of injurious stimuli are:
(1) aerobic respiration involving mitochondrial oxidative
phosphorylation and production of ATP
Result: 1- ATP depletoion
2- Mitochondrial damage
3- loss of Calcium homeostasis
4- Generation of reactive oxygen species
(2) the integrity of cell membranes, on which the ionic and osmotic
homeostasis of the cell and its organelles depends
(3) the cytoskeleton
(4) the integrity of the genetic apparatus of the cell
(5) protein synthesis
MECHANISMS OF CELL INJURY

The most important targets of injurious stimuli are:
(1) aerobic respiration involving mitochondrial oxidative
phosphorylation and production of ATP
Result: 1- ATP depletoion
2- Mitochondrial damage
3- loss of Calcium homeostasis
4- Generation of reactive oxygen species
(2) the integrity of cell membranes, on which the ionic and osmotic
homeostasis of the cell and its organelles depends
(3) the cytoskeleton
(4) the integrity of the genetic apparatus of the cell
(5) protein synthesis
(1) DEPLETION OF ATP


ATP depletion and decreased ATP synthesis are frequently associated with
both hypoxic and chemical (toxic) injury
Depletion of ATP to <5% to 10% of normal levels has widespread effects
on many critical cellular systems:
◦ Plasma membrane energy-dependent sodium pump is reduced, resulting
in cell swelling
◦ increased rate of anaerobic glycolysis, glycogen stores are rapidly
depleted. Glycolysis results in the accumulation of lactic acid. This
reduces the intracellular pH, resulting in decreased activity of many
cellular enzymes.
◦ Failure of the Ca2+ pump leads to influx of Ca2+
◦ In cells deprived of oxygen or glucose, unfolded protein formed, that
may lead to cell injury and even death.
MITOCHONDRIAL DAMAGE
◦ Mitochondria are important targets for virtually all
types of injurious stimuli, including hypoxia and
toxins.
◦ Cell injury is frequently accompanied by
morphologic changes in mitochondria.
Result in apoptosis
INFLUX OF INTRACELLULAR CALCIUM AND
LOSS OF CALCIUM HOMEOSTASIS




Calcium ions are important mediators of cell injury.
Cytosolic free calcium is maintained at extremely low
concentrations (<0.1 μmol) compared with extracellular levels
of 1.3 mmol, and most intracellular calcium is sequestered in
mitochondria and endoplasmic reticulum.
Such gradients are modulated by membrane-associated,
energy-dependent Ca2+, Mg2+-ATPases.
Ischemia and certain toxins cause an early increase in
cytosolic calcium concentration, owing to the net influx of
Ca2+ across the plasma membrane and the release of Ca2+
from mitochondria and endoplasmic reticulum
Failure of intracellular calcium homeostasis
Important mechanism of cell damage.
Free radical are chemical species with a single
unpaired electron in an outer orbital.
This state is unstable and react with organic and
inorganic chemical.
MECHANISMS OF INJURY BY FREE RADICALS
Cell injury by oxygen radicals
1.
2.
3.
Superoxide
Hydrogen peroxide
Hydroxy radical
MECHANISMS OF INJURY BY FREE RADICALS
Cell injury by oxygen radicals
1.
2.
3.
Superoxide
Hydrogen peroxide
Hydroxy radical
What happen when the cell is injured by free radicals?
1.
2.
3.
Lipid peroxidation
Protein damage
DNA damage
GENERAL MECHANISMS OF INJURY –FREE RADICALS
Normal mechanism to protect against free radical injury
1. Enzyme
A. Superoxide dismutase.
2O2- + 2H ---> H2O2 + O2
B. Glutathione peroxidase.
H2O2 + 2 GSH ---> 2H2O + GSSG
C. Catalase.
2H2O2 ----> O2 + 2 H2O
2.
•
•
•
Antioxidant:
vit. E, vit. C
Sulfhydryl containing compounds e.g. cysteine
Proteins e.g., transferrin and albumin
MECHANISMS OF CELL INJURY

The most important targets of injurious stimuli are:
(1) aerobic respiration involving mitochondrial oxidative
phosphorylation and production of ATP
(2) the integrity of cell membranes, on which the ionic
and osmotic homeostasis of the cell and its organelles
depends
(3) the cytoskeleton
(4) the integrity of the genetic apparatus of the cell
(5) protein synthesis
Integrity of Cell Membranes
Mechanisms of membrane damage in cell injury:

Decreased O2 and increased cytosolic Ca2+ are
typically seen in ischemia but may accompany other
forms of cell injury.

Production of reactive oxygen species

Lysis of enzymes

Activation of complement system

Lysis by viruses
Effect of plasma membrane damage
1.
2.
Loss of structural integrity
Loss of function
MECHANISMS OF CELL INJURY

The most important targets of injurious stimuli are:
(1) aerobic respiration involving mitochondrial oxidative
phosphorylation and production of ATP
(2) the integrity of cell membranes, on which the ionic and
osmotic homeostasis of the cell and its organelles depends
(3) the cytoskeleton
(4) the integrity of the genetic apparatus of the cell
(5) protein synthesis
Cytoskeletal abnormalities



Cytoskeletal filaments serve as anchors connecting the
plasma membrane to the cell interior.
Activation of proteases by increased cytosolic calcium
may cause damage to elements of the cytoskeleton.
This damage results, particularly in myocardial cells, in
detachment of the cell membrane from the cytoskeleton,
rendering it susceptible to stretching and rupture.
MECHANISMS OF CELL INJURY

The most important targets of injurious stimuli are:
(1) aerobic respiration involving mitochondrial oxidative
phosphorylation and production of ATP
(2) the integrity of cell membranes, on which the ionic and
osmotic homeostasis of the cell and its organelles depends
(3) the cytoskeleton
(4) the integrity of the genetic apparatus of the cell
(5) protein synthesis
(4) the integrity of the genetic apparatus of the cell

Caused by:
1. Ionizing radiation
2. Viruses
3. Mutagenic chemicals
(4) the integrity of the genetic apparatus of the cell

Effect of DNA abnormalities:
1. Failure of synthesis of proteins and enzyme
2. Failure of mitosis
3. Progression to cancer
MECHANISMS OF CELL INJURY

The most important targets of injurious stimuli are:
(1) aerobic respiration involving mitochondrial oxidative
phosphorylation and production of ATP
(2) the integrity of cell membranes, on which the ionic and
osmotic homeostasis of the cell and its organelles depends
(3) the cytoskeleton
(4) the integrity of the genetic apparatus of the cell
(5) protein synthesis



Oxygen is required for oxidative phosphorylation.
Defective ATP production occur in:
a] Hypoglycaemia.
b] Hypoxia due to :
1. Respiratory obstruction or disease.
2. Ischemia.
3. Anaemia.
4. Alteration of hemoglobin.
c] Enzyme inhibition by cyanide.
d] Uncoupling of oxidative phosphorylation.
First cells affected are those with highest demand of
oxygen.


Effect of defective energy production:
Morphologic changes in reversible injury:
A] Intracellular accumulation of water and electrolytes due to failure of
energy-dependent sodium pump
(cloudy swelling or hydropic changes)
B] Changes in organelles, swollen due to loss of
osmotic regulation.
C] Switch to anaerobic metabolism with
production of lactic acid, reduction in intracellular
pH and detachment of ribosomes from RER.
D] Clumping of nuclear chromatin.
These changes are reversible if oxygenation
is restored.
Vacuolar (hydropic) change in cells lining the proximal tubules of the kidney
Reversible
changes
Hydropic vacuoles in the endoplasmic reticulum of hepatocyte
Reversible changes
Hydropic vacuoles in the endoplasmic reticulum of hepatocyte
Vacuoles
M
Nucleus

Morphologic changes in irreversible injury:
1. Severe vacuolization of the mitochondria, with
accumulation of calcium-rich densities.
2. Extensive damage to plasma membranes.
3. Massive calcium influx activate phospholipase, proteases, ATPase and
endonucleases with break down of cell component.
4. Leak of proteins, ribonucleic acid and metabolite.
5. Breakdown of lysosomes with autolysis.
6. Nuclear changes: Pyknosis, karyolysis, karyorrhexis.
IRREVERSIBLE CELL INJURY- NECROSIS
- Dead cell are either collapsed and form a
whorled phospholipid masses or degraded
into fatty acid with calcification.
- Cellular enzymes are released into circulation. This provides important clinical
parameter of cell death.
Cell Pathology
This is a lesion
caused by
oxygen
deprivation
Following ischemic heart injury, the following sequence is observed:
-rapid biochemical and ultrastructural responses
-light microscopic evidence of reversible injury after several minutes
-ultrastructural evidence of irreversible injury in 20-60 minutes
-unequivocal light microscopic evidence of cell death after 11-12 hours
How Ionizing Radiation Kills Cells
•Proliferating Cells - by DNA damage.
Leads to apoptosis.
•Nonproliferating cells- by lipid peroxidation.
How Viruses Kill Cells
•Directly Cytopathic Viruses – e.g. Poliovirus
•Indirectly cytopathic Viruses - e.g. hepatitis B
Summary of Cytopathic Viruses
•Direct cytopathic viruses insert their proteins into the plasma
membranes, disrupting the cells permeability (membrane damage)
•Indirect cytopathic viruses also in insert their proteins into the
plasma membrane, but to create an antigenic target for cytotoxic T
lymphocytes.
How Chemicals Kill Cells :
Group I : interact directly with cellular contents to cause
damage (mercury, lead and iron (toxic heavy metals)
Group II: whose metabolite is toxic e.g. hepatotoxins: (Carbon
tetrachloride(CCl4), acetominophen, bromobenzene)
Group III: bind cytochrome P450 (the mixed function
oxygenase involved in drug metabolism)
Summary of Liver Necrosis by Cytotoxic Chemicals
The metabolism of hepatotoxic chemicals by mixed function
oxidation (cytochrome P450) leads to irreversible cell injury.
This is caused by membrane damage to the cell as a result of
lipid peroxidation.