Cell Injury and Cell Death

Causes of cell injury

Oxygen deprivation
 Hypoxia
causes:
 Reduced blood flow(ischemia)
 Cardiorespiratory failure
 Anemia
 Carbon monoxide poisoning
 Severe blood loss
Physical agents
 Mechanical trauma
 Extremes of temperature
 Sudden changes in atmospheric pressure
 Radiation
 Electric shock
 Chemical agents and drugs
 Arsenic
 Cyanide
 Mercuric salts
 Environmental and
air pollutants
 Insecticides
 Herbicides
 Carbon monoxide
 Asbestos
 Alcohol
 Therapeutic drugs
Infectious agents
 Viruses
 rickettsia
 Bacteria
 Fungi
 Tapeworms/parasites
Immunologic reactions
 Endogenous self-antigens
 External agents(microbes and
environmental substances)
Genetic derangements
 Chromosomal anomalies
 Sicklecell anemia
 Deficiency of functional proteins
 Inborn errors of metabolism
 Accumulation of damaged DNA
 Misfolded proteins
Nutritional imbalances
 Protein-calorie deficiencies
 Anorexia nervosa
 Nutritional excesses
 obesity
Morphologic
alterations
in cell injury
Reversible injury characteristics
 Generalized swelling of the cell and its
organelles
 Blebbing of the plasma membrane
 Detachment of ribosomes from the ER
 Clumping of nuclear chromatin
 Decreased generation of ATP
 Loss of cell membrane integrity
 Defects in protein synthesis
 Cytoskeletal damage
 DNA damage
Reversible injury
Two features:
1.Cellular swelling
 Cells are incapable of maintaining ionic
and fluid homeostasis
 Result of failure of energy-dependent ion
pumps in the plasma membrane
2.Fatty change
 occurs in hypoxic injury,toxic or
metabolic injury
 Lipid vacuoles in the cytoplasm
 Dependent on fat metabolism
 Hepatocytes
 Myocardial cells
Feature Necrosis Apoptosis
Cell size Enlarged(swelling) Reduced(shrinkage)
nucleus Pyknosis-karyorrhexis- Fragmentation into
karyolysis nucleosome-size
fragments
Plasma disrupted Intact;altered structure,
membrane especially orientation of
lipids
Cellular Enzymatic digestion; may Intact; may be released
contents leak out of cell in apoptotic
Adjacent frequent No
inflammation
Physiologic or Invariably pathologic Often physiologic,
pathologic (culmination of means of eliminating
role irreversible cell injury) unwanted cells; may be
pathologic after some
forms of cell injury,
especially DNA damage
Patterns of tissue necrosis
 Coagulative necrosis
 Architecture of dead tissues is preserved
for a span of at least some days
 The injury denatures not only structural
proteins but also enzymes
Liquefactive necrosis
 Digestion
of dead cells resulting in
transformation of the tissue into a liquid
viscous mass
Gangrenous necrosis
 Usually applied to a limb
Caseous necrosis
 Foci of tuberculous infection
 “caseous”(cheeselike)
 Friable white appearance of the area of
necrosis
Fat necrosis
 Focalareas of fat destruction resulting
from release of activated pancreatic
lipases into the substance of the pancreas
and the peritoneal cavity
Fibrinoid necrosis
 Immune reactions involving blood vessels
 Complexes of antigens and antibodies are
deposited in the walls of arteries
Mechanisms of cell injury
Principles:
 Cellular response to injurious stimuli
depends on the nature of the
injury,duration,and its severity
 Consequences of cell injury depend on
the type,state and adaptability of the
injured cell
 Cell injury results from different
biochemical mechanisms acting on several
cellular components
 Any injurious stimulus may simultaneously
trigger multiple interconnected
mechanisms that damage cells
Depletion of ATP
Depletion of ATP to 5% to 10% has
widespread effects:
 The activity of the plasma membrane
energy-dependent Na pump(ouabain-
sensitive Na,K ATPase) is reduced
 Cellular energy metabolism is altered
 Failure of the Ca pump leads to influx of
Ca
 Structural disruption of
the protein
synthetic apparatus occurs
 Proteins may become misfolded(unfolded
protein response)
 Irreversible damage
Mitochondrial damage
Two major consequences:
 Results in the formation of mitochondrial
permeability transition pore which results
in loss of mitochondrial membrane
potential
 Mitochondria sequester proteins that are
capable of activating apoptotic pathways;
cytochrome c and caspases
Influx of calcium and loss of calcium
homeostasis
Mechanisms:
 Opening of mitochondrial permeability
transition pore and failure of ATP
generation
 Activation of enzymes with potentially
deleterious cellular effects
 Phospholipases,proteases,
endonucleases,ATPases
 Induction of apoptosis by caspases
Accumulation of oxygen-derived
free radicals(oxidative stress)
Conditions:
 Chemical and radiation injury
 Cellular aging
 Microbial killing by phagocytes
Free radicals
 Chemical species that have a single
unpaired electron in an outer orbit
Reactive oxygen species
 A type of oxygen-derived free radical
produced normally in cells during
mitochondrial respiration and energy
generation,but degraded and removed by
cellular defense mechanisms
Oxidative stress:
 Cell injury
 Cancer
 Aging
 Degenerative diseases(Alzheimer disease)
Generation of free radicals
 Reduction-oxidation reactions that occur
during normal metabolic processes
 Absorption of radiant energy
 Inflammation
 Enzymatic metabolism of exogenous
chemicals or drugs
 Transition metals such as iron and copper
 Fenton reaction:
 H2O2+Fe2+ Fe3++OH+OH-
 Nitric oxide(NO)
Removal of free radicals
Antioxidants
 Vitamin E,vitamin A,vitamin C,glutathione
Binding of iron and copper to storage and
transport proteins (transferrin,ferritin,
lactoferrin, ceruloplasmin)
Enzymes:
 Catalase
 Superoxide dismutase(SOD)
 Glutathione peroxidase
Pathologic effects of free radicals
 Lipidperoxidation in membranes
 Oxidative modification of proteins
 Lesions in DNA
Defects in membrane permeability
Mechanisms of membrane damage:
 Reactive oxygen species
 Decreased phospholipid synthesis
 Increased phospholipid breakdown
 Cytoskeletal abnormalities
Consequences of membrane damage:
 Mitochondrial membrane damage
 Plasma membrane damage
 Injury to lysosomal membranes
Damage to DNA and proteins
 Ifdamage is too severe to be corrected,
the cell initiates a suicide program that
results in death by apoptosis
Clinico-Pathologic Correlations
Ischemic and hypoxic injury
This is the most common type of cell injury
in clinical medicine
Hypoxia
 Reduced oxygen availability
Ischemia
 Supply of oxygen and nutrients is
decreased most often because of reduced
blood flow
Mechanisms of ischemic cell injury
 Loss of oxidative phosphorylation
 Decreased generation of ATP
 Failure of Na pump
 Loss of potassium
 Influx of sodium and water
 Cell swelling
 Influx of calcium
 Progressive loss of glycogen
 Decreased protein synthesis
 Blebs
 Myelin figures
 *if oxygen is restored,all of these
disturbances are reversible
 *if ischemia persists, irreversible injury
and necrosis ensue
Ischemia-reperfusion injury
 Reperfused tissues may sustain loss of
cells that are irreversibly damaged at the
end of ischemia
 *new damaging processes are set in
motion during reperfusion
Mechanisms:
 Reactive oxygen and nitrogen species
 Associated with inflammation
 Activation of complement system
Chemical (toxic) injury
 Directinjury by combining with critical
molecular components
 Chemicals are converted to reactive toxic
metabolites,which act on target molecules
APOPTOSIS
 Isa pathway of cell death that is induced
by a tightly regulated suicide program in
which cells destined to die activate
enzymes that degrade the cells’ own
nuclear DNA and nuclear and cytoplasmic
proteins
 Programmed cell death
 Apoptosis in physiologic situations
 Embryogenesis
 Involution of hormone-dependent tissues upon
hormone withdrawal (endometrial cell
breakdown in menstrual cycle, ovarian follicular
atresia in menopause, regression of lactating
breast after weaning, prostatic atrophy after
castration)
 Cell loss in proliferating cell populations
 Elimination of potentially harmful self-reactive
lymphocytes
Death of host cells that have served their
useful purpose:
 Neutrophils in acute inflammatory
response
 Lymphocytes at the end of an immune
response
Apoptosis in pathologic conditions
DNA damage
 Radiation
 Cytotoxic anticancer drugs
 Hypoxia
Accumulation of misfolded proteins
 Mutations in the genes encoding these
proteins
 ER stress
Cell death in certain infections
 Viral infections(adenovirus,HIV,HBV)
Pathologic atrophy in parenchymal organs
after duct obstruction (pancreas,parotid
gland,kidney)