Download doc 1- Cell Injury

I.
Introduction to Pathology
a. Study of the causes of disease and the associated changes that give rise to symptoms
b. Two important subjects within pathology:
i. Etiology: origin of disease
ii. Pathogenesis: development of disease
II.
Adaptive Responses to Cellular Stress
a. Adaptations are reversible changes in number, size, phenotype, and function of the cells in
response to stress.
b. Successful adaptation restores homeostasis
c. Unsuccessful adaptation allows for cell injury
d. Principle adaptive responses:
i. Hypertrophy:
1. Increase in the size of cells, resulting in an increase in organ size (dysplasia).
2. Physiological hypertrophy:
a. Ex, adult muscle cells have a limited capacity to divide. To adapt to
increased load caused by exercise, the muscle cells undergo
hypertrophy.
b. Ex, hypertrophy of uterine muscle during pregnancy
3. Pathological hypertrophy:
a. Ex, heart enlargement due to hypertension
4. Induced by mechanical triggers (stretch of muscle cells) and trophic triggers
(growth factors, adrenergic hormones).
5. Inadaptive response:
a. There is a limit to cell size
b. If the cells can’t compensate for increased load at the cell size limit, tissue
degeneration begins.
ii. Hyperplasia:
1. Increase in the number of cells, also resulting in increased organ size
2. Can only occur in tissues that can rapidly divide
3. Physiological hyperplasia
a. Hormonal hyperplasia
i. Ex, expansion of breast tissue during puberty
b. Compensatory hyperplasia
i. Residual tissues grows after the loss of part of an organ
ii. Stimulated by peptide growth factors secreted by remaining cells
iii. Ex, restoration of liver tissue after resection
4. Pathological hyperplasia
a. Most are caused by excessive hormone or peptide growth factor signaling
b. In wound healing, growth factors are secreted by leukocytes.
c. Certain viral infections cause excessive growth factor production, leading
to epithelial lesions.
d. Can allow for the development of cancer
iii. Atrophy
1. Decrease in cell size, in severe instances causing a decrease in organ size
2. Atrophic cells are smaller but still functional
3. Caused by decreases in load, innervation, blood supply, nutrients, or endocrine
stimulation
4. Physiological atrophy:
a. Ex, decreased hormone signaling to reproductive tissues during
menopause
5. Pathological atrophy:
a. Ex, decreased innervation
6. Senile atrophy: associated with the aging of organs.
7. Often accompanied by autophagy
iv. Metaplasia
1. Reversible replacement of one differentiated cell type with another type
2. Environmental stress induces replacement with a cell type better able to cope
a. Ex, in the lungs of chronic cigarette smokers, ciliated epithelial cells are
replaced with stratified squamous epithelial cells, which can survive the
toxic smoke.
3. Normal occurrence during organ development
4. Possibly occurs by the reprogramming of stem cells to differentiate along a new
pathway
III.
Cell Injury
a. Injury occurs if the cells are unable to adapt to the stress or if the stimulus is inherently injurious.
b. All diseases are associated with cell injury
c. Irreversible cell injury:
i. If the injury is severe and persistent, cells die by necrosis or apoptosis
1. Cell function can cease long before cell death
2.
ii. Key functional and morphological changes:
1. Mitochondrial dysfunction
2. Membrane dysfunction
d. Reversible cell injury:
i. If the injury is mild and transient, cells return to their normal homeostasis
ii. Key functional and morphological changes
1. Cellular swelling
2. Fatty change
3. Will be reversed if the damage is removed
iii. Nuclear degeneration and severe membrane damage hasn’t yet occurred
iv. Many medical treatments focus on the recovery of cells that have not yet died.
e. Some organelles are more sensitive to injury, and induce cascade reactions:
i. Mitochondria and plasma membrane:
ii. ER: protein synthesis requires narrow conditions to occur properly
1. The high rates of protein turnover means the cell is quickly affected by changes
in ER function.
iii. Nucleus: DNA damage affects all cellular processes
f. Example- heart attack
i. Stress on the myocardial cells by hypertension or narrowed value
ii. Cells can adapt through hypertrophy, increasing the size of the entire heart to generate
more contractile force.
iii. If hypertrophy is insufficient, cells will be suffer from ischemia and be injured.
iv. Widespread injury will lead to an infarction, possibly affecting the heart beat or electrical
signaling, causing a heart attack.
IV.
Causes of Cell Injury
a. Hypoxia
i. Oxygen deficiency
ii. Interferes with ATP production
iii. Most commonly caused by ischemia, but can also be caused by anemia or carbon
monoxide poisoning.
b. Ischemia:
i. Loss of blood supply, decreasing oxygen and nutrient delivery
1. Hypoxia is more rapidly damaging than the nutrient deprivation.
ii. Infarction:
1. Death of cells due to ischemia
2. Size of infarction is determined by the severity and duration of ischemia
3. An infarction in the heart causes a heart attack
4. An infarction in the brain causes a stroke.
iii. Sensitivity to ischemia varies by cell type
1. The brain is the most sensitive organ to ischemia
a. Lethal within 4-5 minutes of impaired blood flow
2. Kidneys are easy to transplant in part due to their resistance to ischemia
iv. Causes of ischemia
1. Thrombus:
a. Blood clot on the vessel wall
2. Embolus:
a. Thrombus has left the vessel wall and is carried with the blood flow
b. As the vessels branches into small capillaries, the clot will cause a
blockage.
3. External pressure on the blood vessel
a. Often caused by a tumor growing near a vessel
4. Smooth muscle spasm
a. Contraction of vessels is normally used to regulate blood flow during
hemorrhage.
b. When triggered under abnormal circumstances, the contraction can cut
off blood flow to healthy tissue
c. Often a cause of mortality in cocaine users
c. Chemical agents
i. “The dose makes the poison”, as with glucose, salt, and water.
ii. Ex, cirrhosis of the liver due to alcohol
d. Infectious agents
i. Discussed in greater detail later in the course
ii. Viruses in some instances can lead to tumors
iii. Bacterial toxins affect many cellular functions, can injure just amount any part of the cell
e. Immune reactions
i. Reactions that are excessive, persisting, or targeted to host tissues can cause injury
f. Physical injury
i. Thermal: frostbite and burns
ii. Mechanical:
1. Most physical injuries are due to car-related accidents
a. Especially in developing countries
b. Drivers using mobile phones increase their risk of accidents by 4 times,
as well as for pedestrians.
iii. Pressure: extreme changes in atmospheric pressure or under-water pressure
iv. Radiation: DNA damage from the sun and x-rays
v. Electrical: Ex, lightning strike affects the heartbeat, often the source of lethality
g. Genetic abnormalities
i. Acquired genetic abnormalities are involved in cancer
ii. Genetic variation can increase susceptibility to other sources of injury
1. Ex, albinos have no melanin to protect against UV
2. Ex, spinal muscular atrophy is caused by an abnormality on chromosome 5,
causing the atrophy of nerves for muscle fibers.
h. Malnutrition
i. Include under- and over-nutrition
i. Aging
i. Cellular senescence decreases old tissue’s ability to respond and adapt to stresses.
V.
Necrosis
a. Always a pathogenic process
b. Activation:
i. Ischemia, toxin exposure, infections, and trauma
c. End results:
i. Enzymes leak out of lysosomes, digesting the cell from the inside
ii. Plasma membrane is compromised, leaking cellular contents into the environment
1. Leaking contents cause local inflammation to remove the dead cells
2. Testing for these contents in circulation allows for tissue-specific diagnosis of
necrosis.
iii. Nucleus and DNA are degraded
d. Patterns of tissue necrosis:
i. Coagulative necrosis:
1. Underlying tissue architecture is preserved and the proteolysis of dead cells is
blocked.
2. The solid mass of dead cells that remains forms scar tissue until it is removed by
phagosomes.
3. Often seen in infarcts (ischemic necrosis) in all solid organs except the brain
ii. Liquifactive necrosis:
1. Fungal/bacterial infection stimulate the accumulation of immune cells at the site
of necrosis.
2. The leukocyte enzymes digest and “liquefy” the area, creating pus
iii. Caseous necrosis
1. The site has a consistency half-way between that of coagulative and liquefactive
necroses.
a. Tissue architecture is obliterated but there is a distinct border
2. Characteristic of tuberculosis infection
iv. Gangregous necrosis
1. Loss of blood supply is followed by coagulative necrosis and bacterial infection
2. Only occurs on bacteria-accessible tissue- the epidermis and the gut.
v. Fat necrosis
1. Destruction of fat tissue by the release of activated pancreatic lipases into the
pancreas and peritoneal cavity.
VI.
Apoptosis
a. Can be either physiological or pathogenic
i. Normal part of embryogenesis, organ development, and maintenance.
b. Caused by the deprivation of growth factors or excess DNA/protein damage
c. Characterized by nuclear degeneration without the loss of membrane integrity
d. Features of necrosis vs. apoptosis
i.
VII.
Biochemical Mechanisms of Cell Injury
a. Disruption of mitochondrial function
i. Depletion of ATP
1. Glycolytic pathway can generate ATP in the absence of oxygen (hypoxia)
through the anaerobic pathway  accumulation of lactic acid  decrease in pH
 decrease in enzymatic activity
a. Tissues with greater glycolytic activity like the liver will survive hypoxia
better than the brain.
2. Failure of ATP-dependent Na/K pumps  altered osmosis  cell swelling
3. Reduction in protein synthesis  altered membranes (proteins are central to
membrane function).
ii. Abnormal oxidative phosphorylation produces ROS
iii. Formation of mitochondrial permeability transition pore (MPTP)
1. Releases proteins into the cytosol, signaling that damage is too extreme and
apoptosis should be activated.
b. Disruption of calcium homeostasis
i. Ischemia and certain toxins cause a release of calcium from intracellular stores
ii. Failure of ATP-dependent calcium pump  a 2nd influx of calcium
iii. Calcium influx activates several catabolic enzymes:
1. Phospholipases: degrade membranes
2. Proteases: degrade proteins and subsequently membranes
3. Endonucleases: fragment DNA and chromatin
4. ATPases: depletes ATP
iv. Calcium activates apoptosis and MPTP formation
c. ROS production
i. Species with one lone electron
1. Most are derived from oxygen (superoxide, hydroxide radical, peroxide)
ii. Produced under physiological conditions:
1. Natural byproduct of metabolism and inflammation
2. Controlled with enzymes, antioxidants from diet such as vitamins D and E.
a. Enzymes: superoxide dismutase, glutathione peroxidase, and catalase
3. Phagocytes produce lots of ROS to degrade the engulfed material or to kill
pathogens
iii. ROS damage is induced by excessive inflammation, UV light, ionizing radiation,
cigarette smoke, and air pollution.
iv. Effects of ROS:
1. Lipid peroxidation of membranes
2. Cross-linking of proteins
3. DNA damage
d. Membrane damage
i. Caused by:
1. Lipases and proteases stimulated by calcium influx
2. Decreased phospholipid synthesis due to ATP depletion
3. Lipid peroxidation by ROS
4. Cytoskeleton abnormalities caused by proteases and ER-disruption
5. Lipid-catabolism products from lipases
ii. Effects:
1. Damaged lysosomal membranes  leakage of strong enzymes  degradation
of cellular components from the inside-out
2. Mitochondrial membrane damage  more ATP depletion and apoptosis
3. Compromised plasma membrane  loss of cellular contents and swelling
iii. Calcium influx activates lipases and proteases, degrading the membrane
e. DNA damage
i. Caused by endonucleases released by calcium influx
f. Protein damage
i. Caused by disruptions to ER function and proteases from calcium influx
ii. Leads to the accumulation of misfolded/unfolded proteins and aggregates