Cell & Tissue Death

PHRM 3550

What are the 4 aspects of the disease process?

etiology, pathogenesis, morphologic changes, & clinical significance

What is etiology?

the cause of a disease

What is pathogenesis?

the sequence of events from the initial stimulus to the expression of the disease

What are morphologic changes?

structural changes in cells or tissues caused by disease

What are clinical significances?

the functional consequences of the morphologic changes

What are the 2 categories of etiologic factors?

intrinsic factors & acquired factors

What are intrinsic factors in etiology?

genetic factors

What are acquired factors in etiology?

infectious, nutritional, chemical, & physical factors

What does pathogenesis involve?

multiple steps; the timing varies between diseases & individuals

Can morphologic changes be characteristic of the disease?

yes

Can morphologic changes be used to diagnose the etiologic process?

yes

What are functional changes determined by?

the specific morphologic changes, their distribution, the rate & order of changes, & the body's ability to adapt

What are the 4 major pathways of tissue injury induction?

adaptation, cell injury, ageing, & cell death

Is cellular adaptation both physiological and pathological?

true

What are physiological cellular adaptations?

normal responses to environmental change (e.g., muscle hypertrophy from exercise)

What are pathological adaptations?

abnormal responses to stress or disease (e.g., cardiac hypertrophy from hypertension)

What are the 2 types of cell injury?

reversible (sub-lethal) & irreversible (lethal)

What are the classifications of cell injury?

reversible injury & irreversible injury

What are free radicals?

electrically uncharged atoms or groups that have an unpaired electron

What must injured cells do?

they must either adapt or die

What are the 3 major types of cell death?

apoptosis, necrosis/oncosis, & autophagy

What is apoptosis?

type I cell death, programmed cell death that does not cause inflammation

What is necrosis?

unregulated cell death that causes inflammation

What is autophagy?

type II cell death involving self-digestion by the cell

How is cell death measured?

by morphological & biochemical changes

What are examples of morphological measurements of cell death?

cell size, plasma membrane integrity, & organelle membrane integrity

What are examples of biochemical measurements of cell death?

leakage of intracellular enzymes & activation of proteins like caspases, p53, & proteases

Why does cellular adaptation occur?

in response to environmental change

What are the types of cellular adaptive changes?

atrophy, hypertrophy, hyperplasia, metaplasia, & dysplasia

What is atrophy?

a decrease in cell size

What is hypertrophy?

an increase in cell size

What is hyperplasia?

an increase in the number of cells

What is metaplasia?

a reversible replacement of one mature cell type by another

What is dysplasia?

an abnormal change in cell size, shape, & organization

What are the mechanisms of atrophy?

less endoplasmic reticulum, fewer mitochondria, acidosis, & more autophagic vesicles

Where does atrophy most commonly occur?

in skeletal muscle, heart, secondary sexual organs, & brain

What are the mechanisms of hypertrophy?

more endoplasmic reticulum, more mitochondria, more myofilaments, increased DNA synthesis, & growth-factor signaling

How does hypertrophy occur?

it is stimulated by mechanical stretch & trophic hormones or growth factors

In what cells does hypertrophy usually occur?

in cells that cannot divide well, especially heart & skeletal muscle

What are the mechanisms of hyperplasia?

cell-cycle changes, DNA synthesis, increased cellular components, & hormonal or growth factor signaling

What is compensatory hyperplasia?

increased cell number to compensate for tissue loss (e.g., wound healing, liver regeneration)

What is hormonal hyperplasia?

increased cell number due to hormonal stimulation (e.g., pregnancy, estrogen-dependent organs)

What is pathological hyperplasia?

abnormal proliferation of cells (e.g., endometrium)

What are the types of hyperplasia?

compensatory, hormonal, & pathological

What is BPH?

benign prostatic hyperplasia, a pathological hyperplasia of the prostate

What is dysplasia actually?

an abnormal growth of cells with altered size, shape, & organization

Where does dysplasia occur?

usually in epithelial cells

Where is dysplasia found relative to cancer cells?

next to

What is dysplasia indicative of?

a strong indicator of cancer or precancerous change

What are the mechanisms of metaplasia?

reprogramming of stem or founder cells; precursor cells maturing down a different pathway

How is metaplasia activated?

it usually requires a signal

What do most diseases begin with?

cell injury

What are the general mechanisms of cell injury?

ATP depletion, formation of reactive oxygen species (ROS), alteration in calcium (Ca2+), & alteration in membrane permeability

What is hypoxia?

a lack of oxygen (O2)

What are the causes of hypoxia?

decreased O2 in the air, loss of hemoglobin, decreased red blood cells, respiratory or cardiovascular disease, & mitochondrial dysfunction

What are the types of hypoxia?

ischemia (decreased blood flow) & anoxia (no blood flow)

What are the cellular responses to hypoxia?

decreased ATP, failure of the Na+/K+ pump & Na+/Ca2+ exchange, cellular swelling, & possible progression to reperfusion injury

What are free radicals and ROS?

electrically uncharged atoms or groups with an unpaired electron (reactive oxygen species)

What are the major ROS?

superoxide (O2-), hydroxyl ion (OH-), & hydrogen peroxide (H2O2)

What is the mechanism of ROS damage?

the unpaired electron makes the molecule unstable; it stabilizes by giving away or stealing an electron from another molecule

What are the results of ROS damage?

damage to proteins, carbohydrates, lipids, & DNA

Why are ROS dangerous?

they damage cellular components by stealing electrons

What do ROS do to cells?

they cause lipid peroxidation, protein alteration, & DNA alteration

How are ROS eliminated?

by antioxidants & scavengers

What are the types of ROS termination?

endogenous & exogenous

What are endogenous ROS terminators?

glutathione (GSH), cysteine, catalase, & superoxide dismutase

What are exogenous ROS terminators?

vitamin C & vitamin E

What does ROS stand for?

reactive oxygen species

What does "the dose makes the poison" mean?

any chemical can be harmful depending on the dose

What are examples of chemicals that can induce cell injury?

lead, carbon monoxide, ethanol, mercury, prescription drugs, & social/street drugs

What are the mechanisms of chemical-induced cell injury?

direct toxicity by interacting with cellular components & indirect toxicity by inducing free radicals

What enzyme system is involved in chemical injury?

cytochrome P450 monooxygenases in the endoplasmic reticulum, which can bioactivate or detoxify chemicals

When does cell death occur?

when injury is irreversible

What can cell death lead to?

tissue loss

What does tissue loss then lead to?

organ dysfunction or failure

What are the mechanisms and responses to necrosis?

cellular swelling, membrane rupture, release of cellular contents, & inflammation

What is pyknosis?

nuclear shrinkage & condensation, a feature of necrosis

What is the cellular morphology of apoptosis?

cell shrinkage, chromatin margination, nuclear fragmentation, apoptotic bodies, blebbing, & maintained membranes

What are the differences between necrotic and apoptotic cell death?

apoptosis

Are single cells or groups of cells affected in apoptosis?

single cells

Are single cells or groups of cells affected in necrosis?

groups of cells

Is inflammation present in apoptosis?

no

Is inflammation present in necrosis?

yes

What determines how a cell will die?

mitochondrial function & membrane integrity

What does depletion of ATP cause?

failure of the Na+/K+ pump

What does failure of the Na+/K+ pump lead to?

cellular swelling

What does cellular swelling then lead to?

membrane damage & cell death

What is p53?

a tumor suppressor protein

What processes does p53 mediate?

cell cycle arrest, DNA repair, & apoptosis

What is mutated in over 50% of human cancers?

p53

What does p53 mutation cause?

loss of tumor suppression leading to uncontrolled cell growth

What is autophagy?

type II cell death, self-digestion via lysosomes

How is autophagy activated?

by starvation, stress, or cellular damage

What is the cellular morphology of necrosis?

swelling, membrane rupture, & loss of cellular contents

What is the nuclear morphology of necrosis?

pyknosis (shrinkage), karyorrhexis (fragmentation), & karyolysis (dissolution)

What are the biochemical pathways and signaling cascades of necrosis?

ATP depletion, calcium influx, activation of proteases, & no caspase activation

What does necrosis involve?

enzymatic digestion of cell contents

What does enzymatic digestion in necrosis cause?

release of cellular contents leading to inflammation

What is the most obvious sign of cellular injury?

cellular swelling

What are the types of necrotic tissue loss?

coagulative, liquefactive, caseous, fat, & gangrenous necrosis