Cell Injury and Cell Death Flashcards
Define Pathology:
the study of disease
Define Etiology:
origin or cause of disease (the why)
Define Pathogenesis:
steps/mechanisms in development of a
disease (the how)
Define Pathophysiology:
the functional changes associated with
or resulting from disease (the what happens in the body
because of the disease)
Define Prognosis:
the likely course/outcome of a disease
Define Sequela(e):
pathologic conditions resulting from a disease
Cells actively change in response to the
“____” in their environment to maintain a ____
stress, steady state (homeostasis)
Sources of stress can be _______ or _______
Endogenous (inside the body), Exogenous (outside environment)
Examples of endogenous stress:
- Hypoxia - oxygen deficiency
- Immunologic reactions
- Genetic defects
- Aging
Examples of exogenous stress:
- Physical agents - trauma, hot, cold, radiation
- Chemicals and drugs
- Microbiologic agents (bacteria, viruses etc.)
- Nutritional imbalances
What are the three kinds of tissue in terms of proliferative capacity?
Continuously dividing tissues, Stable Tissues, and Permanent Tissues
What is another name for Continuously dividing tissues?
labile tissues
What are examples of Continuously dividing tissues?
skin, oral cavity, vagina, cervix, exocrine ducts,
GI tract
What is another name for stable tissues?
quiescent
What is stable tissue?
A type of tissue that only divide in response to injury/stimulus
What are examples of stable tissues?
endothelial cells, fibroblasts, smooth muscle, most solid organs (kidney, pancreas, liver)
What is permanent tissue?
A type of tissue that does not proliferate after birth having become fully mature or terminally
differentiated
What are examples of permanent tissues?
neurons, cardiac muscle, skeletal muscle
Four types of cellular response/adaptation?
Hyperplasia, Hypertrophy, Atrophy, and Metaplasia
The four types of cellular response/adaptation can respond to both ______ or ______ stress
normal, pathologic
Define Hyperplasia
production of new cells from stem cells
Define Hypertrophy
increase in cell size (in non-dividing
cells)
Define Atrophy
decrease in cell size and number
Define Metaplasia
adult cell changes into another cell type
What happens to cells that can’t adapt?
- Reversible injury (non-lethal)
- Irreversible injury (cell death): Necrosis or apoptosis
Where can hypertrophy and hyperplasia occur together in the body?
(uterus)
or if in non-dividing cells then only
hypertrophy occurs
Hypertrophy and hyperplasia can be ______ or ______
physiologic, pathologic
Match one letter with one number:
A) physiologic Hyperplasia:
B) physiologic Hyperplasia + hypertrophy:
C) pathologic Hyperplasia:
D) pathologic Hypertrophy:
1) uterus during pregnancy
2) cardiac
3) breast during puberty or pregnancy
4) endometrial hyperplasia, benign prostatic
hyperplasia
A-3
B-1
C-4
D-2
(T/F) Pathologic hypertrophy/hyperplasia is an uncontrolled process
False. These are controlled processes (different than a neoplasm which shows uncontrolled growth)
What causes atrophy?
decreased hormone stimulation, blood
supply/nutrition, workload, innervation, or aging
How are proteins degraded?
- Cytoskeleton broken down by proteasomes (Ubiquitin-proteasome degradation)
- Cellular components are “self-eaten” (autophagy). Autophagic vacuoles of cellular components fuse with lysosomes leading to hydrolytic breakdown. Used to survive when nutrients are scarce
What is metaplasia?
A technically reversible response to “stress”
where one adult cell type turns into another cell
type (reprogramming of stem cells)
What are two example of metaplasia?
- Smokers: respiratory epithelium → squamous
epithelium, which can turn to cancer - Gastric reflux: squamous epithelium →
gastric/intestinal epithelium (Barrett esophagus),
which can progress to cancer
What are two other examples of metaplasia?
- Vitamin A deficiency can cause metaplasia
because it is essential for differentiation of
specialized epithelial surfaces (e.g. conjunctiva).
When lacking, this squamous lining begins to
keratinize which can lead to blindness
(keratomalacia) - Mesenchymal (connective tissue) cells can
undergo metaplasia usually reacting to
pathologic stress. Ex. muscle tissue changing to
bone after trauma (myositis ossificans)
Injury occurs when stress ______ the cell’s adaptive ability
exceeds
Degree of injury depends on stress _____, _____ and _____
type, severity and cell type affected
What is ischemia? hypoxemia?
- ischemia (decreased blood supply to tissues),
- hypoxemia (low concentration of blood oxygen)
Decreased O2 impairs ___________ → decreased ____ production → cell ______
oxidative phosphorylation, ATP, injury
Define an ischemic shock
generalized drop in blood pressure causing poor
tissue perfusion
When does hypoxemia occur?
- High altitude- decreased PaO2
- Hypoventilation- increased PaCO2 results in decreased PaO2
- Diffusion defect (e.g. thicker barrier in pulmonary fibrosis)
- Blood bypasses the lung (e.g. shunt) or oxygenated air can’t reach the blood (e.g. when the lung collapses)
Decreased O2 carrying capacity arises with _______ loss or altered affinity for O2
hemoglobin (Hb)
Three examples of decreased O2 carrying capacity
Anemia, Carbon monoxide poisoning, and Methemoglobinemia
Define Anemia
(decrease in RBC mass)- PaO2 and SaO2 are normal
Define Carbon monoxide poisoning
CO binds Hb better than O2
Define Methemoglobinemia
Iron in heme is oxidized to Fe3+ which can’t bind O2
Four Mechanisms leading to cell injury
- ATP depletion and production of reactive oxygen species (ROS) in mitochrondria
- Ca2+ influx into the cytoplasm
- Cell membrane damage (plasma, mitochondrial
and lysosomal) - DNA damage and protein misfolding
Explain ATP depletion
- Na/K+ pump stops working- leads to ↑ sodium and water in cytosol → cell swelling (including ER-ribosome detachment → decreased protein synthesis)
- Ca2+ pump stops working- leads to ↑ Ca2+ in cytosol
- Switch to anaerobic glycolysis → lactic acid buildup lowers pH → denatures protein and precipitates DNA
What is the effect of reactive oxygen species (ROS)?
- Peroxidized lipids → membrane damage
- Oxidation of DNA → mutations
- Oxidation of protein → protein breakdown/misfolding
How are reactive oxygen species (ROS) made?
Made during mitochondrial respiration due to
imperfect reaction of O2 to H2O which forms
superoxide (O2-)
Free radicals and ROS decay spontaneously and
are broken down by:
- superoxide dismutase (superoxide to H2O2 )
- glutathione peroxidases (in cytoplasm) and catalase (in peroxisomes) convert H2O2 to water
__________ block free radical formation or scavenge them
Antioxidants
Examples of antioxidants
(vitamins A, E, C and β-carotene)
Ischemia causes release of intracellular _____
stores into the ______ then later ______ across
the plasma membrane
Ca2+, cytosol, influx
Elevated cytosolic Ca2+: (two effects)
- activates enzymes which damage membranes,
proteins, DNA and ATP - can also induce apoptosis by activation of caspases and increasing mitochondrial permeability
(cytochrome c release)
Plasma membrane damage leads to: (two effects)
- cytosolic enzymes leaking into serum (e.g. cardiac troponin)
- Calcium influx
Mitochondrial membrane damage leads to: (two effects)
- Loss of electron transport chain
- Cytochrome c leaking into cytosol (activates
apoptosis)
Lysosome membrane damage leads to: (two effects)
hydrolytic enzymes leaking into the cytosol which
are activated by high intracellular calcium
Cell __________ and _________ are altered with cellular swelling
morphology (appearance), function
Define hydropic degeneration
accumulation of water droplets in cytoplasm. Causes organ to appear pale/swollen
Define fatty change
(degeneration) in cells involved in fat
metabolism- lipid vacuoles in cytoplasm. Causes
organ to appear yellow/greasy
In _____________, if stimulus is removed, tissues return to normal
Reversible Injury
Two predictors of Irreversible injury:
- Cell can no longer make ATP (ATP levels drop)
- Membranes lose their integrity
(T/F) In irreversible stress, cells lose their function as a result of change in their morphology
False. Cells lose their function long before they
change morphology or die
What is the main histologic change in cell death?
the loss of the nucleus
Three forms of nuclear loss
condensation (pyknosis)
fragmentation (karyorrhexis)
dissolution (karyolysis)
What are the two mechanisms of cell death?
necrosis and apoptosis
Define necrosis
Death of a group of cells → release of
cellular contents → acute inflammatory
response
What are the three gross patterns of necrosis?
- Coagulative- most common form
- Liquefactive
- Caseous
Characteristics of coagulative Necrosis
Cell shape and organ structure preserved due to
coagulation of proteins but nucleus disappears
Example of coagulative necrosis
Pattern seen with ischemic infarction (obstruction of blood leading to cell/tissue death) of any organ except the brain
What color/shape is tissue with coagulative necrosis?
Area of infarcted tissue is pale (i.e. called “white”) and often wedge-shaped (pointing to focus of vascular occlusion)
When does coagulative necrosis tissue appear red?
“Red” infarction arises if blood re-enters a loosely
organized tissue (e.g. pulmonary or testicular
infarction)
Characteristics of liquefactive Necrosis
Necrotic tissue that becomes liquefied;
enzymatic lysis of cells and protein results in
liquefaction
Two examples of liquefactive Necrosis
- Brain infarction- proteolytic enzymes from microglial cells liquefy the brain.
- Abscess- proteolytic enzymes from neutrophils liquefy tissue.
Characteristics of gangrenous Necrosis
Coagulative necrosis that resembles mummified
tissue (dry gangrene)
Example of gangrenous Necrosis
Characteristic of ischemia of the lower limb and
GI tract
When does “wet gangrene” occur?
If superimposed infection of dead tissues
occurs, then liquefactive necrosis ensues (wet
gangrene)
Characteristics of caseous necrosis
- Soft and friable with “cheese-like”
appearance - Tissue architecture is replaced by defined
foci of granulomatous inflammation
(contain granulomas)
Example of caseous necrosis
Tuberculosis or deep fungal infections
Characteristics of fat necrosis
Focal areas of fat destruction from trauma or
enzymatic breakdown
Example of fat necrosis
Acute pancreatitis releases pancreatic enzymes
→ break down membranes and fats of
adjacent adipose tissue in the peritoneum
→ fatty acids released combine with calcium
to form chalky white areas (fat saponification)
Characteristics of fibrinoid necrosis
Necrosis of a vessel wall leading to leakage
of fibrin and other proteins into the wall
which stains bright pink on H&E
Example of fibrinoid necrosis
Immune reactions (vasculitis) and malignant hypertension
Define apoptosis
ATP-dependent “programmed” cell death of single or small groups of cells
Apoptosis eliminates: (four types of cells)
- Unneeded structures- embryogenesis, stopping the immune response
- Old, non-functional cells- intestine turnover, menstrual cycle
- Potentially harmful cells- virus-infected, cancer cells
- Cells with DNA damage that can’t be repairedradiation, drugs etc.
Steps of apoptosis
- Initiated by caspases which activate
endonucleases (degrade DNA) and proteases
(degrade cytoskeleton) - As the dying cell shrinks, the cytoplasm
becomes more eosinophilic and the nucleus
condenses and fragments - Fragments of the cell break off with intact cell
membranes - Phagocytes engulf the fragments
- Little to no inflammatory response
Apoptosis can be _______ or _______
Intrinsic (mitochondrial), Extrinsic (Death Receptor)
Explain the intrinsic (mitochondrial) Pathway of apoptosis
Cell injury, DNA damage or lack of growth
signals
→ a decrease in BCL-2 protein family (antiapoptotic)
→ which allows cytochrome c to leak from the
mitochondria into the cytoplasm
→ activates caspases leading to apoptosis
Explain the extrinsic (Death Receptor) Pathway of apoptosis
- Cells express “death” receptors [TNF
receptor family and Fas (CD95)] - Fas ligand (FasL), mainly on activated T
cells, binds to Fas and activates caspases
leading to apoptosis
(T/F) Intracellular accumulation is always harmful to the cell
False. Abnormal amounts of substances can
accumulate due to injury, which can be
harmless or can impair cellular function
How does substance accumulate in the cell?
- Inadequate removal of normal substance from
cell (e.g.- fatty change) - Genetic or acquired defect in protein folding or
transport - Enzyme deficiency leads to accumulation of
metabolites (storage diseases) - Accumulation of exogenous substances (e.g.
carbon pigment)
Pigments can be ________ or ________
exogenous, endogenous
Example of an exogenous pigment
Carbon- most common exogenous pigment. In
coal dust and urban air. Aggregates in the lung
(anthracosis)
__________ is a brownish-yellow complex of lipid and protein
Lipofuscin “wear and tear”
Background of lipofuscin, origin and accumulation site?
- derived from previous free radical damage of
membranes. - accumulates with age or atrophy in heart, liver and brain (a lot of it causes “brown atrophy”)
Characteristics of melanin
brown/black pigment made by
melanocytes (epidermis and mucosal
surfaces) that screens against UV damage
Characteristics of hemosiderin
golden yellow/brown, hemoglobin-derived pigment present where there is excess of iron
What is pathologic Calcification?
Abnormal tissue deposition of calcium salts
Pathologic Calcification in dead or dying tissue is called:
“dystrophic calcifications”
serum calcium is normal
Pathologic Calcification in normal tissue is called:
“metastatic calcifications”
almost always caused by elevated calcium (hypercalcemia)
Hypercalcemia is caused by:
- Renal failure
- Increased parathyroid hormone (PTH)
- Bone destruction
- Vitamin D disorders
Cell aging is regulated by:
a limited number of genes and pathways
Cell aging results from:
progressive decline in life span and function of cells
Why do cells age?
- Accumulation over time of unrepaired DNA damage
- Decreased cellular replication- after a fixed number of divisions all cells stop dividing (replicative senescence) because of telomere shortening
- Defective proteins- ↓ production, defective folding and repair
- Increasing inflammation
How can cell aging be slowed?
Calorie restriction and physical activity slow aging
