CH1 - Growth Adaptations, Cellular Injury, and Cell Death Flashcards
What are the basic principles of growth adapdations?
An organ is in homeostasis with the physiologic stress placed on it. An increase, decrease, or change in stress on an organ can result in growth adaptations.
What leads to an increase in organ size?
An increase in stress
Hypertrophy occurs via what?
an increase in the size
Hyperplasia occurs via what?
an increase in the number of cells
What does hypertrophy involve?
gene activation, protein synthesis, and production of organelles.
What does Hyperplasia involve?
the production of new cells from stem cells.
Permanent tissues are… Do they undergo hypertrophy or hyperplasia?
cardiac muscle, skeletal muscle, and nerve, cannot make new cells and undergo hypertrophy only.
Pathologic hyperplasia leads to what?
(e.g., endometrial hyperplasia) can progress to dysplasia and,eventually cancer.
What is an exception to pathologic hyperplasia leading to cancer?
benign prostatic hyperplasia (BPH), which does notincrease the risk for prostate cancer,
What leads to a decrease in organ size?
A decrease in stress (e.g., decreased hormonal stimulation, disuse, or decreased nutrients/blood supply) (atrophy).
Atrophy occurs via?
a decrease in the size and number of cells
How does a decrease in cell number occur?
via apoptosis.
Decrease in cell size occurs via what?
ubiquitin-proteosome degradation of the cytoskeleton and autophagy of cellular components.
What happens in ubiquitin-proteosome degradation?
intermediate filaments of the cytoskeleton are tagged with ubiquitin and destroyed by proteosomes.
What does autophagy of cellular components involve?
generation of autophagic vacuoles that fuse with lysosomes whose hydrolytic enzymes breakdown cellular components.
What happens in METAPLASIA?
change in stress on an organ leads to a change in cell type
Metaplasia most commonly involves?
change of one type of surface epithelium (squamous, columnar, or urothelial) to another
How do metaplastic cells handle the new stress?
they are better able to handle the new stress.
Esophagus is normally lined by what?
nonkeratinizing squamous epithelium (suited to handle friction of a food bolus)
Barrett esophagus
Acid reflux from the stomach causes metaplasia to nonciliated mucin-producing columnar cells (better able to handle the stress of acid
Metaplasia occurs via what?
programming of stem cells, which then produce the new cell type.
Is Metaplasia reversible?
with removal of the driving stressor.
Can metaplasia progress to cancer?
Under persistent stress, can progress to dysplasia and eventually result in cancer.
What is an exception to metaplasia leading to cancer?
apocrine metaplasia of breast, which carries no increased risk for cancer.
Vitamin A deficiency can result in what?
metaplasia,
Vitamin A is necessary for what?
differentiation of specialized epithelial surfaces such as the conjunctiva covering the eye.
Keratomalacia
In vitamin A deficiency, the thin squamous lining of the conjunctiva undergoes metaplasia into stratified keratinizing squamous epithelium.
Myositis Ossificans
Mesenchymal (connective) tissues can undergo metaplasia. A classic example is myositis ossificans in which muscle tissue changes to bone during healing after trauma
DYSPLASIA is?
Disordered cellular growth
Dysplasia most often refers to?
proliferation of precancerous cells
Cervical intraepithelial neoplasia (CIN)
represents dysplasia and is a precursor to cervical cancer
Dysplasia often arises from?
longstanding pathologic hyperplasia (e.g., endometrial hyperplasia) or metaplasia (e.g., Barrett esophagus)
Is dysplasia is reversible?
yes, with alleviation of inciting stress.
In dysplasia what happens if stress persists?
dysplasia progresses to carcinoma irreversible)
What is aplasia?
it is failure of cell production during embryogenesis (e.g., unilateral renal agenesis)
What is hypoplasia?
it is a decrease in cell production during embryogenesis, resulting in a relatively small organ (e.g., streak ovary in Turner syndrome)
When does cellular injury occur?
when a stress exceeds the cells ability to adapt
The likelihood of injury depends on what?
the type of stress, its severity, and the type of cell affected.
What are highly susceptible to ischemic injury? As opposed to?
neurons whereas, skeletal muscle is relatively more resistant.
Slowly developing ischemia
eg: renal artery atherosclerosis, results in ATROPHY
acute ischemia
eg: renal artery embolus, results in INJURY
What are common causes of cellular injury?
inflammation, nutritional deficiency or excess, hypoxia, trauma, and genetic mutations.
What is HYPOXIA?
Low oxygen delivery to tissue; important cause of cellular injury
What is the final electron acceptor in the electron transport chain of oxidative phosphorylation?
Oxygen
Decreased oxygen results in what?
impairs oxidative phosphorylation, resulting in decreased ATP production
What does a lack of ATP leads to?
cellular injury
What are some causes of hypoxia?
include ischemia, hypoxemia, and decreased 02 - carrying capacity of blood.
Ischemia is?
decreased blood flow through an organ
Ischemia arises with?
- Decreased arterial perfusion (eg atherosclerosis) 2. Decreased venous drainage (eg Budd-Chiari syndrome) 3. Shock?generalized hypotension resulting in poor tissue perfusion
Hypoxemia is?
a low partial pressure of oxygen in the blood (Pao2< 60 mm Hg, SaO2<90%).
Hypoxemia arises with
- High altitude 2. Hypoventilation 3. Diffusion defect 4. V/Q mismatch
High altitude to hypoxemia, how?
Decreased barometric pressure results in decreased PaO2
Hypoventilation to hypoxemia, how?
Increased Paco, results in decreased PaO2
Diffusion defect to hypoxemia, how?
PAO2 not able to push as much O2 into the blood due to a thicker diffusion barrier (e.g., interstitial pulmonary fibrosis)
V/Q mismatch to hypoxemia, how?
Blood bypasses oxygenated lung (circulation problem, eg: right-to-left shunt), or oxygenated air cannot reach blood (ventilation problem, eg: atelectasis)
Decreased O2-carrying capacity arises with what?
hemoglobin (Hb) loss or dysfunction
What are some examples of Decreased O2-carrying capacity?
- Anemia 2. Carbon monoxide poisoning 3. Methemoglobinemia
Anemia leading to decreased O2 carrying capacity.
(decrease in RBC mass) PaO2 normal; SaO2 normal
Carbon monoxide poisoning
CO binds hemoglobin more avidly than oxygen
What is the PaO2 and SaO2 for carbon monoxide poisoning?
PaO2 normal; SaO2 decreased
Exposures for Carbon monoxide poisoning
include smoke from fires and exhaust from cars or gas heaters.
Classic finding for Carbon monoxide poisoning
cherry-red appearance of skin.
Early sign of exposure for Carbon monoxide poisoning
headache; significant exposure leads to coma and death.
What is Methemoglobinemia?
Iron in heme is oxidized to Fe3+ which cannot bind oxygen
PaO2 and SaO2 for Methemoglobinemia?
PaO2 normal; SaO2 decreased
Methemoglobinemia is Seen with?
oxidant stress (eg sulfa and nitrate drugs) or in newborns
Classic finding for Methemoglobinemia?
cyanosis with chocolate-colored blood.
Treatment for Methemoglobinemia?
intravenous methylene blue, which helps reduce Fe3+ back to Fe2+ state.
Hypoxia results in low ATP how?
impairs oxidative phosphorylation resulting in decreased ATP.
Low ATP disrupts what?
key cellular functions including 1. Na/K pump 2. Ca2+ pump 3. Aerobic glycolysis
Disruption of Na/K pump results in what?
sodium and water buildup in the cell
Disruption of Ca2+ pump results in what?
Ca2+ buildup in the cytosol of the cell
Disruption of Aerobic glycolysis results in what?
switch to anaerobic glycolysis. Lactic acid buildup results in low pH, which denatures proteins and precipitates DMA.
The hallmark of reversible injury is
cellular swelling.
Cytosol swelling results in
loss or microvilli and membrane blebbing.
Swelling of the rough endoplasmic reticulum (RER) results in
dissociation of ribosomes and decreased protein synthesis.
The hallmark of irreversible injury is
membrane damage.
Plasma membrane damage results in
- Cytosolic enzymes leaking into the serum {e.g cardiac troponin) 2. Additional calcium entering into the cell
Mitochondrial membrane damage results in
- Loss of the electron transport chain (inner mitochondrial membrane) 2. Cytochrome c leaking into cytosol (activates apoptosis)
Lysosome membrane damage results in
hydrolytic enzymes leaking into the cytosol, which in turn, are activated by the high intracellular calcium.
The end result of irreversible injury is
cell death.
The morphologic hallmark of cell death is
loss of the nucleus,
loss of the nucleus occurs via
nuclear condensation (pyknosis), fragmentation (karyorrhexis), and dissolution (karyolysis)
The two mechanisms of cell death are
necrosis and apoptosis.
NECROSIS
A. Death of large groups of cells followed by acute inflammation B. Due to some underlying pathologic process; never physiologic C. Divided into several types based on gross features
GROSS PATTERNS OF NECROSIS
A. Coagulative necrosis, B. liquefactive necrosis, C. Gangrenous necrosis D. Caseous necrosis E. Fat necrosis F. Fibrinoid necrosis
What is Coagulative necrosis?
Necrotic tissue that remains firm, cell shape and organ structure are preserved by coagulation of proteins, but the nucleus disappears
Coagulative necrosis is Characteristic of?
ischemic infarction of any organ except the brain
Area of infarcted tissue for Coagulative necrosis?
It is often wedge-shaped (pointing to focus of vascular occlusion) and pale.
What is Red infarction
arises if blood re-enters a loosely organized tissue (e.g. pulmonary or testicular infarction)
What is Liquefactive necrosis?
Necrotic tissue that becomes liquefied; enzymatic lysis of cells and protein results in liquefaction.
Liquefactive necrosis is Characteristic of?
Brain infarction, abscess, pancreatitis
What type of necrosis for brain infarction?
Liquefactive necrosis - Proteolytic enzymes from microglial cells liquefy the brain.
What type of necrosis for abscess?
Liquefactive necrosis - proteolytic enzymes from neutrophils liquefy tissue
What type of necrosis for pancreatitis?
Liquefactive necrosis - Proteolytic enzymes from pancreas liquefy parenchyma.
What is Gangrenous necrosis?
Coagulative necrosis that resembles mummified tissue (dry gangrene)
Gangrenous necrosis is characteristic of?
ischemia of lower limb and GI tract
What is wet gangrene?
superimposed infection of dead tissues occurs, then liquefactive necrosis ensues (wet gangrene).
What is Caseous necrosis?
Soft and friable necrotic tissue with cottage cheese-like appearance. It’s a combination of coagulative and liquefactive necrosis
What is caseous necrosis characteristic of?
granulomatous inflammation due to tuberculous or fungal infection
What is fat necrosis?
Necrotic adipose tissue with chalky-white appearance due to deposition of calcium
What is fat necrosis characteristic of?
trauma to fat (eg. breast) and pancreatitis-mediated damage of peripancreatic fat
Fat necrosis and saponification
Fatty acids released by trauma (eg to breast) or lipase (eg pancreatitis) join with calcium via a process called saponification which is an example of dystrophic calcification in which calcium deposits on dead tissues.
dystrophic calcification
the necrotic tissue acts as a nidus for calcification in the setting of normal serum calcium and phosphate
Dystrophic calcification vs metastatic calcification
high serum calcium or phosphate levels lead to calcium deposition in normal tissues (eg. hyperparathyroidism leading to nephrocalcinosis)
Fibrinoid necrosis
Necrotic damage to blood vessel wall, Leaking of proteins (including fibrin) into vessel wall results in bright pink staining of the wall microscopically
What is fibrinoid necrosis characteristic of?
malignant hypertension and vasculitis
What is apoptosis?
Energy (ATP)-dependent, genetically programmed cell death involving single cells or small groups of cells.
Examples of apoptosis include
- Endometrial shedding during menstrual cycle 2. Removal of cells during embryogenesis 3. CD8+ T cell-mediated killing of virally infected cells
Morphology of apoptosis
- Dying cell shrinks, leading cytoplasm to become more eosinophilic (pink) 2. Nucleus condenses (pyknosis) and fragments (karyorrhexis).
Apoptotic bodies
fall from the cell and are removed by macrophages; apoptosis is not followed by inflammation
Apoptosis is mediated by
caspases that activate proteases and endonucleases
Proteases
break down the cytoskeleton.
Endonucleases
break down DNA,
How are caspases activated?
- Intrinsic mitochondrial pathway 2. Extrinsic receptor-ligand pathway 3. Cytotoxic CD8+ Tcell-mediated pathway
What is the main molecule in the intrinsic mitochondrial pathway?
Bcl2
What happens to Bcl2 in the intrinsic mitochondrial pathway?
Cellular injury, DNA damage, or loss of hormonal stimulation leads to inactivation of Bcl2
In the intrinsic mitochondrial pathway lack of Bcl 2 results in what?
allows cytochrome c to leak from the inner mitochondrial matrix into the cytoplasm and activate caspases.
What is the extrinsic receptor-ligand pathway?
FAS ligand binds to (CD95) FAS death receptor and TNF binds TNF receptor (both activate caspases)
What is an example of FAS ligand binding to FAS death receptor (CD95) on the target cell activating caspases
negative selection of thymocytes in thymus
Cytotoxic CD8+ T cell-mediated pathway releases what?
perforins and granzyme ex CD8+ T-cell killing of virally infected cells is an example.
Perforins
secreted by CD8+ T cell create pores in membrane of target cell
Granzyme
secreted from CD8+ T cell enters pores and activates caspases
Free radicals are what?
chemical species with an unpaired electron in their outer orbit.
When does physiologic generation of free radicals occur?
it occurs during oxidative phosphorylation
How are free radicals generated physiologically?
Cytochrome c oxidase (complex IV) transfers electrons to oxygen. Partial reduction of O2 yields superoxide (O2.) hydrogen peroxide (H202), and hydroxyl radicals (OH.)
Pathologic generation of free radicals arises with?
Ionizing radiation, inflammation, metals, drugs and chemicals
Ionizing radiation and Pathologic generation of free radicals
water hydrolyzed to hydroxyl free radical
Inflammation and Pathologic generation of free radicals
NADPH oxidase generates superoxide ions during oxygen dependent killing by neutrophils.
Metals and Pathologic generation of free radicals
(e.g., copper and iron) Fe generates hydroxyl free radicals (Fenton reaction).
Drugs and chemicals and Pathologic generation of free radicals
P450 system of liver metabolizes drugs (e.g acetaminophen), generating free radicals.
Free radicals cause
cellular injury via peroxidation of lipids and oxidation of DNA and proteins; DNA damage is implicated in aging and oncogenesis.
Elimination of free radicals occurs via what?
Antioxidants, Enzymes, Metal carrier proteins
Elimination of free radicals via Antioxidants
glutathione and vitamins A , C, and E
Elimination of free radicals via Enzymes
SOD, glutathione peroxidase, catalase
Superoxide dismutase
(in mitochondria) superoxide (O2.?>H202)
Glutathione peroxidase
(in mitochondria) GSH + free radical GSSH and H202
Catalase
(in peroxisomes) H2O2 ?> O2 and H202
Elimination of free radicals via Metal carrier proteins
transferrin and ceruloplasmin
Free Radical Injury
Carbon tetrachloride (CCl4) and Reperfusion Injury
Carbon tetrachloride - What is it used for?
Organic solvent used in the dry cleaning industry
How is CCl4 metabolized?
Converted to CC14 free radicals by P450 system of hepatocytes
CCl4 results in what?
cell injury with swelling of RER, ribosomes detach, impairing protein synthesis. Decreased apolipoproteins lead to fatty change in the liver
Reperfusion injury
Return of blood to ischemic tissue results in production of O2-derived free radicals, which further damage tissue. Leads to a continued rise in cardiac enzymes (troponin) after reperfusion of infarcted myocardial tissue
What is an amyloid?
It is a misfolded protein that deposits in the extracellular space, thereby damaging tissues.
What are the shared features of amyloid proteins?
beta-pleated sheet configuration, Congo red staining and apple-green birefringence when viewed microscopically under polarized light Deposition can be systemic or localized,
What is primary amyloidosis?
It is systemic deposition of AL amyloid, which is derived from immunoglobulin light chain
What is primary amyloidosis associated with?
plasma cell dyscrasias (e.g multiple myeloma)
Secondary amyloidosis is?
systemic deposition of AA amyloid, which is derived from serum amyloid-associated protein (SAA).
What is SAA?
It is an acute phase reactant that is increased in chronic inflammatory states, malignancy, and Familial Mediterranean Fever (FMF).
What is FMF due to?
a dysfunction of neutrophils (autosomal recessive) and occurs in persons of Mediterranean origin.
What does FMF present with?
episodes of fever and acute serosal inflammation
FMF can mimic what?
appendicitis, arthritis, or myocardial infarction
How does FMF result in AA amyloid deposition in tissues?
High SAA during attacks deposits as AA amyloid in tissues
What is the most common organ involved in systemic amyloidosis?
kidney
What are the clinical findings of systemic amyloidosis?
Nephrotic syndrome, Restrictive cardiomyopathy or arrhythmia, Tongue enlargement, malabsorption, and hepatosplenomegaly
Diagnosis of systemic amyloidosis requires what?
tissue biopsy, Abdominal fat pad and rectum are easily accessible biopsy targets.
Damaged organs of systemic amyloidosis must be…
transplanted. Amyloid cannot be removed.
What is localized amyloidosis?
Amyloid deposition that is usually localized to a single organ
What is senile cardiac amyloidosis?
Non-mutated serum transthyretin deposits in the heart. Usually asymptomatic; present in 25% of individuals > 80 years of age
Familial amyloid cardiomyopathy
Mutated serum transthyretin deposits in the heart leading to restrictive cardiomyopathy, 5% of African Americans carry the mutated gene.
Non-insulin-dependent diabetes mellitus (type II)
Anylin (derived from insulin) deposits in the islets of the pancreas,
Alzheimer disease
amyloid beta (derived from J-amyloid precursor protein) deposits in the brain forming amyloid plaques
Gene for J-APP is present on…
chromosome 21.
Downs syndrome and Alzheimers?
Most individuals with Down syndrome (trisomy 21) develop Alzheimer disease by the age of 40 (early-onset).
Dialysis-associated amyloidosis
B-microglobulin deposits in joints,
Medullary carcinoma of the thyroid
Calcitonin (produced by tumor cells) deposits within the tumor (‘tumor cells in an amyloid background’).
