Pathology Flashcards
(244 cards)
1
Q
How does the World Health Organisation define health?
A
Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity.
2
Q
How does the World Health Organisation define illness?
A
Illness is a state in which a person’s physical, intellectual, emotional, social or spiritual functioning is diminished or impaired in comparison with the previous experience.
3
Q
Define a syndrome
A
A syndrome is a set of signs and symptoms that occur together. May have a well-defined cause (eg. Down syndrome) or multiple etiologies (eg. acute respiratory distress syndrome).
4
Q
Pathology
A
Study of diseases
5
Q
What are the different approaches to disease?
A
- History and epidemiology of the disease
- Etiology (the why, causes)
- Pathogenesis (the how, mechanism of the disease)
- Pathological alterations (macroscopic, microscopic)
- Pathophysiology (how pathologic changes alter function on different levels of organisation)
- Clinical manifestations
- Imaging and laboratory data
- Diagnosis
- Complication of a disease
6
Q
When the etiology of a disease is unknown, we say it is…
A
idiopathic
7
Q
When the etiology of a disease is known, it can be either… (3)
A
genetic, acquired, multifactorial
8
Q
What is a differential diagnosis?
A
Method of analysis that distinguishes a given disease from others that present similar signs and symptoms.
9
Q
What are predictive factors?
A
Factors that predict potential response to a specific therapy or treatment (drug, biological compound).
10
Q
What are prognostic factors?
A
Factors that provide information about the likely outcomes and course of a disease, regardless of the treatment received - patient’s survival.
11
Q
Example of a prognostic factor
A
In cancers, higher stages are associated with poorer prognosis
12
Q
Example of predictive factor
A
In breast cancer, patients who are ER positive are more likely to respond to hormone therapy.
13
Q
Etiology
A
Causes, “why” of a disease
14
Q
Pathogenesis
A
Mechanism, “how” of a disease
15
Q
Pathophysiology
A
How the structural pathologic changes (pathology) affect the function of the cells and tissues of a patient
16
Q
Hospital diagnostic pathology can be divided into …(2)
A
- Anatomic (diagnostic) pathology
- Clinical pathology
17
Q
Diagnostic (anatomic) pathology encompasses… (4)
A
- Autopsy pathology
- Surgical pathology
- Cytopathology
- Specialty labs
18
Q
Diagnostic (anatomic) pathology is related to the field of …
A
diagnostic imaging (radiology)
19
Q
Autopsy pathology
A
Examination of a body after death to determine the causes of death and evaluate any injury or disease present.
20
Q
There is a decline in autopsies being done in patients. However, autopsy pathology is still important for… (3)
A
- Quality assurance or improvement
- Patient concern with personalized medicine and hereditary conditions
- Helping families get the facts, grieve and find closure
21
Q
Surgical pathology
A
Study and diagnosis of disease through the examination of tissues removed from the body during surgery.
22
Q
Surgical pathology is … than autopsy pathology.
a) much more common
b) much less common
A
a) much more common
Surgical pathology is the main practice of pathologists.
23
Q
Name the 5 surgical procedures used in surgical pathology.
A
- Core (needle) biopsies
- Incisional biopsies
- Excisional biopsies
- Resection
- Exenteration
24
Q
Core (needle) biopsy)
A
Uses a long, hollow tube to obtain a sample of tissue.
25
Incisional biopsy
Surgical procedure during which a cut is made in the skin to remove a sample of abnormal tissue (e.g. of a large mass).
26
Excisional biopsy
Surgical procedure during which an entire lump or suspicious area is removed (e.g. lymph node, breast mass). Purpose is diagnostic examination.
27
Resection
Removal of a larger area of tissue (tumor, organ, part of an organ) for therapeutic purposes. The lesion removed is usually larger than in excisional biopsy.
28
Exenteration
Surgery for treating cancer of reproductive organs. Entire pelvic contents are removed (e.g. uterus, cervix, vagina).
29
Tissue preparation in autopsy and surgical pathology aims to produce a ...
thin translucent section with stains to differentiate cell and tissue components
30
Name the 9 steps of slide preparation before they are analyzed by a pathologist
1. Gross (macroscopic) examination
2. Tissue fixation
3. Tissue processing
4. Tissue embedding
5. Microtomy (sectioning)
6. Staining
7. Mounting
8. Labeling
9. Microscopic review
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1. Gross (macroscopic) examination
Inspection of the specimen and selection of most appropriate sections.
If the biopsy is already a small piece, it can be fixed directly. If we have a larger specimen, we must first sample and cut representative sections.
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2. Tissue fixation
Purpose: To preserve tissue structure and prevent degradation.
Tissue sample is placed in a fixative solution (10% formalin) almost immediately after removal. The faster a tissue is fixed the better. It takes longer for the fixative to penetrate the entire tissue if it is a larger sample.
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3. Tissue processing
Purpose: To dehydrate and embed the samples in a solid medium that can be cut into very thin sections.
1. Graded alcohol baths to dehydrate the tissue
2. Placed in xylene or other clearing agents to remove the alcohol + increase transluscency
3. Infiltrated with paraffin wax (provides firm matrix, allowing thin slicing).
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4. Tissue embedding
Tissue is placed in a mold and surrounded by liquid paraffin wax which hardens as it cools. This makes it easier to cut the tissue into thin sections.
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5. Microtomy (sectioning)
Cutting the tissue into extremely thin slices (3-5 microns thick) for microscopic examination using a microtome.
These sections are then carefully placed on glass slides.
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6. Staining
Purpose: To enhance tissue contrast and highlight cellular structures. The most common stain is hematoxilin and eosin (H&E).
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7. Mounting
A coverslip is placed over the stained tissue section using resin to help preserve the sample and ensure a clear view under the microscope
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8. Labeling
Slide is labeled with relevant patient info for the pathologist and for identification.
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9. Microscopic review
Pathologist reviews the slides under the microscope and examines the tissue for abnormalities (cancer, necrosis, inflammation).
40
Hematoxilin is a…
a) blue/purple stain
b) red/pink stain
It binds to…
a) acidophilic substances
b) basophilic substances
Hematoxilin is a BLUE/PURPLE stain that binds to BASOPHILIC substances.
41
What is a synonym for basophilic? Name examples of basophilic substances bound by hematoxylin
Basophilic = acidic
DNA and RNA in nucleus (stained blue/purple)
42
Eosin is a…
a) blue/purple stain
b) pink/red stain
It binds to…
a) acidophilic substances
b) basophilic substances
Eosin is a PINK/RED stain that binds to ACIDOPHILIC substances
43
Synonym of acidophilic. Names examples of acidophilic substances bound by eosin.
Acidophilic = basic
Proteins (with lysine, arginine) in the cytoplasm
44
The normal slide preparation process takes time. What do we do when a patient is on the operating table and an urgent diagnosis is needed?
- Pathologist does an OR consultation
- Tissue is frozen and cut on a cryostat at -20•C, then stained with H&E
45
Name the advantages and disadvantages of “frozen sections” when an urgent diagnosis is needed.
Advantages: fast, pathologist can make a diagnosis in 5-15 min
Disadvantages: not all specimens can be frozen; creates a small diagnostic error rate
46
Nuclear staining (hematoxilin) reflects…
DNA, genetic material, the regulator if proliferation and metabolic activity (genotype of the cell)
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Cytoplasmic staining reflects…
Effector proteins (enzymes, contractile elements, mitochondria) and the phenotype of the cell (is it a hepatocyte , myocyte, etc)
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When a tissue is more intensely stained with eosin than usual, we say it is…
This is usually an indication of…
highly eosinophilic
usually an indication of necrosis or apoptosis
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Prussian blue stain targets…
ferric iron deposits in tissues (stains blue)
50
Compare a normal liver section to a section of a liver with hemochromatosis when stained with Prussian blue.
Normal liver: cells appear pink (we only see background eosin)
Liver with hemachromatosis: hemachromatosis causes you to absorb too much iron from the food you eat - excess iron is stored in liver and other organs - the section will apear purplish blue, strongly stained by Prussian blue
51
Masson trichrome stain is used for tissues with fibrosis and stains different tissue components in different colors.
Collagen: blue
Muscle: red
Cytoplasm: light red or pink
Nuclei: dark blue
52
Name two stains for microorganisms
1. Ziehl-Neelsen
2. Grocott
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Zhiel-Neelsen
Stains lipid coat of acid-fast bacilli (eg. M. tuberculosis)
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Grocott
Stains fungal organisms (silver stain reacts with carbohydrate capsule) (eg. aspergillus infection in lung transplant patient). Fungi are stained black.
55
Describe the principle of Ag-Ab binding used in immunohistochemistry
In the body, antibodies bind specifically to corresponding antigens (viruses, etc) to eliminate them. Immunohistochemistry utilizes this binding to identify specific cellular macromolecules
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How are antibodies used in immunochemistry made?
- Protein of interest is injected in an animal, which will generate a specific antibody for that protein
- Antibody is purified
- Antibody is applied to histologic sections to detect the presence of the protein of interest
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Antibodies are applied to histologic slides along with a chromogen like peroxidase-diaminobenzidine, producing a … color
brown color
58
Define the cluster of differentiation (CD)
CD number is assigned to antibodies that recognize a given cell surface molecule (e.g. anti-CD20 ani body will recognize cells expressing CD20 on their surface).
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How can we recognize the epithelium?
By doing a keratin stain using antibodies for keratin.
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Immunofluorescence is usually done on... and mainly used in ... pathology
Immuofluorescence is usually done on FROZEN SECTIONS and mainly used in RENAL PATHOLOGY.
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Immunofluorescence usually looks for...
IgA, IgM, IgG
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Electron microscopy is a very imprecise tool, nowadays used mostly only in...
renal pathology
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In electron microscopy we need ultra-thin sections, so the samples are embedded in epoxy resin and cut on...
diamond knives
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Cytopathology examines...
whole cells or sheets of cells (rather than sections of pieces of tissue)
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Cytopathology is divided into (2)
1. gynecologic cytopathology (PAP smears)
2. non-gynecologic cytopathology
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How do procedures, sampling methods and fixation in cytopathology differ from surgical pathology?
Cytopathology uses smears, cytocentrifuge, etc. However, if there is enough tissue, we can make "cell blocks" that are processed similar to surgical pathology samples
67
What is the overall goal in the future of pathology?
Personalized medicine
68
The cell works like a factory that makes proteins. Name the 6 key organelles involved in this process and briefly summarize their role.
1. Ribosome (makes proteins)
2. Endoplasmic reticulum (makes proteins and lipids)
3. Mitochondria (makes energy)
4. Lysosome (gets rid of unwanted waste and debris)
5. Nucleus (stores genetic material)
6. Golgi apparatus (sorts proteins)
69
When a cell undergoes an irreversible injury, it will die by...
necrosis or apoptosis
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What are the different possible types of cell injury (VICTORIAN)?
V: Vascular
I: Infectious
C: Chemical
T: Trauma and temperature
O: Ospital (iatrogenic)
R: Radiation
I: Inherited
A: Autoimmune
N: Nutritional
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The cellular response to injury depends on the... (2)
1. Severity, intensity and duration of the injurious agent
2. The nature and genetic background of the cell
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Reversible injury
Temporary change in function and cellular morphology in response to an injurious agent (cell returns to normal after the agent is removed).
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Macroscopic morphologic features of reversible cell injury (2)
1. Increased organ weight
2. Pale with increased turgor (swollen)
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Light microscopic morphologic features of reversible cell injury (4)
1. Cellular swelling
2. Blebbing (bubbling) of cell membrane
3. Hydronic change/vacuolar degeneration (bubbly appearance)
4. Fatty change
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Ultrastructural (i.e. electron microscopy) morphologic features of reversible cell injury (4)
1. Plasma membrane damage
2. Mitochondrial swelling
3. Dilation of endoplasmic reticulum
4. Detachment of ribosomes
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Fatty change is also known as...
steatosis
77
Define fatty change and name two causes
Fatty change (steatosis) is the abnormal accumulation of lipids in the cellular cytoplasm. It can occur due to alcohol-related liver disease OR in metabolic dysfunction-associated fatty liver disease.
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Is fatty change due to alcohol-related liver disease reversible?
Yes, if the individual stops drinking alcohol!
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Necrosis
Pathologic, uncontrollable cell death in response to severe or persistent injury
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5 macroscopic (gross) patterns of necrosis
1. Coagulative necrosis
2. Liquefactive necrosis
3. Caseous necrosis
4. Fat necrosis
5. Fibrinoid necrosis
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Coagulative necrosis features (3)
1. Cellular outline is maintained
2. Protein degradation
3. Inflammatory response is sparse
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Liquefactive necrosis features (2)
1. Loss of cellular outlines/structural integrity
2. Enzymatic digestion of necrotic tissue (leading to its liquefaction) and inflammation (pus)
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Coagulative necrosis is often due to...
hypoxia/ischemia
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Caseous necrosis features (2)
1. Special type of necrosis in mycobacterial infection (tuberculosis)
2. Amorphous granular debris surrounded by granulomatous inflammation
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In caseous necrosis, a mix of different types of inflammatory cells including ... and ... surround a center necrotic debris.
macrophages and giant cell macrophages
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Pathologists will usually perform special stains to look for ... when caseous necrosis is seen.
mycobacterial or fungal organisms
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Caseous necrosis is often seen in...
children
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Fat necrosis features (2)
Fat necrosis = death of fat tissue
1. Fat destroyed through action of lipases on adipocytes
2. Grossly appears as chalky white areas (lipids are broken down into fatty acids which react with calcium in a process call saponification)
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Fat necrosis is often observed in the ...
pancreas
(due to release of pancreatic enzymes that digest fat)
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Fibrinoid necrosis features (2)
1. Autoimmune diseases (like vasculitis) lead to deposition of immune complexes (antigen-antibody complexes) in blood vessel walls leading to damage and leakage of the immune complexes and plasma proteins from the injured vessels.
2. Fibrinogen (a plasma protein) can leak out of the damaged vessels into the surrounding tissue and combines with other debris to creat a fibrinoid appearance under the microscope (appears bright pink - highly eosinophilic - and amorphous).
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Fibrinoid necrosis is often seen in ... (2)
vasculitis (group of disorders that destroy blood vessels by inflammation) and transplant rejection
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In what type of necrosis do the tissue and cells remain recognizable?
Coagulative necrosis, because cell outline is maintained.
*Note however that nuclei are missing because the cells are dead!
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Necrosis - light microscopy cytoplasmic changes (4)
1. Increased eosinophilia (stains bright pink due to accumulation of eosinophils)
2. Hyaline change (glassy pink appearance due to glycogen loss in cytosol)
3. Vacuolation (bubbly appearance due to loss of organelles)
4. Calcification (calcium buildup in necrotic or dying tissues)
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Necrosis - light microscopy nuclear changes (4)
1. Pyknosis
2. Karyorrhexis
3. Karyolysis
4. Complete loss of nucleus
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Pyknosis
Irreversible condensation of chromatin in the nucleus of a dying cell (nucleus shrinks and becomes darkly-stained under microscope).
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Karyorrhexis
Destructive fragmentation of the nucleus of a dying cell.
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Karyolysis
Complete dissolution of the chromatin and nucleus of a dying cell.
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How does pyknosis affect the basophilia of the nucleus?
Pyknosis increases basophilia due to condensation of the chromatin
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How does karyolysis affect the basophilia of the nucleus?
Loss of basophilia due to dissolution of the DNA.
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Apoptosis
Programmed cell death involved in both pathologic AND physiologic processes; controlled cell death.
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Physiologic causes of apoptosis (5)
1. Embryogenesis
2. Involution (shrinkage) of hormone-dependent tissues
3. Homeostasis in proliferating cell populations
4. Elimination of self-reactive lymphocytes (prevents autoimmune disorders)
5. Destruction of inflammatory cells after they are no longer needed
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Example of involution of hormone-dependent tissues
Uterus after childbirth returns to normal size after a period of enlargement.
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Pathologic causes of apoptosis (4)
1. DNA damage (radiation, hypoxia, cytotoxic agents)
2. Misfolded protein accumulation
3. Induced by virus or host response
4. Pathologic atrophy
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Hypoxia
When tissue or organ is deprived of adequate oxygen supply
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Cytotoxic
Toxic to living cells
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Describe the 4 steps of apoptosis in mammals
1. Cytochrome C must exit the mitochondria to bind Apaf-1
2. Cyt C and Apaf-1 complex bind procaspase-9, which undergoes a cascade of events to become caspase-9
3. Caspase-9 induces autoproteolytic cleavage of procaspase-3, to form active caspase-3
4. Caspase-3 can destroy cells by apoptosis
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Bax-protein
Pro-apoptotic factor - can dimerize and create a channel in the mitochondrial membrane, allowing cytochrome C release
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Bcl-2 and Bcl-x1 protein
Anti-apoptotic factors - bind Bax and prevent it from forming a channel - no Cyt C release
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Bad protein
Pro-apoptotic factor - binds Bcl-2/Bcl-x1 - Bax is free to form a channel and release Cyt C
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What happens to the apoptotic cascade is protein kinase PI-3 is activated by upstream trophic factors?
1. Bad protein gets phosphorylated
2. Rather than binding Bcl-2 it binds protein 14-3-3
3. Bcl-2 can bind Bax
4. Bax cannot form a channel and Cyt C cannot be released from the mitochondria
5. No apoptosis
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Bcl-2 and Bcl-x1 are produced in response to...
growth factors (GF)/survival signals
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How will withdrawal of growth factor/survival signals affect Bcl-2 and the rest of the cascade?
1. Reduced production of Bcl-2
2. Bax can dimerize and form a Cyt C channel
3. More apoptosis
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BH3-only proteins are...
sensory proteins
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BH3-ony proteins can shift the balance towards increase of Bax under 4 conditions.
1. Withdrawal of GF
2. Withdrawal of survival signals
3. Detection of DNA damage
4. Severe protein misfolding
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Describe the "extrinsic" or "death receptor" apoptotic pathway
1. Death receptor activation: FasL/TNF bind the Fas receptor or TNFR1 on the extracellular side
2. Formation of death domain: On the cytoplasmic side, ligand-binding activates cross-linking of receptor proteins and formation of a death domain that activates caspases in the cytosol
3. Active caspases carry out apoptosis
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Two receptors involved in the "extrinsic" or "death receptor" apoptotic pathway
1. Fas receptor (CD95)
2. TNF receptor 1 (TNFR1)
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Two extracellular ligands important for activating the "extrinsic" or "death receptor" apoptotic pathway
1. Fas ligand (FasL)
2. Tumor necrosis factor (TNF)
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Describe an example in the immune system of the "extrinsic" apoptotic pathway in action
Cytotoxic T lymphocytes express FasL on their surface, allowing them to recognize self-reactive lymphocytes which express the Fas receptor (CD95). The interaction between FasL and Fas receptor triggers apoptosis of the self-reactive lymphocytes. This process helps prevent autoimmunity.
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ALPS
Autoimmune lymphoproliferative syndrome
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Describe ALPS and how it relates to the "extrinsic" apoptotic pathway.
Patients with ALPS have a defect in Fas receptor gene. This disease is characterized by the failure in apoptotic elimination of self-reactive lymphocytes (because the cytotoxic T-cell is unable to recognize them).
Consequences: Accumulation of self-reactive lymphocytes, autoimmune symptoms and lymphoproliferation after infection
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Morphologic features of apoptosis (4)
1. Cell shrinkage
2. Condensation of chromatin
3. Blebbing, fragmentation and formation of apoptotic bodies
4. Phagocytosis of apoptotic bodies
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Fraser syndrome
Autosomal recessive disorder associated with defects in genes involved in apoptosis. Can lead to failure in separation of digits (fingers and toes). Interferes with physiologic apoptosis.
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Is necrosis ATP-dependent or independent? Is apoptosis ATP-dependent or independent?
Necrosis: ATP-independent
Apoptosis: ATP-dependent
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Necrosis vs Apoptosis - cell size
Necrosis: Cell swelling
Apoptosis: Cell shrinkage
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Necrosis vs Apoptosis - nucleus
Necrosis: Pyknosis, Karyorrhexis, Karyolysis (uncontrolled)
Apoptosis: Fragmentation (controlled)
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Necrosis vs Apoptosis - plasma membrane
Necrosis - Disrupted
Apoptosis - Intact with altered structure (apoptotic bodies)
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Necrosis vs Apoptosis - cell content
Necrosis: Disrupted, enzymatic digestion leads to leakage
Apoptosis: Intact, released in apoptotic bodies
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Necrosis vs Apoptosis - inflammation
Necrosis: frequent
Apoptosis: absent
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Necrosis vs Apoptosis - pathologic/physiologic?
Necrosis: always pathologic
Apoptosis: pathologic or physiologic
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Damage by injurious agents is usually caused because of interference in ... biochemical processes.
MULTIPLE biochemical processes
131
Name the 4 principal mechanisms of cell injury
1. Hypoxia/ischemia
2. ROS (reactive oxygen species)
3. Radiation mutations
4. Mutations, cell stress, infections
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How does hypoxia affects aerobic and anaerobic respiration?
Aerobic energy production decreases.
Anaerobic glycolysis can continue since nutrients continue to be delivered to cells.
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How does ischemia affect aerobic and anaerobic respiration?
Aerobic and anaerobic respiration are affected, due to diminshed blood flow and thus diminished nutrient flow to cells.
134
Describe the mechanism by which hypoxia/ischemia/radiation may lead to necrosis (or apoptosis).
Hypoxia, ischemia and radiation may cause mitochondrial damage. This will decrease ATP production in the cell and decrease energy-dependent functions in the cell. Moreover, disruption of the normal ETC within the mitochondria will increase reactive oxygen species (ROS or free radicals) in the cell, which will damage lipids, proteins and nucleic acids. This damage will cause cell injury and lead to necrosis.
135
Describe the mechanism by which reactive oxygen species and other injurious agents can damage cellular membranes and lead to necrosis.
ROS can damage lysosomal membranes, which leads to leakage of enzymes that damage the macromolecules in the cell. Moreover, ROS can damage the plasma membrane, disrupting transport functions and causing leakage of cellular contents. This type of cell injury can lead to necrosis.
136
Describe the mechanism by which radiation and mutations can lead to apoptosis.
Radiation and mutations can cause DNA damage, which can cause:
- cell cycle arrest
- activation of BH3-only sensory proteins, which upregulate Bax and Bak
Upregulation of Bax and Bak (pro-apoptotic factors) leads to apoptosis.
137
Describe the mechanism by which mutations, cell stress and infections interfere with the ER and lead to apoptosis.
Mutations, cell stress and infections can damage the endoplasmic reticulum, which will interfere with proper protein folding. The accumulation of misfolded proteins will lead to apoptosis.
138
Define reperfusion injury
Tissue damage that occurs when blood supply is restored to an area that was previously deprived of oxygen an nutrients (ischemia).
139
Reperfusion injury is complex, but it is likely due to... (3)
1. increased generation of ROS
2. influx of calcium
3. activation of leukocytes
(all caused by reoxygenation)
140
Name two "scavengers" that get rid of normal levels of ROS in a healthy cell
Glutathione peroxidase
Catalase
141
ROS cause membrane damage by acting on the lipids in the membrane, a process known as...
lipid peroxidation
142
Usually, calcium concentrations are tightly regulated in the cell. However, ... can cause calcium overload in the cell, causing it to die by necrosis.
membrane damage (often due to accumulation of ROS)
143
When the endoplasmic reticulum is put under mild stress... (adaptive unfolded protein reponse)
1. Low amounts of misfolded proteins are produced
2. There is an increase in chaperone synthesis
3. Chaperones fix misfolded proteins or ensure their degradation
4. There is a reduction in the load of misfolded proteins
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When the endoplasmic reticulum is put under severe stress... (apoptosis)
1. High amounts of misfolded proteins are produced
2. Chaperone system is overwhelmed
3. Sensory BH3-only proteins become activated and upregulate Bax and Bak
4. Caspases in the cell are activated, leading to apoptosis of the cell
145
Cell injury (reversible or irreversible) occurs when a cell is unable to adapt to an injurious stimuli. What are the four main adaptations in response to injury when the cell is capable of adapting?
1. Hypertrophy
2. Hyperplasia
3. Atrophy
4. Metaplasia
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Hypertrophy
Increase in cell size (increased synthesis of cell structural components)
147
Hypertrophy occurs in dividing and non-dividing cells in response to (2)
1. Increased functional demand
2. Hormonal stimulation
148
Hypertrophy is:
a) physiologic
b) pathologic
Both a) and b)
149
Name the two mechanisms by which hypertrophy can occur
1. Mechanical
2. Trophic factor
150
Hypertrophy is the result of increased ... synthesis, re-expression of ... genes and induction of ... genes.
Hypertrophy is the result of increased protein synthesis, re-expression of developmental genes and induction of structural genes.
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Give an example of physiologic hypertrophy
In response to normal, healthy stimuli: Increase in muscle mass in the heart of an endurance athlete allows it to pump blood more effectively.
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Give an example of pathologic hypertrophy
In response to abnormal, unhealthy stimuli: Hypertension can lead to thickening of the wall of the left ventricle in response to chronically elevated blood pressure. This will reduce chamber size and limit the amount of blood the heart can pump, reducing cardiac output. Thickened muscle also requires more oxygen supply, but the blood supply cannot increase correspondingly. The heart becomes more susceptible to ischemia and at risk of a heart attack.
153
Why do cardiomyocytes increase in size after a myocardial infarct?
The cardiomyocytes undergo hypertrophy to compensate for the lost, dead heart muscle tissue.
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Hyperplasia
Increase in cell number
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Hyperplasia is caused by ... (2) leading cells with ... to divide.
Hyperplasia is caused by STRESS and NOXIOUS STIMULI leading cells with PROLIFERATIVE CAPACITY to divide (less commonly stem cells).
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Hyperplasia is:
a) physiologic
b) pathologic
Both a) and b)
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5 mechanisms through which hyperplasia can occur
1. Growth factors/hormones
2. Growth receptors
3. Activation of signalling pathways
4. Activation of cell cycle regulators
5. New production from stem cells
158
Name an example of physiologic hyperplasia
Simple endometrial hyperplasia:
During the menstrual cycle, the endometrium undergoes physiologic hyperplasia in response to estrogen.
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Name an example of pathologic hyperplasia
Benign prostatic hyperplasia (BPH):
Prostate gland enlarges due to an increase in the number of prostatic cells. This type of hyperplasia is driven by hormonal imbalances.
160
Atrophy
Decrease in cell size
161
Atrophy can be caused by...(9)
1. Decreased workload
2. Loss of innervation
3. Loss of endocrine stimulation
4. Loss of blood supply
5. Inadequate nutrition
6. Chronic inflammation
7. Aging ("senile") atrophy
8. Autoimmune disorders
9. Mechanical pressure
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Atrophy is:
a) physiologic
b) pathologic
Both a) and b)
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3 mechanisms by which protein is degraded leading to atrophy
1. Lysosomal enzyme pathway
2. Ubiquitin-proteasome pathway
3. Autophagic vacuoles
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Name an example of pathologic atrophy
Atrophy of the intestinal villi is a key feature of the pathology of Celiac's disease.
165
Metaplasia
Replacement of one cell type by another
166
Metaplasia is:
a) pathologic
b) physiologic
a) ALWAYS pathologic
167
Metaplasia is caused by (2)
1. Chronic inflammation
2. Cytostatic drugs
168
Describe the mechanism through which metaplasia occurs
Reprogramming of stem cells or undifferentiated cells
169
Name an example of metaplasia
Intestinal metaplasia: When epithelial cells lining the stomach transform into cells resembling those found in the intestine in response to chronic irritation or inflammation. This condition is often considered precancerous.
170
Describe squamous metaplasia in the respiratory tract (causes, etc)
Squamous metaplasia in the respiratory tract is caused by smoking. Normal columnar epithelial cells are replaced by squamous epithelial cells in response to chronic irritation and inflammation created by cigarette smoke. While squamous cells are more resilient to injury, this metaplasia can compromise the normal function of the respiratory tract. For instance, squamous cells do not have cilia or the ability to produce mucus, making smokers more prone to infections.
171
Persistent cell stress can lead to intracellular ... of various substances.
intracellular accumulations
172
Name three examples of brown pigments that are considered intracellular accumulations.
1. Lipofuscin: yellow-brown pigment that accumulates in aging cells (esp. liver, heart, brain). It is a marker of oxidative stress.
2. Melanin: brown pigment that accumulates in skin cells in response to UV light or pathologic conditions like melanoma.
3. Iron, stored as hemosiderin (after tissue injury or bleeding, red blood cells are broken down by macrophages)
173
Cholesterolosis of the gallbladder
Accumulation of cholesterol in the gallbladder wall ("strawberry gallbladder"
174
Gaucher cells
Abnormal macrophages seen in Gaucher's disease, a lysosomal storage disorder
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Calcification
Deposition of calcium in cells or tissues
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Name the two types of calcification
1. Dystrophic calcification
2. Metastatic calcification
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Dystrophic calcification (3)
1. Occurs in damaged or necrotic tissue
2. Clumped, amorphous, basophilic material
3. Calcium is concentrated in membrane-bound vesicles in cells with membrane damage
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Metastatic calcification (1)
Occurs when there are elevated levels of calcium in the blood (hypercalcemia) leading to calcium deposition in otherwise healthy tissues.
179
Causes of hypercalcemia (4)
1. Increase in parathyroid hormone (reabsorption of calcium from bone)
2. Destruction of bone due to malignancy
3. Vitamin D disorders
4. Renal failure
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What are the 4 symptoms of inflammation?
1. Redness
2. Swelling
3. Pain
4. Heat
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Define inflammation
Process by which the body recognizes and removes harmful stimuli (defense mechanism); response to infection, tissue damage, non-self recognition
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Inflammation is important to... (3)
1. Fight infection
2. Heal wounds
3. Repair injury
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... are mandatory to initiate the process of inflammation?
Blood vessels
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Define acute inflammation
Initial, rapid, short-term response to infection and tissue damage
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Define chronic inflammation
Prolonged, low-grade immune response to infection or injury (when the acute response fails to clear the stimulus)
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Name the 2 vascular changes characteristic of acute inflammation
1. Vasodilation
2. Increased vascular permeability
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Describe vasodilation
Widening of small blood vessels (arterioles) in the affected area: leads to localized increase in blood flow and pressure (heat and redness)
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Describe increased vascular permeability (vascular leakage)
Walls of blood vessels become more permeable, allowing fluid, proteins and immune cells to leak out into the surrounding tissue (swelling). Endothelial cells contract to form endothelial gaps.
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Arteriolar dilatations are also called...
vascular ectasia
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Describe the process of exudation
Exudation is the movement of fluid, proteins and immune cells from the vascular system to the surrounding tissue in response to increased permeability of small blood vessels and localized increase in hydrostatic blood pressure. Protein leakage outside the vessels also increases the osmotic pressure in the interstitial tissue, drawing more fluid out of the blood vessels.
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Define exudate
Extravascular fluid with a high protein concentration and containing cellular debris.
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Describe the process of transudation
Movement of vascular fluid out of the blood vessels and into surrounding tissue due to an increase in hydrostatic pressure or decrease in osmotic pressure inside the vessels (NOT increase in vascular permeability).
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Define transudate
Extravascular fluid with low protein content (mainly just albumin), usually not associated with inflammation.
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Define pus and explain its yellowish-green color
Pus is a purulent exudate: it is an inflammatory exudate rich in leukocytes, debris of dead cells and microbes. It is yellowish-green due to enzymes released by neutrophils.
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Name the 3 consequences of vascular leakage
1. Accumulation of protein-rich fluid in the extravascular tissues causes edema
2. Localized increase in blood viscosity, which leads to blood stasis (slowing of blood flow)
3. Leukocyte (WBC) migration
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Describe leukocyte migration (diapedesis) (5)
1. Leukocytes roll along the endothelium
2. Leukocytes adhere to the endothelium
3. Leukocytes migrate across the endothelium via endothelial gaps (diapedesis)
4. Leukocytes pierce the basement membrane
5. Leukocytes move and migrate in the interstitial tissue via cell-matrix interactions
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Describe the role of selectins in the recruitment of leukocytes to the site of injury
Selectins are adhesion molecules that mediate the initial, loose interaction between leukocytes and the endothelial cells of blood vessels. They facilitate the "rolling" of leukocytes along the endothelial surface, slowing them down.
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Describe the role of integrins in the recruitment of leukocytes to the site of injury
Integrins are adhesion molecules on the surface of leukocytes that mediate firm adhesion to endothelial cells.
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Cytokines are signalling molecules that help recruit leukocytes to the site of inflammation. A sub-type of cytokines are...
chemokines
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Describe the role of chemokines (CXCL8, CXCR1) and the role of other cytokines (TNF-a, IL-1) in the recruitment of leukocytes
Other cytokines (TNF-a, IL-1): Induce the expression of adhesion molecules (integrins and selectins)
Chemokines (CXCL8, CXCR1): Attract leukocytes to the site of inflammation by creating a chemical gradient that leukocytes follow (chemotaxis)
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Define chemotaxis
Movement of immune cells in response to chemoattraction to different chemical substances
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Name examples of chemoattractants that direct leukocytes during inflammation (4)
1. Chemokines (cytokines)
2. Bacterial products
3. Complement
4. Leukotrienes
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What type of leukocyte is the first to arrive at the site of infection or injury?
Neutrophil
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Name 4 key features of neutrophils
1. Type of phagocyte
2. Part of the innate (general) immune system
3. Nucleus divided into 2-5 lobes
4. Predominates at the site of inflammation during the first 6-24 hours
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What type of leukocyte replaces neutrophils after the first 6-24 hours?
Monocyte
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Name key features of monocytes
1. Type of phagocyte
2. Part of the innate (general) immune system
3. Bean-shaped, unilobar nucleus
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Upon migrating into tissue, monocytes differentiate into...(2)
macrophages or dendritic cells
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Leukocyte margination
Movement of leukocytes to the periphery of blood vessels
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Phagocytosis
Process by which phagocytes like neutrophils and macrophages engulf and digest pathogens
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The first step of phagocytosis is recognition and binding of the pathogen. This is accomplished via...
Mannose receptors: receptors on the surface of phagocytes that recognize and bind to carbohydrates (mannose) present on the surface of many pathogens.
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The second step of phagocytosis, after recognition and binding, is...
Engulfment: the phagocyte membrane fuses around the pathogen and forms a PHAGOSOME
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The third step of phagocytosis is the killing and degradation of the pathogen inside the phagocyte. This is accomplished by...
Fusion of phagosomes with lysosomes: lysosomal enzymes, reactive oxygen intermediates (ROIs) and nitric oxide (NO) kill the pathogen.
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After phagocytosis, neutrophils undergo... and are ingested by...
After phagocytosis, neutrophils undergo APOPTOSIS and are ingested by MACROPHAGES.
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What are toll-like receptors?
Receptors expressed on the surface of leukocytes - they are a type of pattern recognition receptor (PRR) that recognizes pathogen-associated molecular patterns (PAMPs). When a PAMP is detected, TLRs activate leukocytes.
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PRR and PAMP
PRR: Pattern recognition receptor
PAMP: pathogen-associated molecular pattern
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Toll-like receptors play a key role in the ... immune system.
innate (general) immune system
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What is the ligand that activates the toll-like receptor TLR3?
viral double-stranded DNA
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Vasoactive amines are an example of chemical mediators of inflammation. What is their effect? Name two examples.
Histamine: causes vasodilation, important for inflammatory and allergic reactions (eg. anaphylaxis, itching, swelling)
Serotonin: causes both vasoconstriction and vasodilation (depending on the blood vessel), involved in blood clotting, migraines
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Another type of chemical mediators of inflammation are arachidonic acid metabolites. Name three examples.
Prostaglandins
Leukotrienes
Lipoxins
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Arachidonic acid metabolites (role summary)
Arachidonic acid is converted to pro-inflammatory mediators. Regulate inflammation, immune response, blood clotting.
221
Prostaglandins are involved in...(3)
inflammation, pain, fever
222
Leukotrienes are...
chemoattractants, recruit neutrophils to the site of inflammation
223
Lipoxins play a role in...
resolving inflammation
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Tumor necrosing factor (TNF) and interleukin-1 (IL-1) are both ... mainly produced by....
cytokines mainly produced by activated macrophages (but also other cell types)
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TNF and IL-1 main role is...(2)
recruitment of leukocytes to the site of inflammation and promotion of fever
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Explain what we mean when we say TNF and IL-1 have local ubiquitous action and systemic effects.
TNF and IL-1 have a potent pro-inflammatory effect.
Local ubiquitous action: they act at the site of inflammation (local) in all the tissues (ubiquitous)
Systemic effect: effects can spread throughout the body to produce a widespread response like fever
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TNF plays a significant role in severe cases of Covid-19, which is an example of...
systemic inflammatory response syndromes (SIRS)
228
Acute inflammation is a short-term response to injury or infection. What allows its rapid termination?
Many chemical mediators (e.g. cytokines) have a short half-life, which leads to a rapid decline in quantity, so inflammatory signals stop.
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name 3 types of stop signals that help terminate the acute inflammatory response.
1. Arachidonic acid is now converted into anti-inflammatory products (instead of pro-inflammatory)
2. Secretion of TGF beta
3. Inhibition of TNF
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Tissue macrophage half-life is prolonged. Explain how this helps terminate acute inflammation.
Their prolonged half0life allows them to shift from a pro-inflammatory role (M1) to an anti-inflammatory role (M2)
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M1 macrophages (3)
- Activated by pro-inflammatory cytokines
- Involved in initial inflammatory response
- Enhance ability to kill microbes
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M2 macrophages (2)
- Activated by anti-inflammatory cytokines
- Involved in resolving inflammation and promoting tissue repair
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M1 macrophages are...
a) classically activated
b) alternatively activated
a) classically activated
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What are the 3 possible outcomes of acute inflammation?
1. Resolution
2. Fibrosis after healing (e.g. hypertrophic scar)
3. Progression to chronic inflammation
235
What are the 3 hallmarks of chronic inflammation?
1. Angiogenesis (formation of new blood vessels)
2. Mononuclear cell infiltrate (lymphocytes and macrophages rather than neutrophils)
3. Fibrosis (scar tissue replaces healthy tissue)
236
Name 4 types of acute inflammation
1. Serous inflammation
2. Fibrinous inflammation
3. Suppurative inflammation
4. Ulcer
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Serous inflammation
Characterized by the exudation of a clear, serous fluid (rich in proteins, low in immune cells). Typically in response to mild irritations (e.g. blister)
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Fibrinous inflammation
Characterized by the accumulation of fibrin (a large protein involved in blood clotting). Resulting exudate is thick and sticky. Indicates more severe injury.
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Suppurative inflammation
Characterized by the production of pus (exudate rich in dead neutrophils, microbes, tissue debris). Typically in response to bacterial infection (e.g. acute suppurative appendicitis).
240
Ulcer
Open sore on skin or mucous membrane (often found on stomach lining, eg. peptic or gastric ulcer).
241
Fibrosis is characterized by...
collagen secretion by fibroblasts
242
Name 3 examples of injury that typically lead to chronic inflammation. What do they all have in common?
1. Chronic infections
2. Persistent injury
3. Autoimmune and allergic disease
They all repeatedly trigger tissue damage or infection, constantly activating inflammatory responses
243
Name the 6 key players of chronic inflammation
1. Macrophages
2. Lymphocytes
3. Plasma cells
4. Antigen presenting cells (dendritic cells)
5. Eosinophils
6. Mast cells
244
Name 3 characteristics of macrophages
1. Mononuclear phagocytes
2. Secrete mediators of inflammation (TNF)
3. Display antigens to T lymphocytes
