Ch 2 Flashcards
Causes of cell injury (7)
1.Oxygen deprivation
2.physical agents
3. Chemical/drugs
4.genetic
5.nutritional imbalances
6.infectious agents
7.immunologic
Give an example of hypoxia causing cell injury?
Acute Occlusion of blood vessels - ischemia leading to cell injury
Give an example of physical agents causing cell injury?
Trauma (mechanical), temperature (burns), sudden atmospheric pressure changes, electives shock
Give an example of immunologic agents that cause cell injury?
Viruses
Tapeworms
Parasites
Fungi
What time frame would ischemic changes be seen in light microscopy?
4-12 hrs after onset of ischemia
Is swelling of cell reversible?
Yes if happens in minutes
When does cell swelling become irreversible? (Timeframe)
1-2 hrs
In what order can you see changes in cells (chemical—>macro)
Minutes to hours:
1.biochemical
2.Ultrastructural
Hours to days:
3.Light micro
4.gross morphologic changes
What are features of necrosis:
1.cell size (swelling)
2.nucleus
3.plasma membrane
4.cellular contents
5.adjacent inflammation
6.physiologic/pathologic?
1.enlarged
2.karyorrhexis/pyknosis/karyolysis
3.disrupted
4.enzymatic digestion/leak out of cell
5.frequent
6.pathologic
What are features of apoptosis:
1.cell size (swelling)
2.nucleus
3.plasma membrane
4.cellular contents
5.adjacent inflammation
6.physiologic/pathologic?
1.reduced/shrink
2.fragmentation into nucleosome-size fragments
3.intact however altered structure
4.intact-may be released into apoptotic bodies
5.none
6.physiologic mainly, can be pathologic after cell injury (eg DNA damage)
Why do cells swell when injured?
Influx of water due to failure of ATP dependent Na-K channel (due to failure of mitochondrial oxyfative phosphorylation)
What effect does cell death have on tissues? (Colour, weight, turgor)
Pale
Heavier
Increased turgor
What are the early changes in cells in injury? (Reversible and irreversible)
1.swelling of cell and organelles
2.blebbing of plasma membrane
3.detachement of ribosomes from ER
4. Chromatin clumping
What are vacuoles?
Pinched off segments of ER
What colour does eosinophils take when dyed with H&E dye during cell death?
Red
Why no blue dye seen with H&E during cell death?
RNA binds haematoxylin blue - RNA is lost in cell death
What are ‘myelin figures’?
Phospholipid aggregates from destroyed lipid membranes - seen in cell injury
What are the ultrastructural changes that can be seen in cell injury (5)
1.plasma membrane alterations eg blebbing, blunting, loss of microvilli
2.mitochondrial changes: swelling and appearance of small densities
3.myelin figures
4.Dilatation of ER
5.nuclear alterations
What are the characteristics of necrosis (4)
1.denaturation proteins
2.leakage contents through damaged cell membrane
3.enzymatic digestion
4.local inflammation
Necrosis: what are the possible patterns of nuclear change? 3
- Karyolysis: basophilia within chromatin fading
- Pyknosis: nuclear shrinkage, increased basophilia
3.karyorrhexis: pyknotic nuclear fragmentation (happens after pyknosis)
What are the characteristics of irreversible injury? 2
- Mitochondrial dysfunction
- Cell membrane dysfunction
What are the characteristics of mitochondrial dysfunction in irreversible cell injury?
1.Loss of oxidative phosphorylation
2. Loss of ATP generation
Example of Liquefactive necrosis?
Bacterial/fungal infection into tissues
What is Liquefactive Necrosis?
Cell death and gets digested to form a liquid (accumulation of leukocytes)
What is coagulative necrosis?
1.Secondary Occlusion of blood supply
2. Cell death with preserved architecture
What are the characteristics of coagulative necrosis?
- Preserved architecture
2.high eosinophils (red nuclei)
3.firm texture
What is an infarct?
Localised area of coagulative necrosis
What are the macro characteristics of Casseous necrosis?
1.cheeselike appearance (white, friable)
2. Structure less
3.granular debris within inflammatory border
Wet gangrene is (type of necrosis)
Liquefactive necrosis
Infarct to brain is (type of necrosis)
Liquefactive (unknown reason)
What is fat necrosis?
Focal areas of fat destruction (eg pancreatitis, leakage of lipases from acinar cells into abdominal cavity)
Macroscopic appearance of fat necrosis?
Chalky white appearance (fatty acids + calcium deposits) eg fat saponification
What is fibrinoid necrosis?
Vascular damage: immune reaction within blood vessels (antigen/antibody vs vessel wall)
What is the appearance of fibrinoid necrosis in H&E stains?
Bright pink (protein complexes/antibodies leak out from cells)
What are apoptotic bodies?
Plasma-membrane walled nuclear fragments (has fragments of nucleus and cytoplasm)
What are the 2 pathways for apoptosis?
- Intrinsic (mitochondrial) pathway
2.Extrinsic (death receptor) pathway
Apoptosis: _______ initiates enzymatic segregation of proteins and DNA in a cell
Caspases
What are the triggers of apoptosis?
- DNA damage
2.loss of survival signals - Misfolded proteins (ER stress)
What is the role of BCL2 family in apoptosis?
Inhibits apoptosis
Viral infections eg HIV are a type of (cell death)
Apoptosis
What is the morphology of cells undergoing apoptosis?
- Cell shrinkage
2.chromatin condensation (characteristic) - Formation of cytoplasmic blebs/apoptotic bodies
4.phagocytosis of apoptotic cells (by macrophages)
Apoptosis: What protein is released in the mitochondrial pathway?
Cytochrome C
Apoptosis: the release of cytochrome C is dependent on —– integrity
Mitochondrial wall
How does BCL2 do it’s anti apoptotic function?
Located outside mitochondrial membrane: makes membrane impermeable to prevent leakage of cytochrome c
Apoptosis: what are the pro-apoptotic signals in the mitochondrial pathway?
BAX/BAK
Intrinsic mitochondrial pathway: what is the role of BAD/BIM/Puma/Noxa?
Regulated pro apoptotic initiators: have the ability to activate BAX/BAK to increase mitochondrial permeability
How does cytochrome C cause apoptosis?
Binds to APAF1 –>forms an apoptosome–>bind to caspase9–>activate more caspases
Apoptosis: IAP inhibition causes____
Initiation of caspase cascade
Apoptosis: IAP stands for ____
Inhibitors of Apoptosis
What is the role of IAP in apoptosis?
To prevent inappropriate activation of caspase
Death receptors are members of ____ family
TNF
Example of death receptors?
Type 1 TNFR
Fas (CD95)
The extrinsic (death receptor) pathway activates which caspases?
Caspase 8 and 10
What is efferocytosis?
Phagocytosis of apoptotic cells
Necroapoptosis is triggered by ligation of ____ and ____ viruses
TNFR1
DNA/RNA viruses
Necroapoptosis depends on _____ complex.
RIPK1/RIPK3
Necroapoptosis: RIPK signalling leads to _____ (process) which then forms _____in plasma membrane
Phosphorylation on MLKL
Pores
Pyroapoptosis: involves activation of _____ which then cleaves ____into active form.
Caspase1
IL1
What is Ferroapoptosis?
Excessive iron or ROS overwhelm glutathione dependent antioxidant defenses—>lipid peroxidation
Formation of mammalian growth plate is an example of (cell death)
Necroapoptosis
Examples of necroapoptosis?
1.mammalian growth plate
2.acute pancreatitis
3.ischemia-reperfusion injury
4. Parkinson’s disease
5.CML infections
What is autophagy?
Cell eats own contents
Steps of autophagy?
1.nucleation and formation of isolation membrane (phagophore)
2. Formation of a vesicle (autophagosome)
3.maturation and fusion with lysosomes
____ (marker) is increased during autophagy.
PE-lipidated LC3
Examples of autophagy?
- Alzheimer’s
2.Crohns
3.HSV-1
4.some cancers
Diseases caused by misfolding proteins?
1.Alzheimers (AB protein)
2. Cystic fibrosis (CFTR - transmembrane regulator)
3.Alpha1 antitripsyn deficiency
High intracellular (Ion) causes cell injury
Calcium
Endonucleases (role)
Fragment DNA and chromatin
Phospholipase (role)
Damage cell plasma membrane
Intracellular Ca is sequestered in ____ and ____
ER and mitochondria
DNA damage activates apoptosis by ____ pathway
P53 dependent
Why does ischemia cause faster cell damage than hypoxia?
1.unable to supply substrates through blood for anaerobic glycolysis
2. Unable to clear out metabolites, stops glycolysis
What transcription factor is released in hypoxia induced stress?
HIF-1 (Hypoxia Inducible Factor)
What are the 3 ways ischemia causes cell death?
Reduction in ATP leads to:
1. Failure of Na+ pump>influx of Ca+, H2O, Na+, Efflux K+>ER, cell swelling
2.increased anaerobic glycolysis>decreased glycogen, PH and increased lactic acid>clumping chromatin
3.detachment ribosomes>decreased protein synthesis
Ischemia-reperfusion: What is the mechanism of which oxidative stress causes injury?
1.Damaged cells>Incomplete reduction in O2 in leukocytes >free radicals and Nitrogen
2.complement system: IgM deposits during ischemia, complement binds when reperfusion happens
3.influx calcium from blood
How do chemicals/toxins cause cell injury? 2
- Direct: mercury poisoning vs liver
2.indirect: formation of toxic metabolites: eg cytochrome P450 conversion of CCL4 to CCL3 (dry cleaning)
Example of physiologic hypertrophy?
Estrogen enlarging uterus during pregnancy
What are the triggers that activate transcription factors in cardiac hypertrophy? 3
- Mechanical stretch
- Agonists (eg angiotensin, Alpha adrenergic hormones)
- Growth factors (IGF-1)
Cardiac hypertrophy: what are the transcription factors? 3
GATA4, NFAT, MEF2
Cardiac hypertrophy: How do transcription factors increase hypertrophy?
- Synthesis of contractile proteins
2.induction of fetal genes eg ANF, cardiac alpha actin (decrease workload, increase contractility)
3.prosuce more growth factors
Atrophy: what pathway leads to protein degradation?
Ubiquitin-proteasome pathway
What can cause atrophy?
1.disuse
2.inadequate nutrition
3.pressure eg mass compressing
4.ischemia
5.loss of endocrine stimulation
6.loss of innervation
7.decreased workload
What is a common example of metaplasia in epithelium?
Columnar to squamous eg respiratory tract (bronchi, trachea) in smoker
Barrets oesophagus converts ____ to ____ epithelium.
Squamous to columnar
Myositis ossificans is a type of ____
Metaplasia (bone formation in muscle)
Atrophy is associated with increased (cell death type)
Autophagy
What is a Xanthoma?
Intracellular accumulation of cholesterol within macrophages
What enzyme is defective in Werner syndrome?
DNA Helicase (unable to repair DNA>cell aging prematurely)
What are the mechanisms involved in cell aging?
1.DNA damage
2.Cell senescence (stop dividing): telemere shortening
3.defective protein homeostasis
Telomere shortening is involved in which diseases? 2
- Aplastic anaemia
2.pulmonary fibrosis
What molecular structure maintains correct folding of proteins?
Chaperones
What is the mechanism of which caloric restriction increases longevity? 2
- ILGF-1
- Sirtuins
Lipofuscin
Lipofuscin granules within cardiac myocytes
How is melanin formed?
Tyrosine > dihydroxyphenylalanine
Catalysed by tyrosinase
What are psamomma bodies? Where are they seen?
Necrotic tissues with mineral deposits (seen in papillary cancer)
What are the 4 causes of hypercalcaemia?
- Increased secretion of PTH
- Resorption of bone tissue
- Vitamin D disorders (vit D intoxication)
4.renal failure
What are examples of exogenous pigments?
Carbon
What is an example of endogenous pigments?
1.melanin
2.lipofuscin
3.haemosiderin
Lipofuscin is a breakdown product of ____
Lipid peroxidation
Which part of renal tubules absorb protein?
Proximal tubule (via pinocytosis)
What are Russell bodies?
Eosinophilic inclusions from Distended ER from accumulation of protein
Keratin filaments are found (cell type)
Epithelial cells
Neuro filaments are found in (cell)
Neurons
Desmin filaments are found in (cell)
Muscle cells
Vimentin filaments are found in (cell)
Connective tissue
Glial filaments are found in (cell)
Astrocytes
What are the steps of the inflammatory reaction? 5
1.recognition
2.recruitment
3.removal
4.regulation
5.repair
Inflammatory Rx: what cells involved in Acute Respiratory Distress syndrome (ARDS)?
Neutrophils
Which filament collects in damaged hepatocytes?
Intermediate filaments (Mallory Hyaline)
What are the BH1-4 proteins?
Inhibitors of apoptosis
BCL-2, BCL-XL, MCL-1
How do free radicals cause cell injury?
Destroy phospholipid in cell membrane
What is the peptide that macrophages have that kill microbes?
Cathelicidin - vitamin D dependent
What chemical mediates migration of leukocytes to site of injury?
Chemokines
What substance activates macrophages and monocytes?
IFN Y
How are abscesses formed?
Neutrophils release lysosomes
Recurrent infections in chronic granulomatous disease is caused by
Defect in neutrophil oxygen dependent killing of bacteria
What does C3b do?
Facilitates phagocytosis
Which molecule is responsible for rolling of neutrophils on endothelium?
Selectins
What is the role of C5a in immunity?
Chemotactic: neutrophil activation
Which chemokines (2) can increase vascular permeability by histamine release from mast cells?
C3a and C5a
Serous vs fibrinous inflammation
Both involve mesothelial surfaces eg pericardium
Serous : protein poor fluid
Fibrinous: protein rich (precipitation of fibrin)
Psamomma body
Russell body
