Cellular Alterations 1-5 Flashcards
1
Q
What are the four basic types of cellular adaptations and are they reversible?
A
Hyperplasia, hypertrophy, atrophy, metaplasia
-> all reversible
2
Q
What is the definition of hyperplasia and its etiology?
A
Increased number of cells which can increase tissue volume (cells must be capable of division)
Etiology:
Hormones
Growth factors
Cytokines
3
Q
Give two mechanisms of hyperplasia
A
- Increased transcription of growth factors + receptors
2. Rarely - recruitment of stem cells
4
Q
What are the two types of physiologic hyperplasia and give examples of each?
A
- Hormonal induced
- > proliferation of breast epithelium in puberty / pregnancy
- > smooth muscle of uterus in pregnancy - Compensatory
- > regeneration of liver after hepatectomy
- > enlargement of contralateral kidney after unilateral nephrectomy
5
Q
What are some examples of pathologic hyperplasia?
A
- Endometrial hyperplasia from unopposed estrogen
- Connective tissue hyperplasia in wound healing / repair
- Epithelial hyperplasia due to HPV
6
Q
What is the definition of hypertrophy?
A
Purposeful increase in cell size due to increased synthesis of cellular components, which can lead to increased tissue volume (cells do not need to be capable of division, i.e. myocytes)
7
Q
Give the two types of physiologic hypertrophy?
A
- Hormonal-induced -> increased uterine smooth muscle size during pregnancy (also an example of hyperplasia)
- Increased workload -> increased skeletal muscle size in weightlifters
8
Q
What causes cardiac hypertrophy and what are its basic mechanisms?
A
Increased workload due to valvular stenosis or hypertension
Mechanisms:
Mechanical / trophic signals lead to transcription of normal as well as re-expression of fetal / neonatal genes which are more efficient and increase cardiac capacity / reduce workload
9
Q
What is the definition of atrophy?
A
Decreased cell size due to reduced cellular components and subsequent reduction in tissue volume
10
Q
What typically causes atrophy?
A
A slow ischemia or malnutrition (rapid = necrosis / apoptosis), denervation, reduced workload, decreased hormonal stimulation, compression, aging, and cytokines like TNF
11
Q
What are some physiologic examples of atrophy?
A
- Embryologic structures - i.e. destruction of notocord
- Postpartum uterus
- Postmenopausal endometrium - loss of hormone
12
Q
What are some pathologic examples of atrophy?
A
- Limb muscle atrophy after spinal trauma - disuse and denervation
- Cerebral atrophy - from reduced blood flow / aging
- Skeletal muscle atrophy in starvation
13
Q
How does atrophy occur to reuse cellular components?
A
- Ubiquitin pathway - degradation of proteins in the proteasome
- Autophagic vascuoles - digestion of larger organelles in autophagolysosomes with lipofuscin left behind
14
Q
What is fatty infiltration?
A
Filling of tissues with fat deposits to compensate for loss of cellular size / number (in the event atrophy is accompanied by apoptosis / necrosis)
**This is DIFFERENT than fatty CHANGE
15
Q
What is the definition of metaplasia?
A
Replacement of one mature cell type by another
16
Q
What typically causes metaplasia?
A
Chronic tissue trauma / irritation which leads to signals by cytokines / growth factors to change transcription in stem cells (i.e. basal cells of epithelium) and differentiate to new cell type
17
Q
Give two types of epithelial metaplasia?
A
- Columnar to squamous -> common in respiratory tract of smokers
- Squamous to columnar -> common in lower esophagus of GERD patients, columnar epithelium as in gastric / intestinal glands is better able to handle the acid
18
Q
What is the example of connective tissue metaplasia?
A
Skeletal muscle -> bone after trauma, calsed myositis ossificans
Since they are both derived from mesoderm
19
Q
What is heterophagy?
A
One of the normal functions of lysosomes, occurs in professional phagocytes like neutrophils and macrophages
-> endocytosis of extracellular material and fusion with lysosomes to break down the debris and possible present antigens
20
Q
What is autophagy and when does it occur?
A
Process occurring in most cells which allows for survival in nutrient deprivation
-> moving intracellular material into autophagic vacuoles and forming autophagolysosomes
21
Q
Give an example of abnormal lysosome function.
A
Enzymatic dysfunction (acquired or inherited) which leads to excess accumulation of lysosomal contents and cellular injury -> Lysosomal storage disorders like Gaucher's disease
22
Q
What can lead to upregulation of smooth ER in hepatocytes?
A
Alcohol and barbiturates (like phenobarbital) which are potent inducers of the CYP system -> lead to increased processing of any other CYP-modifying drugs
23
Q
Under what conditions are the number of mitochondria quantitatively altered?
A
- Cellular hypertrophy -> increased number
2. Cellular atrophy -> decreased number (generate energy / save proteins)
24
Q
Give an example of an inherited and acquired alteration of microtubules?
A
- Inherited -> primary ciliary dyskinesia
2. Acquired -> i.e. drug induction via colchicine
25
What happens to intermediate filaments in alcoholic hepatitis?
They form abnormal aggregates which disrupt cytoskeletal function
26
What are three ways in which things can accumulate within cells?
1. Cellular reaction rate imbalances -> absorption / production exceeds elimination
2. Defects in cellular reactions -> altered synthesis, metabolism, or transport
3. Lack of metabolic / secretory pathways
27
Give three etiologies of triglyceride accumulation in liver?
1. Starvation - increased fatty acid uptake from adipose
2. Kwashiorkor - protein malnutrition leads to decreased apoprotein synthesis and decreased VLDL export
3. Alcohol abuse, diabetes, obesity, hypoxia -> alteration of production or removal
28
What is steatosis? How does it appear grossly and under the microscope?
Fatty change - i.e. triglyceride buildup (NOT fatty infiltration)
Grossly - enlarged, greasy, and yellow liver
Microscopic - clear on H&E, with cytoplasmic vacuoles within the hepatocyte parenchyma. Can displace the nucleus to the periphery if vacuoles are large enough.
29
How does cholesterol appear grossly and under the microscope?
Grossly - yellow discoloration
Microscope:
1. Foam cells -> large round cells with clear "bubbly" cytoplasm
2. Extracellular crystalized cholesterol esters
30
Where can foam cells be seen? Give a few examples.
1. Atherosclerotic plaques
2. Xanthomas - usually subcutaneous masses often seen in hyperlipidemia (mentioned in genetics of familial hypercholesterolemia)
3. Sites of necrosis with inflammation
31
What is cholesterolosis?
Accumulation of cholesterol in subepithelium of gallbladder, seen often with gallstones
32
How do protein aggregates appear on the microscope? When can they be seen?
Variably sized, pink eosinophilic inclusions in the cytoplasm.
1. Can be seen in renal tubular epithelial cells in proteinuria (reabsorbed here)
2. Plasma cells with Russell bodies -> normally stain basophilic, but may appear pink with high Ig production
3. alpha-1 antitrypsin mutation in liver leads to accumulation
33
How does glycogen appear on H&E and how can it be definitively told apart from cholesterol / TAGs?
Small, clear, cytoplasmic vacuoles
| -> can be told apart by periodic acid schiff stain for carbohydrates
34
Give two examples of what would cause glycogen accumulation?
1. Diabetes mellitus -> counterintuitive
| 2. Glycogen storage disease -> i.e. Pompe's
35
Give the two exogenous pigments which persist in phagolysosomes which cannot be degraded?
1. Carbon
| 2. Tattooing pigments (dermal macrophages)
36
What is anthracosis?
Blackening of the lung due to inhalation of carbon dust, with black macrophages in lungs and hilar lymph nodes
-> common in coal miners
37
What is lipofuscin? Where is it seen in the microscope? Is it endogenous / exogenous?
Wear-and-tear pigment from subcellular membrane lipid peroxidation / protein remnants which cannot be digested in the autophagolysosome.
All pigments made in the body are endogenous
38
Where is lipofuscin found?
Seen near the nucleus**, finely granular, yellow-brown, only in LONG-LIVED cells like cardiomyocytes and neurons, but NOT macrophages / neutrophils which have a rapid turnover.
39
Where is melanin found? What is it?
Brown-black pigment made by melanocytes, can be phagocytosed by keratinocytes or macrophages
-> can be found in liver in melanoma
40
How is bilirubin made?
Red pulp macrophages eat aged RBCs. Heme component has Fe portion recycled by transferrin, and porphyrin ring is converted to biliverdin (green pigment).
Biliverdin -> unconjugated bilirubin, relatively water insoluble, still in macrophage.
41
How is bilirubin transported?
Unconjugated bilirubin is bound to albumin and transported in plasma
42
How is bilirubin excreted?
Hepatocytes conjugate bilirubin via glucuronidation, and bilirubin is excreted through bile canaliculi and ultimately the common bile duct into the gall bladder.
43
What factors can increase serum unconjugated bilirubin?
1. Increased RBC destruction i.e. hemolytic anemia
2. Hepatocyte dysfunction decreasing conjugation - i.e. genetic errors of UGT activity, or acquired hepatocyte injury from virus / alcohol
44
What factors can increase serum conjugated bilirubin?
1. Hepatocyte dysfunction decreasing secretion of bilirubin
| 2. Cholestasis - due to obstruction leading to decreased bilirubin secretion
45
What are some things that can cause intrahepatic / extrahepatic cholestasis?
Intrahepatic - metastases of the liver, destruction of bile ducts, cirrhosis, etc
Extrahepatic - Gall stones stuck in bile duct (choledocholithiasis), malignancies pushing on bile duct (i.e. pancreatic cancer), etc
46
What causes jaundice and scleral icterus?
Increased plasma levels of bilirubin, conjugated or unconjugated
47
How does bilirubin appear as a pigment under the microscope? How to distinguish from lipofuscin?
A green to golden-brown pigment. Although it can be brown and near the nucleus at times, typically it is found in the bile ducts / bile canaliculi, and is much more globular in appearance (lipofuscin is very granular)
48
What is hemosiderin and how is it made?
A pigment made from aggregation of ferritin micelles which are enveloped by lysosomes and degraded into low bioavailability substance
49
What is ferritin and how does it aggregate?
Ferritin is the storage form of iron used to protect the cells from ROS which iron can make. Aggregates when there is too much iron, which normally is moved from transferrin into the cell. Iron is acquired from breaking down RBCs.
50
How does iron excess happen and what are a few pathologic mechanisms?
The only iron we lose each day is from desquamation, so if we have a long period of iron excess we will have hemosiderin problems.
Mechanisms:
1. Increased dietary absorption of iron
2. Parenteral iron excess from blood transfusions
3. Degradation of hemoglobin by macrophages in localized hemorrhage or hemolytic anemias
51
How does hemosiderin appear under the microscope, and how is it told apart from carbon?
Coarsely granular, rusty-orange to brown, cytoplasmic pigment
Prussian blue stain -> granules stain deep blue (carbon will not change)
52
What serum test is directly proportional to the body's total iron stores?
Circulating serum ferritin (NOT transferrin)
53
What is transferrin saturation? What is the normal amount?
Serum iron levels (variable) divided by iron binding capacity (level of transferrin)
Normally, about 1/3 of transferrin iron-binding sites are filled
54
What is hyaline change?
A smooth, pink tissue appearance in H&E due to accumulation of protein depositions.
It is NOT a diagnosis, just a histological description of going on.
55
What are the two types of hyaline change? Give examples of each.
1. Intracellular - i.e. Alcoholic hyalin building up in hepatocytes due to intermediate filament breakdown. Or Russell bodies in plasma cells.
2. Extracellular - i.e. collagen in areas of longstanding injury, amyloid deposits, and thickened basement membranes
56
What is the most common causative mechanism of depletion of ATP in a cell? What factors can cause this?
Decreased oxygen availability.
1. Ischemia (most common)
2. Decreased oxygenation of blood from respiratory / heart failure
3. Decreased oxygen carrying capacity of blood due to anemia or CO poisoning
57
What is ischemia and its major direct consequences?
Decreased blood flow to a tissue or organ.
Consequences:
1. Hypoxia
2. Decreased supply of nutrients
3. Decreased removal of waste products
58
What are the deleterious cell reactions which can occur with a depletion of ATP?
1. Increased H20 / Na in cell -> Decreased function of Na/K ATPase
2. Drop in cellular pH leading to chromatin clumping -> glycolysis / fermentation
3. Influx of Ca+2 -> failure of Ca+2 ATPase
4. Abnormal protein synthesis -> loss of RER integrity
59
What things can cause an increased cytosolic Ca+2?
1. Decreased activity of Ca+2 ATPase due to ATP depletion
| 2. Increased membrane permeability of subcellular or plasma membranes (often MAC or complement deposition)
60
Why is accumulation of cytosolic calcium bad?
It increases activity of numerous intracellular enzymes with a variety of activities.
1. ATPases -> further deplete ATP
2. Phospholipases -> further degrade membranes
3. Proteases -> degrade structural proteins including cytoskeleton
4. Endonucleases -> breakdown of DNA
61
Other than depletion of ATP and increases in intracellular calcium, what is one additional mechanism of cellular injury / death?
Generation of Free Radicals
62
What factors increase the number of ROS in or around a cell?
1. Aerobic oxidative respiration
2. Ionizing radiation - source of hydroxyl radical
3. Drug / toxin metabolism
4. Neutrophil activation
63
What enzymes are responsible for detoxifying superoxide anion, hydrogen peroxide, and hydroxyl radical?
Superoxide anion: SOD - superoxide dismutase
Hydrogen peroxide: Catalase and glutathione peroxidase
Hydroxyl radical: glutathione peroxidase
64
What are two other mechanisms by which the cell is protected from ROS?
1. Antioxidants like vitamins A, C, and E (A & E in the membrane because they are lipid-soluble, C in the cytoplasm as it's water-soluble)
2. Iron and copper-binding proteins
65
What structures due ROS typically damage?
1. Lipids - via peroxidation of plasma + subcellular membranes
2. Proteins - alteration + degradation
3. DNA
66
What organelle is really bad to injure and how does this happen?
Mitochondria - via activation of Ca+2 dependent intracellular enymes and free-radical mediated damage
67
What can happen when mitochondria are damaged?
1. Decreased production of ATP -> further damage
2. Increased permeability of membrane -> loss of membrane potential
3. Escape of cytochrome c into cytosol -> apoptosis
68
What is thought to be the absolute breaking point of cellular damage where it becomes irreversible?
Lysosomal membrane injury -> release and activation of numerous lytic enzymes into cytoplasm
69
What are some causes of ischemia?
1. Arterial occlusion
2. Venous obstruction
3. Severe hypotension (reduces blood flow due to decreased blood pressure)
70
What determines the extent of the ischemic injury for a cell? Is ischemia typically better or worse than just hypoxia?
Particular cell type's vulnerability, as well as severity + duration of hypoxia.
Ischemia is worse than hypoxia because it also decreases availability of glycolytic substrates and stops waste removal.
71
What is atrophy vs reversible cellular injury?
Atrophy -> decreased metabolic requirements of cell to balance the reduced oxygen supply
Reversible cellular injury -> more rapid than atrophy, leads to depletion of ATP and subsquent Na+ and H20 influx which leads to cellular swelling and decreased function. However, you can come back from this.
72
What causes irreversible cellular injury?
Persistent or more severe hypoxia which leads to degradation of cellular membranes and DNA, mitochondrial and lysosomal damage
73
What are myelin figures?
Ultrastructural membrane formations which are very characteristic of necrotic cell death
74
What is reperfusion injury and its main mechanism?
Exacerbation of ischemia cell damage after blood flow is restored to the area, primarily due to production of oxygen free radicals (ETCs were saturated with electrons before oxygen rapidly came in)
75
What is an example of direct cellular toxicity by a chemical?
Cyanide inhibits oxidative phosphorylation by binding cytochrome c oxidase
76
What is the mechanism of carbon tetrachloride toxicity (CCl4)?
CCl4 is metabolized by CYP450s in the liver to make CCl3 radical, which starts the lipid peroxidation of membranes in the cell.
- > decreases RER protein synthesis in liver, leading to apoprotein deficiency and fatty change of liver
- > also damages mitochondria / cellular membranes leading to cellular death longterm
77
What is the cellular swelling of reversible cellular injury called? Is this always apparent?
Hydropic change or vacuolar degeneration
-> not always apparent morphologically, when injurious agent is mild / short lived
78
How does hydropic change appear grossly, microscopically, and on EM?
Grossly - organ will be pale & heavy
Microscopically - cells enlarged with pale / clear cytoplasm (like lipid / glycogen inclusions -> distinguish with PAS)
Electron microscopy - cell surface blebs, distended mitochondria / ER
79
What is a reversible cellular injury morphology which is common in heart and liver? What causes it?
Fatty change
- > due to ER injury, decreases protein synthesis (i.e. apoprotein)
- > intracellular accumulation of fat
80
How does fatty change appear microscopically?
As cytoplasmic lipid vacuoles
81
What is the first thing to go away during cellular injury?
Cell function (followed by biochemical alteration)
82
Does physiological necrosis occur?
No - it is always pathologic
83
How does the appearance of the cytoplasm change in necrosis and why?
1. Increased eosinophilia
- > RNAase degradation from lyosomes
- > Decreased pH due to lactic acidosis
- > denatured proteins accumulate
2. Dense, clumped, irregular appearance
- > decreased glycogen which normally gives cell a granular appearance
- > disrupted cytoskeleton from enzymatic activation
84
What are the three types of nuclear change which occur in necrosis?
1. Karyolysis - fading of nuclear chromatin
2. Karyorrhexis - nuclear fragmentation
3. Pyknosis - nuclear condensation and shrinkage
85
What causes the nuclear changes in necrosis?
Decreased pH -> clumping of chromatin
Activated lysosomal enzymes -> DNAses
86
What frequently surrounds areas of necrosis?
Host inflammatory response, including PMNs and MACs
87
What are the ultrastructural changes in necrosis?
Myelin figures, membrane disruptions, and amoprhous intracellular debris
88
Does necrosis persist indefinitely?
No, ultimately areas of necrosis will undergo enzymatic degradation and phagocytosis by immune system
89
What is the type of necrosis present in most tissues? What is its cause?
Coagulation necrosis = infarcation
- > cause is hypoxia / ischemia in ALL tissues
- > hypoxia / ischemia will NOT cause coagulative necrosis in the CNS, however
90
What is the microscopic morphology of coagulative necrosis?
Initial preservation of tissue architecture, with eosinophilic ghost cellular remnants / structural outlines intact
91
What are the causes of liquefactive necrosis? What is the exception?
1. Pyogenic bacterial infections with acute inflammatory infiltrate, and release of WBC lysosomal enzymes which enzymatically digest tissue.
2. Exception - caused by hypoxia / ischemia in CNS due to high lipid content and a small amount of PMNs
92
What is the microscopic morphology of liquefactive necrosis? Example?
Focal loss of tissue architecture -> replacement by cellular debris and inflammatory cells (i.e. neutrophils)
Example: Abscess
93
What is wet vs dry gangrene?
Dry - peripheral ischemia of extremities
-> coagulative necrosis
Wet - progression from dry, in which ischemic tissue becomes infected
-> liquefactive necrosis
94
What is caseous necrosis?
The necrosis in the center of a granuloma, which is formed by Th1 cells and macrophages
-> i.e. TB and histoplasmosis
95
What is the microscopic morphology of caseous necrosis? How is it distinguished from coagulative?
Focal loss of cellular architecture, replacement with eosinophilic amorphous debris. Area will be surrounded (but not infiltrated) by macrophages and lymphocytes
From coagulative -> will have a ring of cells around it and the cells' normal "ghost" outline will not be there
96
What is fat necrosis and where does it typically occur?
Necrosis from inappropriate release and activation of pancreatic lipases, leading to breakdown of membranes / intracellular TAGs to free fatty acids + MAGs.
-> leads to saponification (soap formation) of calcium bound to free fatty acids
-> typically occurs in pancreas (acute pancreatitis)
97
What is the gross and microscopic appearance of fat necrosis?
Gross - white, chalky patches of fatty on pancreas usually
Microscopic - hazy, basophilic outlines of adipocytes with acute inflammation associated.
-> looks like coagulative necrosis + basophilic hue from the calcium
98
What is fibrinoid necrosis?
Deposition of abundant fibrin due to vascular injury from disorders such as immune-mediated vasculitis or malignant hypertension
99
Where does fibrinoid necrosis normally appear, and what does it look like under the microscope?
Normally appears around blood vessels (small arteries, arterioles, or capillaries)
Has a smudged, hyper-eosinophilic appearance to necrotic areas
100
What do elevated tropinins mean?
There is an increase in permeability of membranes of cardiomyocytes
-> sensitive detection of myocardial injury / coagulative necrosis for 1-2 weeks
101
Which liver enzyme is elevation is most specific for liver injury and why?
Alanine aminotransferase - ALT
Aspartate aminotransferase is present in other tissues as well
102
What marker, when elevated, means there is necrosis of tissue SOMEWHERE?
Elevated lactate dehydrogenase (LD)
103
What enzymes tend to e elevated in acute pancreatitis?
Amylase and lipase
104
What are the two primary differences between apoptosis and necrosis?
1. Apoptosis is not associated with inflammation, whereas necrosis always is
2. Apoptosis can be physiologic or pathologic, whereas necrosis is always pathologic
105
What are some physiologic uses for apoptosis?
Deletion of lymphocytes that recognize self
Loss of hormonal / growth factor stimulation (i.e. regression of lactating breast, along with atrophy)
embryologic structures
106
What are some pathologic mechanisms / causes of apoptosis? What is ER stress?
Viral infections -> kill virus-infected cell (normal thing, but occurs in pathology)
Irreparable DNA damage following radiation / chemo "genotoxic stress"
Accumulation of misfolded proteins which cell cannot refold in time "ER stress"
107
What is the mechanism by which cytotoxic T cells induce apoptosis?
If they detect foreign antigen on MHC Class 1:
Use perforins to open up the cell, which mediates entry of granzymes.
Granzymes activate caspases and also Bid protein, which stimulates cytochrome C release from mitochondria
108
What are the two general pathways of apoptosis? Are they interconnected? Which caspases mediate them?
1. Intrinsic - mitochondrial-initiated pathway - mediated by caspase-9
2. Extrinsic - death receptor-initiated pathway - mediated by caspase-8
They are both interconnected. I.e. death receptor pathway can induce activation of intrinsic pathway.
109
What are the first steps in induction of the intrinsic pathway?
Sensor proteins are activated due to stressors like DNA damage or excessive misfolded proteins.
Pro-apoptotic proteins like BAX and BAK replace anti-apoptosis protein BCL-2 in mitochondrial membrane
-> increasing mitochondrial membrane permeability
110
What occurs once mitochondrial membrane permeability has been increased in the intrinsic apoptosis pathway?
1. Cytochrome c is release into the cytosol
2. Cytochrome c forms a complex into the "apoptosome"
3. Apoptosome activates caspase 9, which neutralizes other inhibitors of apoptosis
4. Caspase 9 activates cascade of additional caspases into execution phase
111
What is the main mechanism of the extrinsic apoptosis pathway?
FasL on T-cells binds Fas receptor on cell to die.
1. Binding of FasL
2. Fas receptors cross-link
3. Binding of Fas-associated death domain (FADD) adaptor protein
4. Activation of Caspase 8 and executioner caspases
112
What do caspases do in the execution phase?
They are proteases which rapidly, sequentially activative other caspases
1. Degradation of cytoskeleton and matrix
2. Endonuclease activation - specific internucleosome DNA cleavage sites (can be seen as a ladder on gel electrophoresis)
113
How are cell membranes modified in apoptosis and what is the purpose of this?
Phosphatidylserine becomes expressed on the outside rather than interior of cells
- > enhanced macrophage recruitment and phagocytosis
- > efficient removal of apoptotic cell without inflammation
114
How can apoptosis be seen on morphology?
Cells are often hard to find and coexist with necrosis
- > rounded, condensed, hypereosinophilic cell which is reduced in size, with peripherally compacted nuclear chromatin
- > will form dense, membrane-bound apoptotic bodies
115
What type of death pathway does TNF binding usually trigger?
Caspase-8-mediated death receptor-dependent cell death (extrinsic pathway)
116
What is necroptosis? Can it be physiologic?
Programmed cell death with features of apoptosis and ultimately necrosis
Yes, it is a mechanism which can be active physiologically
117
Why does the necroptosis pathway exist?
If the caspase-8 pathway is inhibited (i.e. by a pathogen evasion mechanism or a tumor mutation), apoptosis will still occur via necrosis
-> necrosome causes metabolic alterations and necrotic cell death via decreased ATP and increased ROS
118
What is pyroptosis? What cell types does it usually occur in?
A form of programmed cell death in which one cell sacrifices for the good of all, leading to massive cytokine release and immune recruitment
Usually in macrophages and dendritic cells
119
How does pyroptosis work and what cytokines are involved?
Microbial infections / certain tissue damage results in activation of inflammosome, leading to release of IL-1 and IL-18 via Caspase-1 mediated pathway.
120
What is the relative activity of telomerase in somatic, stem, and germ cells?
Germ cells - total activity
Stem cells - partial activity
Somatic cells - no activity - senescence after a finite number of divisions (Limited proliferative capability)
121
What is cumulative nonlethal cellular energy? What factors contribute?
A determinant of aging
- > repetitive damage by oxygen derived free radicals from Ox-Phos
- > Repeated damage and decreased repair of DNA
- > Decreased normal folding of proteins / accumulation of misfolded proteins
122
What are the two major types of pathologic calcification and which is most common? Which one is associated with abnormal serum calcium levels? Which will produce tissue dysfunction?
1. Dystrophic - most common, associated with tissue damage / necrosis. Much more likely to cause tissue dysfunction
2. Metastatic - associated with abnormally high serum calcium
123
What is the pathogenesis of dystrophic calcification?
In cell injury / necrosis, there is increased membrane permeability. Extracellular vesicles form which bind calcium, and calcium pours into the cell.
- > phosphate binds intracellular and extracellular calcium
- > development of calcium phosphate crystals in and around necrotic tissue (i.e. bicuspid aortic valve)
124
What is the pathogenesis of metastatic calcification? Causes?
```
Increased serum calcium levels leads to systemic deposition of calcium salts
Causes include:
-> excess PTH leading to bone resoprtion
-> lytic skeletal disorders
-> increased vitamin D activity
```
125
What tissues are more susceptible to metastatic calcification?
Normal organs with alkaline interstitium (calcium precipitates in basic conditions)
- > places which secrete acids
- > stomach, kidneys, lungs
126
How do calcifications appear grossly?
Hard, white foci
127
How do calcifications appear under the microscope?
Basophilic particulate material
128
What are two unique variants of dystrophic calcification?
1. Psammoma bodies - circular, onion-like concretions with concentric layering
2. Ectopic bone - i.e. myositis ossificans
