Cell injury, death and adaptations Flashcards
1
Q
What is Pyknosis?
A
Clumping and shrinking down of chromatin in cell nuclei during necrotic cell death.
2
Q
What tissue/cellular changes are considered reversible stress responses?
A
Hypertrophy
Hyperplasia
Atrophy
Metaplasia
3
Q
What is karyorrhexis?
A
The fragmentation chromosomes and nuclear content seen in necrosis. Nuclear membrane is lost here.
4
Q
What is karyolysis?
A
The melting of the chromatin in the nucleus seen during necrosis. The membrane of the nucleus remains intact.
5
Q
What changes are seen during cell injury in cells that store fat?
A
The rapid accumulation of triglycerides occurs leading to saturation with triglyceride filled vacuoles. Happens due to the failure of lipid trafficking mechanisms that usually occur in these cells when they aren’t injured. E.g. hepatocytes.
6
Q
Do dying cells take on more hematoxylin dye or more eosin? Why?
A
Dying or injured cells appear to have more pink (eosin) cytoplasm than other cells. This is because RNA which usually binds blue hematoxylin is not as abundant in the cytoplasm of injured or dying cells. Further, denatured cytoplasmic proteins take on more eosin.
7
Q
What happens to the endoplasmic reticulum during necrosis?
A
Becomes swollen and, when it becomes pinched off, I forms vacuoles. This is sometimes referred to vacuolar degeneration and is seen in dying cells.
8
Q
Does surrounding pancreatic tissue die via necrosis or apoptosis primarily during acute pancreatitis?
A
Necrosis. The leaked lipases, amylases etc destroy tissues around them.
9
Q
Why do necrotic cells take on a glassy appearance?
A
Loss of glycogen particles.
10
Q
What are myelin figures?
A
After a cell has died by necrosis, it forms a clump of phospholipid called a myelin figure.
11
Q
What are the possible degradation pathways for myelin figures?
A
They can either by phagocytosed by immune cells or further degraded into fatty acids that can become calcified and cause pathogenic calcification.
12
Q
What is coagulative necrosis? What aetiologies are suggested by this finding?
A
Necrosis with preserved tissue architecture that lasts for days, presumably due to inactivation of digestive enzymes at the same time as the cells died. This finding suggests infarcted tissue everywhere except the brain. Brain infarction causes liquefactive necrosis.
13
Q
What is liquefactive necrosis?
A
Digestion of dead cells resulting in transformation of the tissue into a viscous liquid. Seen in brain infarctions, bacterial or fungal and fungal infections.
14
Q
What is gangrenous necrosis?
A
Refers to a limb that has had tissue undergo necrosis in multiple planes. Can involve coagulative necrosis plus liquefactive necrosis if there are bacteria involved.
15
Q
What is caseous necrosis?
A
Cheese like necrosis derived from mycobacterial infections. Microscopically is a granuloma with central necrosis.
16
Q
How does fat necrosis appear? What’s its most common cause?
A
Acute pancreatitis causes fat degrading enzymes to mix with peritoneal fat, causing the metabolism of triglycerides to fatty acids that calcify and turn white.
17
Q
What is fibrinoid necrosis?
A
Vascular damage usually secondary to immune complex disease. These deposits cause leak of proteins out of vessel cells forming bright pink eosin staining amorphous structures in vessel walls.
18
Q
What is dystrophic calcification?
A
When necrotic tissue is not completely cleared by surrounding cells or immune cells, it becomes calcified. This is dystrophic calcification.
19
Q
What does cellular swelling, fatty change, plasma membrane blebbing, loss of microvilli, mitochondrial swelling, ER dilation, and eosinophilia all suggest what?
A
Cell injury, but not yet necrosis!
20
Q
What signs indicated the point of no return to necrosis has likely taken place?
A
Nuclear pyknosis, karyorrhexis and karyolysis. Organellebrane destruction. Plasma membrane destruction. Myelin figures.
21
Q
What situations lead to pathological apoptosis?
A
DNA damage from radiation or other causes.
Accumulation of misfolded proteins in th ER
Viral infections can induce apoptosis
Cytotoxic t cells can force apoptosis
Organ duct blockage
22
Q
Do apoptotic cells shrink or swell?
A
The shrink
23
Q
What cells are most likely to phagocytose apoptotic cells or cell bodies?
A
Macrophages
24
Q
What are the key enzymes that coordinate apoptosis?
A
Caspases
25
What are the two pathways that can lead to apoptosis?
Intrinsic (triggered by mitochondria) and extrinsic (triggered by receptor binding)
26
Which apoptosis pathway is responsible for apoptosis in most situation?
The intrinsic mitochondrial pathway
27
What protein family is primarily responsible for modulating the permability of mitochondrial membranes and so intrinsic apoptosis?
The BCL2 family of proteins.
28
What are the most significant antiapoptotic BCL2 family proteins involved in intrinisc apoptosis?
BCL2, BCL-XL and MCL1. These proteins reside in the mitochondrial out memebrane, in the ER membranes and in the cytosolic membrane. The prevent permeability of the membrane and so prevent the leak of caspase activating proteins out of the mitochondrial intermembrane space.
29
What are the most signficiant pro-apoptotic BCL2 family proteins involved in intrinsic apoptosis?
BAX and BAK. On activation BAX and/Bak oligomerise and increase the mitochondrial out membrane permeability by forming a channel. They may even form a channel. They also inhibit BCL2 itself which has antiaptotic function.
30
What are the regulated apoptosis inititors (pro-apoptotic) from the BCL2 family linked to cellular stress sensors? What's the other name for these?
Sometimes called the BH3- only proteins. This is because they only have the BH3 domain (other BCL-2 families have BH1-4)
-BAD
-BIM
-BID
-Puma
-Noxa
31
What proteins do growth factors influence in order to reduce the risk of apoptosis?
Growth factors usually leady to increased production of BCL2 +/- BCL-XL +/ - MCL-1 which all contribute to mitochondrial membrane stability and impermeability, this preventing apoptosis and promoting longevity.
32
What do extracellular survival signals do to BCL2 exert anti-apoptotic effects on the cell?
Extracellular signals usually bind to their receptors and exert their effects on apoptosis by increasing the concentration of BCL2 inctracellularly.
33
What does cytochrome C bind to once released from the cytosol to continue the intrinsic apoptosis cascade of events? The complex of this structure and cyctochrome see creates a new organelle called what?
It binds to APAF-1 (apoptosis activating factor 1). This complex is called the apoptosome!
34
What does the apoptososome bind to to continue the apoptosis pathway?
APAF-1 coupled with cytochrome C from the intermembrane space of mitochonria (the apoptosome) binds to an activated caspase-9. Caspase-9 is then catalytically active.
35
After Caspase-9 is made catalytically active by the apoptosome (cyctochrome C and APAF-1), what does it do?
Caspase-9 triggers a caspase cascade - caspase-3 and others, that trigger the controlled distruction o f the cell.
36
What are Smac/DIABLO? (hint: to do with apoptosis)
Smac (second mitochondrial activatory of caspases) AKA DIABLO (direct IAP (inhibitor of apoptosis) binding protein with low pI) - are proteins other than cytochrome C that are released from the mitochondria as part of intrinsic apoptosis. They bind do inhibitors of apoptosis, neutralise them, and thus drive the cell towards apoptosis.
37
What's the family of receptors generally associated with extrinsic apoptosis? What are its 2 key members?
Tumor necrosis factor receptor - specifically, the members of this family that have the intracellular 'death' domain. Note that some of the receptors in this family are associated with inflammation and proliferation, but they critically lack the death domain. Key members of this TNF death receptor family is Fas (CD95) and TNFR1.
38
What extrinsic apoptosis receptor is involved in the death of self-reactive T cells during maturation?
Fas-FasL
39
What extrinsic apoptosis initiating protein is used by cytotoxic T-cells to intitiate apoptosis on cells infected with virus or tumour cells?
Fas ligand
40
When Fas becomes bound to Fas-ligand, it complexes with other Fas (>3). Their death domains now complexed are able to bind to an adaptor protein called what?
Fas-associated death domain (FADD).
41
FADD, the Fas-associated death domain adaptor protein that binds to Fas-Fas ligand intracellularly, binds to and activates what key enzyme to continue the extrinisc apoptosis pathway?
Caspase 8 OR Caspase 10
42
Caspase 8, once activated by FADD (the result of Fas-Fas ligand binding), does what as part of the extrinsic apoptosis pathway?
Once active, it is the linking stage of the extrinsic with the intrinsic apoptosis pathway. Caspase 8 cleaves other caspases in th executioner pathway like Caspase 3 and caspase 6. It has the same enzymatic activity as Caspase 9 from the intrinsic apoptosis family.
43
What is the role of FLIP (FLICE (Fas-associated death domain–like interleukin 1β–converting enzyme) Inhibitory Protein) AKA CFLAR (Capase 8 and FADD-Like Apoptosis Regulator)? What pathogens take advantage of this?
FLIP aka CFLAR inhibtis the binding of FADD (Fas-associated death domain, generated by the binding of Fas L- Fas as part of the extrinisc apoptosis pathway) to Caspase 8. FLIP/CFLAR therefore blocks the progression of extrinisic apoptosis. v-FLIP is a viral version of this protein that is used to prevent its host cells from undergoing apoptosis at the hand of T-cell initiated Fas L.
44
What are the best studied 'executioner caspases'?
Caspase 3 and 6. Both can be activated by Caspase 8 or 10 (extrinsic pathway) or caspase 9 (intrinsic pathway).
45
What apoptotic cells do their plasma membranes to make them more apetising to phagocytes?
They pressent more phosphatidylserine on the outer leaflet of the plasma membrane phospholipid bilayer (the inverse of the health cell state).
46
What is efferocytosis?
It refers to the extremely rapid clearance of cells that have died via apoptosis.
47
Necroptosis is what?
Hybrid cell death - part necrosis part apoptosis.
48
What occurs during necroptosis?
The cell dies in a necrotic way but it is triggered by an internal signalling cascade. In this way, it apperas to be hybrid of necrosis and apoptosis.
49
Are caspases involved in necroptosis?
No. Although the process of necroptosis starts in a similar way, with binding of an TNF family receptor (the best studied is TNFR1), the intracellular signalling leading to cell death is by different proteins.
50
In TNFR1 necroptosis, what are the intracellular signalling molecules involved?
Receptor-interactin protein kinase 1 and 3 form a multiprotein complex with TNF ligated TNFR1 intracellular domains (RIPK3). This phosphosphorylates MLKL (Mixed lineage kinase domain-like protein), These MLKL molecules polymerise into oligomers and disrupt the plasma membrane leading to necrosis.
51
Do cells that die via necroptosis appear necrotic or apoptotic under light microscopy?
Necrotic. The apoptosis like feature of necroptosis is that the necrosis is initiated with intracellular signalling.
52
In TNFR1 necroptosis, what protein is eventually responsible for plasma membrane rupture?
MLKL (mixed lineage kinase domain-like protein)
52
What is pyroptosis?
Apoptosis accompanied by the release of the pyrogen IL-1. This is mediated by recognition of microbial products by intracellular toll like receptors leading to inflammasome activation, which casuses Caspase 1 activation, which cleaves an IL-1 precursor leading to its release. Caspase 4 and 5 are later actived and cause the controlled death of the cell.
53
Which caspase is responsible for IL-1 precursor activation?
Caspase 1
54
How does pyroptosis compare with apoptosis?
Apoptosis is purely non-inflammatory and non-necrotic process driven by caspases. Like apoptosis, pyroptosis is also non-necrotic. It is unlike apoptosis however in that it is a purposfully proinflammatory process that is driven by caspases that do this acitvely - caspase 1,4,5.
55
What is ferroptosis?
Death caused by excessive intracellular levels of iron or reactive oxygen species. Resembles necrosis under light microscopy.
56
How do increased iron or reactive oxygen species cause cell death in ferroptosis?
The excess iron or reactive oxygen species overwhelm the glutathion-dependent atioxiant defences in the cell, and unchecked membrane lipid peroxidation. This disrupts the plsama membrane, interfering with its fluidity, lipid-protein interactions, ion permeability, and transmembrane signalling pathways. The process is however regulated by specific intracellular signalling pathways and can be everted if the causeative agents are reduced - thus the distinction from necrosis.
57
Does ferroptosis look more like necrosis or apoptosis under light microscopy?
Necrosis. The process is however regulated by specific intracellular signalling pathways and can be everted if the causeative agents are reduced - thus the distinction from necrosis in name.
58
Autophagy describes what?
A cell eating its own contents. It's the way in which intracellular contents are recycled.
59
What are the steps involved in autophagy?
'Initiation' and 'nucleation' complexes combine and trigger the engulfment of no longer needed intracellular components in membrane derived from the ER to be begin forming the autophagosome. A key protein (microtubule-associated protein light chain 3) is involved in ensuring the elongation of the membrane around th autophagmosome until it becomes fully enclosed. The autophagosome then fuses with lysosomes which destroy its contents for reuse.
60
What is thought to be the main diver of transcription of autophagy related genes?
Deprivation of nutrients and growth factors. This leads to conservation of energy and re-use of inctracellular contents via autophagy.
61
What does microtubule-asscoiated portein light chain 3 (LC3) bind to that enables to to elongate the autophagosome membrane?
It forms a covalent linkage with phosphatidylethanolamine (PE) to form PE-lipidated LC3. This substance increases substantially during autophagosome formation and acitivity and so is used as a marker of autophagosome activity in the laboratory.
62
Does the autophagosome randomly include intracellular contents for destruction?
No, there is some evidence to show that PE-LC3 (phosphatidylethanolamin lipidated light chain 3) selects for ineffective organelles and clumped non-functional protein.
63
What do Alzheimers and Huntington's disease have to do with autophagy?
They are both diseases that are associated with failure of the autophagy mechanism to keep pace with the accumulation of abnormal proteins. Deletions in autophagy related genes have been shown to accelerate neurodegenerative disease phenotypes in rodents.
64
What effect do hypoxia, radiation and some toxins all have mitcochondria?
They all disrupt the oxidative phosphorylation pathway and reduce its ability to produce ATP for the cell leading inactivity of plasma membrane sodium/potassium ATPase and cell death.
65
What is the impact of Na/K atpase function?
Influx of sodium with increased intracellular osmolality, leading to water influx and cell swelling.
66
Other than reduced production of ATP, what does mitochondiral oxidatative phosphorylation disruption lead to?
Accumulation fo ROS that cause damage to cells. Glycolysis, lipolysis, and glycogenolysis became the primary ways of manufacturing ATP, leading to the byproduct of lactate - this raises cell pH and causes impaired enzymatic function intracellularly.
67
What happens to ribosomes in an ATP deplete environment?
They detach from rought ER. Protein synthesis is impaired.
68
What type cell death ensues if there is irreversible damage to too many mitochondria leading to impaired ATP production?
Necrosis
69
What is the most frequent change to DNA that occurs during DNA damage and leads to p53 mediated apoptosis?
The deamination of cytosine to uracil.
70
What cell cycle in hibitor, that prevents cells from moving through checkpoint inhibitor 1 (out of the G1 phase), is commonly activated in the setting of detected DNA damage?
p53.
71
How does p53 initiate apoptosis in the context of excess detected DNA damage?
It activates intrinsic apoptosis pathway by activating the proapoptic protein BAX.
72
What is a reactive oxygen species?
It is an oxygen containing molecule that has an unpaired electron its outermost orbit.
73
What happens to molecules adjacent to reactive oxygen species?
An electron is torn away from them and they are damaged. This can be the end of events, however in some situations, the target molecule itself becomes reactive oxygen species (or multiple) and a chain reaction or amplifying event can occur.
74
How is the majority of reactive O2 produced in the body?
Incomplete oxidative phosphorylation in leukocytes
75
How is H2O2 (hydrogen peroxide, reactive O2 species) usually generated in the body?
Generated by superoxidase dismutase (SOD) from O2- (ROS O2) in the cytsol, or by oxidase in peroxisomes
76
How is the OH (hydoxyl) reactive oxygen species (ROS) generated in the body?
Hydrolysis of H2O (e.g. by radiation), or from H2O2 by the Fenton reaction (oxidation of H2O2 by iron ions).
77
How is the ROS (reactive oxygen species) peroxynitrite (ONOO-) generated in the body?
By the interaction of O2 sans electron and nitrous oxide (NO is synthesised in many cells by NO synthase, e.g. endothelial cells)
78
How is a the ROS O2 sans electron elimated?
Conversion to H2O2 and O2 by superoxide dismutase (SOD)
79
How is H2O2 (hydrogen peroxide) inactivated so it doesn't cause cell damage?
Conversion to H2O and O2 by catalase in peroxisomes, and by glutathione peroxidase in the cytosol or mitochondria
80
What is the role of glutathione peroxidase?
The conversion of hydrogen peroxide (highly destructive) to H2O and O2 in the cytosol or mitochondria.
81
What enzyme is responsible for hydrogen peroxide break down in peroxisomes?
Catalase
82
What does catalase do?
It converts hydrogen peroxide into water and oxygen. Used physiologically to protect against H2O2, but also produced by microbes (e.g. staph aureus) to protect themselves from oxidative bursts.
83
How is OH (the hydroxyl ROS) neutralised in cells?
Glutathione peroxidase
84
How is ONOO- (the reactive O2 species peroxynitrite) eliminated to prevent unwanted damage?
Conversion to HNO2 (nitric acid, a very weak acid) by peroxiredoxins
85
What are peroxiredoxins?
Enzymes that are able to neutralise peroxynitrite (ONOO-, a reactive oxygen species) in the cytosol and mitochondria to prevent unwante ROS induced damage.
86
Out of the main reactive oxygen species ROS encountered in the human body (O2 sans electron, H2O2, OH, ONOO-), which is the most reactive and most destructive?
OH, hydroxyl radicals
87
With regards to potential cell damage, what is the role of protein binding to iron ions in the cell or circulation?
Free ioninic iron (E.g. Fe3+) will perticipate in the Fenton reaction to preduce substantial quantities of -OH (hydroxyl O2 free radicals). To prevent this, ioninc iron is usually protein bound so it can't undergo a Fenton reaction.
88
What is the chemical reaction catalysed by superoxidase dismutases?
2O2 (sans electron) + 2 H -> H2O2 + O2.
H2O2 is then further broken down to water and non-reactive O2 by catalase.
89
What are the three main ways theat free radiacals damage the cell?
Lipid peroxidation (damaging the plasma membrane), oxidative modification of proteins, and DNA lesions (ROS can cause single and double stranded DNA breaks).
90
What is the effect of uncontrolled calcium concentration rise intracellularly?
Phopholipase, endonuclease, ATPase, and protease activity all increases in an uncontrolled manner, leading to the destruction of the cell inside out.
91
What is the result of intra-endoplasmic reticulum misfolded protein excess?
Activation of the ER stress response that initially leads to overproduction of chaperone proteins. This increased concentration is negatively regulatory and leads to reduced protein production to take stress of the ER. If the stress persists, eventually intrinsic apoptosis via activation of downstream caspases takes place.
92
Familial hypercholesterolaemia is inherited problems with the LDL receptor. What way do cells die as a result of this mutation?
Misfolded LDL causes ER stress and apoptosis.
93
What is the difference between hypoxia and ischaemia?
Ischaemia is the entire loss of blood supply to tissue due. Hypoxia is the deprivation of oxygen from tissue. Blood flow may continue to occue in hypoxic tissue.
94
Why is ischaemia more catastrophic than hypoxia?
Under hypoxic conditions, ATP production can continue, albeit in an ineffecient way, through glycolysis/glycogenolysis/lipolysis. Ischaemia deprives the tissue of the substrates for glycolysis - so this ceases as well. Further, waste products of metabolism are not washed away in ischaemic tissue leading to furhter tissue damage.
95
How do cell sdie from ischaemia?
ATP production reduced to glycolysis -> sodium/K pump failure -> water influx and cell oedema -> pH rise due to lactate production leads to DNA damage -> ribosomal detachment -> necrotic death
96
What key enzyme activates in the presence of hypoxia to stimulate the production of new bloods vessels?
Hypoxia inducible factor -1.
97
What functions does hypoxia inducible factor-1 (HIF-1) have?
Initiates intracellular survival pathway signalling, enhances glycolysis, and stimulates the production of new blood vessels
98
What are the mechanisms at play in ischaemia-reperfusion injury?
Oxidative stress (incomplete redox reactions much higher incompletely perfused tissue)
Intracellular calcium overload Inflammation (via the introduction of a truckload of DAMP recognising innate immune cells)
Complement activation
99
What is hypertrophy?
Increase in the size of the cells that make up an organ, leading to increased size of that organ.
100
How do cells get bigger in hypertrophy?
By increasing the amount of intracellular material - including structural components.
101
During pregnancy does the uterus undergo hypertrophy or hyperplasia?
Hypertrophy. In response to oestrogen receptors.
102
Which dowstream signalling pathway for growth is thought to be the most important in the hypertrophic response to mechanical force?
The phosphoinositide 3-kinase (PI3K)/AKT.
103
What are some of the extracellular signals that appear to contribute to intitiating the hypertrophic response?
Ageniotensin, IGF-1 and alpha-adrenergic hormones
104
What does hyperplasia occur instead of hypertrophy?
Many of the triggers are the same external factors, a perhaps more important factor is if the cell type affected has the ability to divide easily. Cardiomyocytes don't readily divide, so they are more likely to undergo hypertrophy. Breast tissue however is able to under hypertophy and dose so under the influence of oestrogen.
105
Hyperplasia is by definition not cancerous. Why doe we still worry about malignancy when hyperplasia is found?
If there is disproportionate cell division occuring in an inappropriate setting, then this is fertile ground for the accumulation of mutations that could lead to cancer. E.g. endometrial hyperplasia is risk factor for endometrial cancer.
106
What kind of cellular change is seen in tissue is seen in response to infection by human papilloma virus?
Hyperplasia. Important in the cervix - hyperplasia here is considered a precancerous lesion.
107
What are the subtypes of atrophy?
Disuse atrophy - from underutilisation of tissue. E.g. when in a plaster cast.
Denervation atrophy - realy the same as disuse, but the cause is loss of innervation of muscle group meaning that it cannot be used and atrophies.
Diminished blood suppply - atrophy by forced lack of nutrients.
Malnutrition atrophy
Loss of endocrine stimulation atrophy (e.g. vaginal atrophy)
Pressure atrophy - e.g. from a tumour on surrounding tissue (effectively the same as diminished blood supply atrophy).
108
What is atrophy?
Reduction in the size of an organ due to its reduction in cell size AND number.
109
What are the main pathways utilised by cells undergoing atrophy to reduce their size?
Ubiqutin-proteaosome pathway is the main one. Autophagy occurs in some situations.
110
Seen in atrophic tissue, what are the residual components of the autophagosome that have resisted digestion called? (visible under light microscope)
Residual bodies. An example of a residual body is called lipofuscin granules. These granules discolour tissue brown, which is why when it's seen it's sometimes called 'brown atrophy'.
111
What is metaplasia?
A reversible change in which one cell type is replaced by another. Usually due to a change in the environment the tissue finds itself.
112
What is the most common type of metaplasia seen?
Change from columner to squamous metaplasia. Seen in smokers in their bronchial epithelium.
113
What type of metaplasia does Vitamin A deficiency lead to?
It causes columner to squamous metaplasia in the respiratory tract, but also in the cornea.
114
What type of metaplasia is seen following the chronic inflammation of the salivery glands, bile ducts, an pacncreatic ducts?
Metaplasia from stratified secretory columner epithelium to stratified squamous epithelium.
115
Metaplasia is not malignancy - so why is it concerning?
2 reasons - loss of function of the intended tissue. Take respiratory metaplasia for example - the pseudostratified columner ciliated epithelium that lines it is able to produce mucus to trap organisms effectively, then use the motility of the cilia to cause effective expectoration of foregn substances and microbes. Squamous epithelium seen after metaplasia is unable to do this. Secondly the transformation of the tissue creates a mitotic burden on the affected tissue, which leads to an increased risk of errors during replication leading to maligancny.
116
With regard to metaplasia is interesting about Barrett oesophagus?
It represents metaplasia from normal squamous cells to intestinal columnar epithelium. Metaplasia is more commonly the other way round (e.g. smoking's effect on the columnar epithelium of the bronchi)
117
What is connective tissue metaplasia?
It's when connective tissue (mesenchymal tissue, that is e.g. bone, cartilege, ligament, tendon etc) form where they shouldn't. Sometimes occurs following intramuscular haemorrhage (myositis ossificans).
118
Is connective tissue metaplasia associated with increased cancer risk?
Unlike other forms of metaplasia, connective tissue metaplasia appears to present no increased risk of malignancy.
119
How does metaplasia occur?
It is not the transformation of an already differentiated cell type. It is the change of external stimuli on the stem cells servicing the affected tissue that differentiate in a different way as a result of the changed stimuli.
120
What are the diseases called associated with deficiencies in lysosomal enzyme quantity of function?
Lysosomal storage disease.
121
What is steatosis?
The accumulation of triglycerides within parenchymal cells.
122
What is a xanthoma?
Inctracellular accumulation fo cholesterol in macrophages (foamy macrophages) clump together in connective tissue and form xanothomas.
123
What is cholesterolosis?
The accumulation of cholesterol laden macrophages in the lamina propria of the gallbadder
124
In amyloidosis, are the protein deposits seen under light microscopy usually seen intracellularly or extracellularly?
Extracellularly
125
In nephrotic disease, what is likely to be seen in the cells of the proximal renal tubules?
Reabsportion droplets - reabsorption of some of the protein that is being lost in the glomerulus is seen as small vacuoles of protein in the proximal renal tubular cells, taken up by pinocytosis. The protein appears pink (eosinophilic). The ER of these cells becomes hughely distended and forms 'Russell bodies' (dense homogenous eosinophillic inclusions).
126
Patients with some mutations of alpha-1 antitrypsin end up with accumulations of this protein in the liver. Where do these proteins accumulate?
In the endoplasmic reticulum. This leads to cell death via the ER misfolded protein response casuing apoptosis.
127
In alcoholic liver disease, steatosis is a common finding under light micrscopy. There also a classical change to the cytoskeletal structures within hepatocytes - what is this?
Accumulations of keratin filamints occurs. In alcoholic liver disease, these clumps of keratin intermediate filaments are called alcoholic hylaine.
128
Accumulation of cytoskeletal structures occurs in alcoholic liver disease (keratin intermediate filaments - alcoholic hyaline). Cytoskeletal protein accumulation occurs in neurodegenerative diseases like alzheimers disease. What are they called?
Neurofibrillary tangles invlolving the the tau protein are found in alzheimers and other neurodegenerative diseases.
129
What is meant by the term hyaline change?
Hyaline refers to alteriation within cells or in the extgrcellular space giving rise to a homogenous, glassy, pink appearance in H+E stained tissue.
130
Does hyaline change suggest protein accumulation?
Not necessarily - it's a descriptive term rather than something associated with specific pathology. Some protein aggregation pathological processes appear hyaline (e.g. reabsoprtion droplets, Russell Bodies, alcoholic hyaline), but so to the arteries of patient's with hypertension without any protein aggregation process.
131
What does intracellular glycogen look like under light micrscopy?
When H+E stained - clear vacuoles. When Best carmine or Periodic Acid Schiff, it stains a rose-to-violet colour. Diastase digestion of paralell sections is often needed to ensure the substance being observed is glycogen and not protein that can also take on this appearance.
132
What stains are needed to observe glycogen?
Periodic Acid Schiff (PAS) or Best carmine.
133
What common disease might you expect to see excess glycogen in the renal tubular epithelial cells, as well as within the liver, the beta islets in the pancrease and within heart muscle?
Type 2 diabetes mellitus
134
In glycogen storage diseases (a group of genetic diseases), why is glycogen accumulated in cells?
Genetic defects in the proteins required in the processing and use of glycogen. This leads it its accumulation in cells, that eventually causes injury and cell death.
135
What is lipofuscin?
And endogenous intracellular (oftne perinuclear) pigment (yellow-brown) that results from free radical induced cellular injury - explicitly the injury to lipids. It is, in of its self, not harmful, but tells of previous free radical injury.
136
When calcium is deposited in necrotic tissues locally, what is it called?
Dystrophic calcification. This occurs despite normal serum levels of calcium and when there is normal calcium metabolism functin.
137
When calcium is deposited in otherwise normal tissues, what is this called?
Metastatic calcification. This is almost always the result of hypercalcium due to some disruption to normal calcium metabolism.
138
How does cacluim appear under light microscopy with h+e staining?
Purple, basic, amorphous granular clumps. They can be intra or extracellular.
139
What are the causes of increased serum calcium?
1) Increased PTH production (endogenous parathyroid related or ectopic from malignancy e.g. SCC)
2) PTH independent resorption of bone secondary due to boney tumours, mets, Paget's disease, immobilisation
3) Vitamin D related - intoxication, sarcoidosis (macrophages activate a Vit D precursor), and hypecalcaemia of infancy (abnormal increased sensitivity to vitamin D)
4) renal failure (retention of phosphate, secondary hyperparathyroidism.
5) aluminium intoxication (renal dialysis patients).
6) Milk-alkali syndrome (excess ingestion of calcium and absorbable ant-acids)
140
How does sarcoidosis cause hypercalcaemia?
Uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages. Note thought that only about 10% of patients with sarcoidosis present with hypercalcaemia, and it is rarely severe.
141
What are the most commonly affected tissues in metastatic calcification? Why are they most likely to be affected?
Interstitium of the:
Gastric mucosa
Kidneys
Lungs
Systemic arteries
Pulmonary veins
They all exrete acid.
142
If a patient is a coal miner and presents with HRCT with fibrosis, what di you exptect to see on histology of the lungs?
Intracellular pigment accumulation - carbon.
143
What gene is mutated in Werner syndrome?
DNA helicase - an enzyme that unwinds DNA so that it can be accessed. These patients prematurally age. DNA helicase is critcial to replication and repair and other functions requring DNA unwinding.
144
What are thought to be the main control mechanisms governing the number of replicative cycles until a cell enters senesence?
Telomere atrition - after the protective caps are worn down by repeated replication, the substantive chromosomal DNA becomes damaged on replication which prevents the cell from crossing the G1->S checkpoint.
Defective protein homeostasis/autophagy
Overactive cell replication and sirtuin availability (as seen by calorific restriction studies leading to long living which reduces IGF-1 and increases sirtuins)
145
Intermittent fasting leads to the increased production of what clasxs of molecules?
Sirtuins
146
What do sirtuins do?
Transcription regulators that promote transcription of:
1) metabolism inhibitors
2) apoptosis suppressors
3) improve protein folding
4) antioxidant functions.
5) improved insulin sensitivity
6) promote DNA repair through de-acylation
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