Cell Injury Flashcards
(446 cards)
1
Q
What is pathology?
A
The study of suffering
2
Q
What does pathology investigate?
A
The structural and functional changes in cells, tissues, and organs that are seen in disease.
It is the study of disease and cellular malfunction
3
Q
What are diseases the result of?
A
Intrinsic abnormalities or external factors, or both
4
Q
What is an intrinsic abnormality?
A
Genetic
5
Q
Give an example of an external factor?
A
Infections
6
Q
What does diagnostic pathology involve?
A
Studying the structural and functional alterations in cells and tissues in order to arrive at a diagnosis
7
Q
What results in the symptoms and signs of a disease?
A
The morphological changes in cells and tissues and their distribution within an organ
8
Q
What does all disease start with?
A
Molecular or structural alterations in cells
9
Q
When are cells able to maintain homeostasis?
A
When subjected to mild changes in environmental conditions
10
Q
What happens when environmental changes are more severe?
A
Cells undergo physiological and morphological adaptations in an attempt to remain viable
11
Q
How may cells react to injury?
A
They may increase or decrease their level of activity
12
Q
What does wether cells increase or decrease their activity with injury depend on?
A
The nature and intensity of the injury
13
Q
How may a cell increase its level of injury?
A
Hyperplasia
14
Q
How may a cell decrease its level of activity?
A
Atrophy
15
Q
What happens when cells reach their limits of adapative response?
A
They may show evidence of reversible injury, or become irreversibly injured and due
16
Q
What does the degree of cell damage depend on?
A
Type, duration and severity of an injury, and the type of tissue thats involved
17
Q
How was it discovered that cells are the basic unit of the body?
A
Through the microscope
18
Q
Where does the ultimate abnormality lie in disease?
A
The cell
19
Q
What can damage cells?
A
Hypoxia Physical agents Chemical agents and drugs Micro-organisms Immune mechanisms Dietary insufficiency and deficiencies, and dietary excess Genetic abnormalities
20
Q
What is hypoxia?
A
Oxygen deprivation
21
Q
What does hypoxia result in?
A
Decreased aerobic oxidative respiration
22
Q
How can energy production continue in hypoxia?
A
Through glycolytic energy production
23
Q
What happens if hypoxia is persistent?
A
Cell adaptation, cell injury and cell death
24
Q
What cell adaptation may be used in hypoxia?
A
Atrophy
25
How long can a cell tolerate hypoxia?
It varies
Some neurones can only tolerate a few minutes
Dermal fibroblasts can tolerate a number of hours
26
What is ischaemia?
A loss of blood supply due to reduced arterial supply or reduced venous drainage
27
What can cause a reduced arterial supply of blood?
Obstruction of an artery
| Hypotension
28
What does ischaemia cause?
A reduced supply of oxygen and metabolic structure
29
What is the result of ischaemia also causing a decreased supply of metabolic substrates?
It occurs more rapidly and is more severe than seen with hypoxia
30
What can the causes of hypoxia be classified as?
Hypoxaemic
Anaemic
Histiocytic
Ischaemic
31
What is meant by hypoxaemic?
The arterial content of oxygen is low
32
Why may hypoxamia occur?
Reduced inspired pO2 at altitude
33
What happens in anaemic hypoxia?
There is a decreased ability of haemoglobin to carry oxygen
34
What can cause anaemic hypoxia?
Anaemia
| Carbon monoxide poisioning
35
What causes ischaemic hypoxia?
Interruption to blood supply
36
What causes histiocytic hypoxia?
Inability to utilise oxygen in cells due to disable oxidative phosphorylation enzymes
37
What can cause histiocytic hypoxia?
Cyanide poisioning
38
What physical agents could cause cell injury?
```
Direct trauma
Extremes of temperature (burns and severe cold)
Sudden changes in atmospheric pressure
Electric currents
Radiation
```
39
What chemical agents and drugs can cause hypoxia?
```
Glucose and salt in hypertonic solutions
Oxygen in high concentrations
Poisons
Insecticides
Herbicides
Asbestos
Alcohol
Illicit drugs
Therapeutic drugs
```
40
What microorganisms can cause hypoxia?
Viruses
Bacteria
Fungi
Other parasites
41
How do immune mechanisms cause cell injury?
Hypersensitivity reactions
| Autoimmune reactions
42
What happens in hypersensitivity reactions?
The host tissue is injured secondary to an overly vigorous immune reaction
43
Give an example of a hypersensitivity reaction
Urticaria (hives)
44
What happens in autoimmune reactions?
The immune system fails to distinguish self from non-self
45
Give an example of an autoimmune reaction
Grave’s disease of the thyroid
46
Give an example of a genetic abnormality that can cause cell injury
Inborn errors of metabolism
47
What are the principal targets of cell injury?
Cell membranes
Nucleus
Proteins
Mitochondria
48
What is the cell membrane important for?
The plasma membrane plays an essential role in homeostasis
| The organellar membrane compartmentalise organelles
49
Why is the compartmentalisation of organelles by membranes important?
Because they contain potent enzymes that can themselves cause damage
50
What does the nucleus contain?
The genetic material of the cell
51
Why are proteins important in the cell?
Structural proteins form the cytoskeleton
| Enzymes involved in the metabolic processes of the cell
52
What happens in the mitochondria?
Oxidative phosphorylation and production of ATP
53
What is the most common cause of cell injury?
Hypoxia and ischaemia
54
How is hypoxia similar to other types of other cell injury?
Many of the changes seen in hypoxia also occur in other causes (although the sequence of events may be different)
55
What happens as the cell becomes deprived of oxygen?
There is decreased production of ATP by oxidative phosphorylation in the mitochondria, and so the levels of ATP in the cell
56
At what level of ATP depletion do vital cellular functions become compromised?
When levels drop to less than 5-10% of normal concentrations
57
Why does a drop in cellular ATP levels cause vital cellular functions to become compromised?
There is a loss of activity of the Na/K plasma membrane pump.
With the lack of oxygen, the cell switches to the glycolitic pathway of energy production
Ribosomes detach from the endoplasmic reticulum (as energy is required to keep them attached)
58
What is the result of the loss of activity of the Na/K plasma membrane pump?
Intracellular concentration of Na rises, and so water enters the cell. This means the cell and its organelles swell up.
Ca also enters the cell, and this results in damage to cell components
59
What is the process of cell swelling called?
Oncosis
60
What is the problem with the cell switching to the glycolytic pathway of ATP production?
It results in an accumulation of lactic acid, which reduces the pH of the cell
61
What does the lowering of pH in the cell result in?
Affects the activity of many enzymes within the cell
| Chromatin clumping is seen
62
What happens when ribosomes detach form the endoplasmic reticulum?
Protein synthesis is disrupted
63
What is the result of the disruption of protein synthesis due to detachment of ribosomes?
Can be intracellular accumulations of substances such as fat and denatured proteins
64
What happens at some point when a cell is injured?
The injury becomes irreversible and the cell will eventually die
65
How do most cells die in hypoxia?
Oncosis
66
What will happen when a cell has been irreversibly injured?
The tissue will eventually appear necrotic
67
What actually kills the cell in hypoxia?
It is not clear exactly what kills the cell, but a key event is the development of profound disturbances in membranes integrity and therefore an increase in membrane permeability followed by a massive influx of Ca into the cytoplasm
68
What level is cytosolic free Ca usually?
Usually at a very low level, as its kept within mitochondria and the endoplasmic reticulum
69
What happens to Ca when cells are severely damaged?
It enters the cell from outside, across the damaged plasma membrane, and it released from stores in the endoplasmic reticulum and mitochondria
70
Why is the influx of cytosolic Ca damaging?
Because calcium ions are biologically very active and high concentrations within the cytoplasm results in the activation of an array of potent enzymes such as ATPases, phospholipases, proteases and endonucleases
71
What is the problem with increased action of ATPases?
Decreases the concentrations of ATP further
72
What is the problem with increased action of phospholipases?
Causes further membrane damage
73
What is the problem with increased action of proteases?
Breaks down membrane and cytoskeletal proteins
74
What is the problem with increased action of endonucleases?
Damages DNA, causing nuclear chromatin to clump
75
What happens when lysosomal membranes are damaged?
Their enzymes leak into the cytoplasm further damaging the cell
76
What happens whilst Ca enters cells whose membranes are irreversibly damaged?
Intracellular substances leak out into the circulation
77
How can intracellular substances that have leaked into the circulation be detected?
In blood samples
78
What does the type of substance detected in blood samples indicate?
Where the cellular damage is occurring
79
Give a summary of hypoxic cell injury
- Cell is deprived of oxygen
- Mitochondrial ATP production stops
- ATP-driven membrane ionic pump runs down
- Sodium and water seep into the cell
- The cell swells, and the plasma membrane is stretched
- Glycolysis enables the cell to limp on for a while
- The cell initiates a heat-shock (stress) response
- The pH drops as the cells produce energy by glycolysis and lactic acid accumulates
- Calcium enters the cell
- Calcium activates phosholipases, proteases, ATPase and endonucleases
- The ER and other organelles swell
- Enzymes leak out of lysosomes and these enzymes attack cytoplasmic components
- All cell membranes are damaged and start to show blebbing
- At some point the cell dies, possibly killed by the burst of a bleb
80
What happens if blood flow is returned to a tissue that has been subject to ischaemia, but isn’t yet necrotic?
Sometimes the tissue injury sustained is worse than if blood flow was not restored
81
What is it called when a cell is injured because blood flow is returned after ischaemia?
Ischaemia-reperfusion injury
82
What may ischaemia reperfusion injury be due to?
Increased production of oxygen free radicals with reoxygenation
Increased number of neutrophils following reinstatement of blood supply, resulting in more inflammation and increased tissue injury
Delivery of complement proteins and activation of the complement pathway
83
How do some chemicals act to injure the cell?
By combining with a cellular component
84
How does cyanide act?
It binds to mitochondrial cytochrome oxidase and blocks oxidative phosphorylation
85
What are free radicals?
A reactive oxygen species
86
What do free radicals have?
A single unpaired electron in an outer orbit
87
What is the problem with free radicals having a single unpaired electron?
It is an unstable configuration, and because of this free radicals react with other molecules, often producing more free radicals
88
When are free radicals particularly produced?
In chemical and radiation injury, ischaemia-reperfusion injury, cellular ageing, and at high oxygen concentrations
89
What do free radicals do to cells?
They attach lipids in cell membranes and cause lipid peroxidation
They can damage proteins, carbohydrates, and nucleic acids.
90
How can free radicals damage proteins, carbohydrates and nucleic acids?
They can become bent out of shape, broken or cross linked
91
What are free radicals known to be?
Mutagenic
92
Are free radicals always pathological?
No- they are also involved in many physiological events
93
What produces free radicals for physiological purposes?
Leukocytes
94
What physiological events are free radicals involved in?
Killing bacteria
| Cell signalling
95
Which free radicals are of particular biological importance in cells?
OHº (hydroxyl)
O 2 - (superoxide)
H 2 O 2 (hydrogen peroxide)
96
What is the most dangerous free radical?
Hydroxyl (OHº)
97
How can hydroxyl be formed?
Radiation can directly lyse water
| The Fenton and Haber-Weiss reactions
98
What is the Fenton reaction?
Fe 2+ + H 2 O 2 → Fe 3+ + OH - + OHº
99
What is the Haber-Weiss reaction?
O 2 - + H + + H 2 O 2 → O 2 + H 2 O + OHº
100
What do the Haber-Weiss and Fenton reactions show to be important?
The removal of superoxide and hydrogen peroxide rapidly, so the more dangerous hydroxyl can’t be formed
101
Where is the Fenton reaction important?
In injury where bleeding occurs
102
Why is the Fenton reaction important in injury where injury occurs?
As when blood is around, iron is available for the production of free radicals
103
What does the body have to prevent injury caused by free radicals?
Defence systems
104
What is the bodys defence system against free radicals known as?
The anti-oxidant system
105
What happens if there is an imbalance between free radical production and free radical scavenging?
Free radicals build up and the cell or tissue is said to be in oxidative stress
106
What does oxidative stress cause?
Cell injury
107
What does the antioxidant system consist of?
Enzymes
Free radical scavengers
Storage proteins
108
What enzymes are involved in the antioxidant system?
Superoxide dismutase (SOD)
Catalases
Peroxidases
109
What does SOD do?
Catalyses the reaction O 2 - → H 2 O 2
110
What is the advantage of SOD?
H 2 O 2 is significantly less toxic to cells
111
What do catalases and peroxidases do?
Complete the process of free radical removal?
| H 2 O 2 → O 2 + H 2 O
112
What do free radical scavengers do?
Neutralise free radicals
113
Give 4 examples of free radical scavengers
Vitamins A, C and E
| Glutathione
114
What do storage proteins do?
Sequester transition metals in the extracellular matrix
115
Give two examples of storage proteins?
Transferrin and ceruloplasmin
116
What do transferrin and cerulopasmin do?
Sequester iron and copper (which catalyse the formation of free radicals)
117
What are heat shock proteins (HSPs)?
Stress proteins, unfoldases, chaperonins
118
What is the heat shock response triggered by?
Any form of injury (not justhead)
119
Are HSPs found in unstressed cells?
Yes, in lower concentrations
120
What cells show the heat shock response?
All cells from any organism, animal or plant
121
What do cells do when submitted to stress?
Turn down their usual protein synthesis and turn up the synthesis of HSPs
122
What is shown by all organisms using HSPs?
They must play a key role in survival
123
Are HSPs secreted?
No, they remain within the cell
124
What are HSPs concerted with?
Protein repair (analogous to DNA repair)
125
When are HSPs important?
When the folding step in protein synthesis does astray, or when proteins become denatured during cell injury
126
What do HSPs recognise?
Proteins that are incorrectly folded
127
How do HSPs repair proteins?
By ensuring that they are refolded correctly
128
What happens if refolding of a damaged protein is not possible?
It is destroyed
129
Why are HSPs important in cellular injury?
As the heat shock response plays a key role in maintaining protein viability and thus maximising cell survival
130
Give an example of a HSP
Ubiquitin
131
What is the problem with determining when a cell died?
It is hard to identify cells that died minutes ago to hours ago, and hard to distinguish reversible injury from cell death. Histologic sections do not give us the time of cell death, and there is also little to be seen by the naked eye around the time of cell death
132
How is the diagnosis of cell death probably best made?
On functional rather than morphological criteria, e.g. increased permeability of the cell membrane
133
How can permeability of the cell membrane be assessed?
By the dye exclusion technique, where dye is put into the cells’ medium
134
What do the results of the dye exclusion technique mean?
It the dye doesn’t enter the cell, it’s alive.
| If the cell soaks it up, they are dead
135
What 3 main alternations can be seen in cell death with swelling?
Cytoplasmic changes
Nuclear changes
Abnormal intracellular accumulations
136
What cytoplasmic changes are seen in cell death with swelling?
There is reduced pink staining of the cytoplasm.
| This may be followed by increased pink staining.
137
Why is there reduced pink staining in cell death?
Accumulation of water
138
Is reduced pink staining a reversible change?
Yes
139
Why may there be a progression to increased pink staining?
Due to detachment and loss of ribosomes from the ER, and accumulation of denatured proteins
140
Is increased pink staining a reversible change?
No
141
What nuclear changes can be seen in cell injury?
Chromatin is subtly clumped
| May be follow be various combinations of pyknosis, karryohexis, and karryolysis of the nucleus
142
Is subtle clumping of chromatin reversible?
Yes
143
What is pyknosis?
Shrinkage
144
What is karryohexis?
Fragmentation
145
What is karryolysis?
Dissolution
146
What reversible changes have been detected in cellular injury by the electron microscope?
Swelling
Cytoplasmic blebs
Clumped chromatin
Ribosome separation from the ER
147
What swells in reversible cell injury?
Both the cells and the organelles
148
Why is there swelling in cell injury?
Due to the Na/K pump failure
149
What are cytoplasmic blebs symptomatic of?
Cell swelling
150
What causes clumped chromatin?
Reduced pH
151
Why is there ribosome separation from the ER?
Due to failure of energy-dependant process maintaining ribosomes in the correct location
152
What irreversible changes have been detected in cellular injury by the electron microscope?
Increased cell swelling
Nuclear changes- pyknosis, karyolysis, karyorrhexis
Swelling and rupture of lysosomes
Membrane defects
Appearance of myelin figures
Lysis of the endoplasmic reticulum
Amorphous densities in swollen mitochondria
153
What does the swelling and rupture of lysosomes reflect?
Membrane damage
154
What are myelin figures?
Damaged membranes
155
What is lysis of the endoplasmic reticulum due to?
Membrane defects
156
In summary, what is cell swelling due to?
The failure of ionic pumps in the cell membrane through lack of energy supply
157
What is implied by cell swelling being due to failure of ionic pumps?
As well as occurring with hypoxia, oncosis would also be expected to occur with poisons that interfere with a cell’s energy metabolism or the integrity of the cell membrane
158
What happens as cells undergo oncosis?
They (and the tissue as a whole) increases in weight
159
What is oncosis?
Cell death with swelling
| The spectrum of changes that occur prior to death in cells injured by hypoxia and some other agents
160
What is apoptosis?
Cell death with shrinkage
161
What is apoptosis induced by?
A regulated intracellular program where the cell activates enzymes that degrade its own nuclear DNA and proteins
162
What is necrosis?
In a living organism, the morphological changes that occur after a cell has been dead for some time, e.g. 4-24 hours
163
What are the changes in appearance seen in necrosis due to?
Largely the progressive degradative action of enzymes on the lethally injured cell
164
What does necrosis describe?
Morphological changes, it is NOT a type of cell death
165
What happens to the nucleus in oncosis?
It fades away by karyolysis
166
What happens to the nucleus in apoptosis?
It becomes very dense and breaks up (karyorrhexis)
167
When is necrosis seen?
When there is damage to the cell membranes (plasma and organelle), and lysosomal enzymes are released into the cytoplasm and digest the cell.
168
What is the result of lysosomal enzymes digesting the cell?
Cell contents leaks out, and inflammation is often seen
169
How long do necrotic changes take to develop?
Happens over a number of hours, e.g. it takes 4-12 hours until microscopic changes are seen after a myocardial infarction
170
What eventually happens to necrotic tissue?
It is removed by enzymatic degradation and phagocytosis by white cells
171
What may happen if some necrotic tissue remains?
It may calcify
172
What is the calcification of necrotic tissue called?
Dystrophic calcification
173
What are the two main types of necrosis?
Coagulative and liquifactive
174
What is liquifactive necrosis also known as?
Colliquitive
175
What can happen to cells proteins as cells are dying?
They can either undergo denaturation or autolysis
176
What tends to happen to denatured proteins?
They coagulate
177
What happens when proteins undergo autolysis?
They undergo dissolution by the cells own enzymes
178
When do protein lysis and coagulation start to occur?
When the cell is still alive
179
What determines which of the two main patterns of necrosis are seen?
The balance between the two key processes- coagulation and autolysis
180
What happens when protein denaturation is the dominant feature?
The proteins tend to ‘clump’, leading to solidity of the dead cells and consequently of the dead tissue. The net result is coagulative necrosis
181
What happens when release of active enzymes, particularly proteases, is the dominant feature?
The dead cells and consequently the dead tissue tends to liquefy, leading to liquifactive necrosis
182
What is seen in most solid organs when the cause of death is ischaemia?
Coagulative necrosis
183
What happens when cell death is associated with large numbers of neutrophils?
Their released proteolytic enzymes lead to liquifactive necrosis
184
Give an example of when necrotic changes might be harder to classify?
The pancreas typically shows coagulative necrosis, but being rich in proteolytic enzymes such as trypsin, the changes are modified to a certain extend
185
What are the two other types of necrosis that only occur under a limited set of circumstances?
Caseous and fat necrosis
186
Are gangrene and infarcts types of necrosis?
No
187
What dominates in coagulative necrosis?
Denaturation of proteins over release of active proteases
188
What consistency is the dead tissue in coagulative necrosis?
Solid
189
How does coagulative necrotic tissue appear to the naked eye?
White
190
What happens to the cells proteins in coagulative necrosis?
They uncoil and become less soluble
191
What happens histologically in coagulative necrosis?
The cellular architecture is somewhat preserved, creating a ‘ghost outline’ of the cells
192
When will the typical changes of coagulative necrosis be seen?
In the first few days
193
What happens to the appearance of coagulative necrosis after the first few days?
The appearances are modified by the fact that the dead tissues incite an inflammatory reaction with consequent infiltration by phagocytes
194
What happens in liquifactive necrosis?
Active enzymatic degradation is substantially greater than denaturation, and this leads to enzymatic digestion (liquefaction) of tissues
195
When is liquifactive necrosis seen?
In massive neutrophil infiltration
196
Give an example of necrosis where there would be massive neutrophil infiltration?
In abscesses
197
Why is their liquifactive necrosis when there is massive neutrophil infiltration?
Because neutrophils release proteases
198
What kind of infections is liquifactive necrosis seen in?
Bacterial
199
What organ is liquifactive necrosis seen in?
Brain
200
Why is liquifactive necrosis seen in the brain?
Because this is a fragile tissue without support from a robust collagenous matrix
201
What happens to the tissue in liquifactive necrosis?
If becomes a viscous mass, and if there is acute inflammation, pus is present
202
What is caseous necrosis characterised by?
Its amorphous debris
203
What is caseous necrosis particularly associated with?
Infections, especially TB
| Granulomatous inflammation
204
What is fat necrosis seen?
When there is destruction of adipose tissue
205
When is fat necrosis most typically seen?
As a consequence of acute pancreatitis
206
Why is fat necrosis seen in acute pancreatitis?
As during inflammation of the pancreas there is a release of lipases from the injured pancreatic acinar cells. These lipases act on fatty tissues of the pancreas and on fat elsewhere in the abdominal cavity, causing fat necrosis
207
What does fat necrosis cause?
Release of free fatty acids, which can react with calcium to form chalky deposits (calcium soaps) in fatty tissue
208
How can calcium soaps be detected?
They can be seen on x-rays and with the naked eye at surgery and autopsy
209
What can fat necrosis occur after?
Direct trauma to a fatty tissue, especially breast tissue
210
Why is fat necrosis in the breast significant?
After it heals it leave an irregular scar that can mimic a nodule of breast cancer
211
What is gangrene?
A clinical term used to describe necrosis that is visible to the naked eye
NOT a type of necrosis
212
How can gangrene be further classified?
Into dry and wet gangrene
213
What does classification of gangrene depend on?
Wether the necrosis is modified by exposure to air resulting in drying (dry gangrene), or by an infection with a mixed bacterial culture (wet gangrene)
214
Can bacteria grow in dry tissue?
No
215
What is dry gangrene responsible for?
The dry, crisp appearance of the gangrenous umbilical cord stump after birth and gangrenous toes
216
What is the underlying process in dry gangrene?
Coagulative necrosis
217
What is the underlying process in wet gangrene?
Liquifactive necrosis
218
Why is wet gangrene, or infected necrosis, very serious?
As bacteria can easily get into the blood stream and it can result in septicaemia
219
What is gas gangrene?
Wet gangrene where the tissue has become infected with anaerobic bacteria that produce visible and palpable bubbles of gas within tissues
220
What is a typical scenario for gas gangrene?
The crushing of a limb in a motorcycle accident
221
How does gas gangrene arise with the crushing of a limb in a motorcycle accident?
The injured tissue loses it blood supply and becomes necrotic resulting in the appearance of gangrene. The tissue is colonised by anaerobic bacteria picked up from the soil and gas gangrene develops.
222
Where is gangrene most commonly seen in clinical practice?
Ischaemic limbs
223
Can gangrenous tissue be salvaged?
No, it is dead
224
What does infarction refer to?
A cause of necrosis, namely ischaemia
225
What is an infarct?
An area of tissue death caused by obstruction of a tissues blood supply
226
What can infarction result in?
Gangrene
227
What are most infarctions due to?
Thrombosis or embolism
228
What can infarctions occasionally be due to?
External compression of a vessel or by twisting of vessels
229
What may externally compress a vessel?
A tumour, or within a hernia
230
Give two examples of where vessels may be twisted?
Testicular torsion
| Volvulus of the bowel
231
What type of necrosis is found in infarcted tissue?
Can be either
232
How can infarcts be described?
By their colour- white or red
233
What does the colour of an infarct indicate?
How much haemorrhage there is into the infarct
234
Where does a white (anaemic) infarct occur?
In ‘solid’ organs- those with good stromal support- after occlusion of an ‘end’ artery
235
What is an end artery?
Any artery that is the sole source of arterial blood to a segment of an organ
236
What is the result of the solid nature of the tissue in a white infarct?
It limits the amount of haemorrhage that can occur ito the infarct from adjacent capillaries
237
What happens to the tissue supplied by the end artery in a white infarct?
It dies, and appears pale/white because of the lack of blood in the tissue
238
Where do white infarcts occur?
In the heart, spleen and kidneys
239
What shape are most white infarcts?
Wedge-shaped, with the occluded artery at the apex of the wedge
240
How do white infarcts appear histologically?
As coagulative necrosis
241
When does a red (heamorrhagic) infact occur?
When there is extensive haemorrhage into dead tissue
242
When may there be extensive haemorrhage into dead tissue?
In organs with a dual blood supply
If numerous anastomoses are present within a tissue
In loose tissue
Where there has been previous congestion
Where there is raised venous pressure
243
Give an example of an organ with dual blood supply?
The lung
244
What happens when there is an occlusion of an artery in an organ with a dual blood supply?
Occlusion of the main arterial supply causes an infarct. The secondary arterial supply is insufficient to rescue the tissue, but does allow blood to enter the tissue, causing a red infarct
245
Where will there be numerous anastomoses?
Where the capillary beds of two separate arterial supplies merge
246
Give an example of an organ that has numerous anastomoses?
Intestines
247
Why does a red infarct occur when there are numerous anastomoses?
For the same reason as in organs with a dual blood supply
248
Give an example of an organ with loose tissue
The lung
249
Why do red infarcts occur in loose tissue?
There is poor stromal support for capillaries, and therefore there is more than usualy haemorrhage into the dead tissue
250
Give an example of where there may have been previous congestion?
In congestive cardiac failure
251
Why do you get red infarcts where there has been previous congestion?
There is more than the usual amount of blood in the necrotic tissue
252
Why does raised venous pressure cause red infarcts?
Increased pressure is transmitted to the capillary bed. As the tissue pressure increases, eventually there is reduced arterial filling pressure in the tissue, which causes ischaemia and subsequent necrosis. Because the tissue was engorged with blood, the resulting infarct is red
253
What are the consequences of an infarct?
Varying, ranging from none to death
254
What do the consequences of infarcts depend on?
Wether the tissue affected has an alternative blood supply
How quickly the ischaemia occurred
How vulnerable a tissue is to hypoxia
The oxygen content of the blood
255
Give 2 examples of places with alternate blood supplies
Lung
| Forearm
256
What may happen if the ischaemia occurred slowly?
There is more time for the development of additional perfusion pathways
257
What may happen if an infarct occurs in an anaemic patient?
It may have more serious consequences
258
What happens as membranes lose their integrity?
Many molecules leak out of the injured cells
259
What are the consequences of molecules leaking out of injured cells?
They can cause local irritation and local inflammation
They may have general toxic effects on the body
They may appear in high concentrations in the blood
260
Why is the appearance of molecules in high concentrations in the blood important?
Because they can be measured and thus aid in diagnosis
261
What are the principal molecules released from injured cells?
Potassium
Enzymes
Myoglobin
262
What concentrations is potassium normally found in?
High concentrations in cells compared to extracellular fluid
263
In terms of potassium, how can a dying cell be considered?
As a ‘potassium bomb’
264
What happens to the heart with high potassium concentrations?
It stops beating
265
How can high potassium concentrations reach the heart?
From a myocardial infarction, or massive necrosis elsewhere in the body, e.g. severe burns, tourniquet shock or tumour lysis syndrome
266
When does tourniquet shock occur?
After a tourniquet is removed having been in place for several hours
267
What is tumour lysis syndrome?
The paradoxical result of successful chemotherapy, when a large mass of tumour cells becomes acutely necrotic
268
What can enzymes indicate?
The organ involved, and the extent, timing and evolution of tissue damage
269
What enzymes are released from injured tissue first?
Those with the smallest molecular weight
270
What is myoglobin released from?
Dead myocardium and striated muscle
271
What happens if large amount of myoglobin are released by damaged striated muscle?
A condition called rhabdomyolosis occurs
272
When is rhabdomyolysis seen?
In severe burns or trauma, strenuous exercise, with potassium depletion and with alcohol and drug abuse
273
What can happen to myoglobin released from striated muscle?
It can plug the renal tubules, resulting in renal failure
274
What is apoptosis?
The death of a single cell (or small cluster of cells) due to activation of an internally controlled suicide program
275
What can apoptosis be regarded a?
An equal and opposite force to mitosis
276
What is apoptosis characterised by?
It’s morphology, and by the type of DNA breakdown that occurs
277
What type of DNA breakdown occurs with apoptosis?
Characteristic, non-random, internucelosomal cleavage of DNA
278
How does the DNA breakdown in apoptosis differ from that in oncosis?
In oncosis, DNA is chopped into pieces of random length
279
When can apoptosis be a normal physiological process?
When cells are no longer needed, to maintain a steady state, during hormone-controlled involution and cytotoxic T cell killing of virus infected or neoplastic cells.
It is also seem in embryogenesis
280
What can cell death by apoptosis impart?
Shape
281
What particular type of cell damage would result in apoptosis?
When damage affects the cells DNA
282
When may damage to a cells DNA be seen?
With some forms of toxic injury and in tumours
283
What does a cell due during apoptosis?
Activates enzymes that degrade its own nuclear DNA and proteins
284
What happens to the membrane during apoptosis?
Membrane integrity is maintained
285
Is apoptosis an active or passive process?
Active- requires energy
286
Are lysosomal enzymes involved in apoptosis?
No
287
How long does apoptosis take?
It is quick- cells are gone within a few hours
288
How do apoptotic cells appear under the light microscope?
Shrunken
Intensely eosinophilic
Chromatin condensation, pyknosis and karyorrhexis are seen
289
How many cells does apoptosis affect?
Single cells, or small clusters
290
What do apoptotic cells show under the electron microscope?
Budding (not blebbing), which progresses to fragmentation of membrane bound apoptotic bodies
291
What do the fragmented membrane bound apoptotic bodies contain?
Cytoplasm, organelles and often nuclear fragments
292
What happens to apoptotic bodies?
They are eventually removed by macrophage phagocytosis
293
Does apoptosis induce inflammation?
No, because no leakage of cell contents occurs
294
What are the key phases of apoptosis?
Initiation
Execution
Degradation/phagocytosis
295
What is apoptosis triggered by?
Two key mechanisms, intrinsic and extrinsic
296
What do both triggering mechanisms of apoptosis culminate in?
The activation of caspases
297
What are caspases?
Proteases that mediate the cellular effects of apoptosis
298
How do caspases act?
By cleaving proteins, breaking up the cytoskeleton and initiating degradation of DNA
299
What does intrinsic apoptosis have as a central player?
Mitochondria
300
Why is intrinsic apoptosis so named?
Because all the apoptotic machinery is within the cell
301
What triggers intrinsic apoptosis?
Various triggers, for example DNA damage or withdrawal of growth factors or hormones
302
What protein is important in intrinsic apoptosis?
p53
303
What do the triggers for intrinsic apoptosis lead to?
Increased mitochondrial permeability, resulting in the released of cytochrome c from the mitochondria
304
What happens once cytochrome c has been released from the mitochondria?
It interacts with APAF1 and caspase 9 to form an apoptosome that activates downstream caspases
305
What is extrinsic apoptosis cause by?
External ligands, such as TRIAL and Fas, that bind to ‘death receptors’
306
What does binding to death receptors lead to?
Casase activation, independently of mitochondria
307
What happens in the degradation phase of apoptosis?
The cell breaks down into membrane bound fragments called apoptotic bodies
308
What do apoptotic bodies do?
Express molecules on their surface that induce phagocytosis of the apoptotic bodies by either neighbouring cells or phagocytes
309
What are the important apoptotic molecules?
```
p53
Cytochrome c, APAF1, caspase 9
Bcl-2
Death ligands
Death receptors
Caspases
```
310
What does p53 do?
Mediates apoptosis in response to DNA damage
311
What do cytochrome c, APAF1 and caspase 9 collectively form?
The apoptosome
312
What does Bcl-2 do?
Prevents cytochrome c release from the mitochondria, and therefore inhibits apoptosis
313
Give an example of a death ligand
TRAIL
314
Give an example of a death receptor
TRAIL-R
315
What happens if a cell can’t metabolise something?
It will remain within the cell
316
When are abnormal cellular accumulations seen?
As metabolic processes become deranged
317
What do abnormal cellular accumulations often seen with?
Sublethal or chronic injury
318
What is the outcome of abnormal cellular accumulations?
They may be reversible, and they can be harmless or toxic
319
What can abnormal cellular accumulations be derived from?
The cells own metabolism
The extracellular space
The outer environment
320
What are the main groups of intracellular accumulations?
```
Water and electrolytes
Lipids
Proteins
Pigments
Carbohydrates
```
321
How can fluid appear when accumulated in cells?
As discrete droplets, or diffuse waterlogging of the entire cell
322
What are discrete droplets of fluid in the cell called?
Vacuoles
323
What is the result of diffuse waterlogging of the entire cell?
Cell swelling
324
What is swelling due to diffuse waterlogging called?
Hydropic swelling
325
What is hydropic swelling due to?
Osmotic disturbance
326
What happens to cells in hydropic swelling?
They are enlarged, but not hypertrophic
327
When does hydropic swelling occur?
When energy supplies are cut off, e.g. with reduced blood supply, metabolic poisons, and sodium ions and water flood into cell
328
What does hydropic swelling indicate?
Severe cellular distress
329
What may hydropic swelling cause?
Further problems, e.g. in the brain where there is no room for expansion due to the skull
330
What happens as brain swelling occurs?
Blood vessels are squeezed and blood flow to the brain is reduced
331
What is steatosis?
The accumulation of triglycerides
332
Where is steatosis often seen?
In the liver
333
Why is steatosis often seen in the liver?
As this is the major organ of fat metabolism
334
What are common causes of liver steatosis?
Alcohol abuse
Diabetes mellitus
Obesity
Toxins, e.g. carbon tetrachloride
335
Does mild steatosis have an affect on cell function?
It doesn’t seem to
| It is clinically asymptomatic
336
Is milk steatosis reversible?
Yes, in about 10 days if the person stops drinking alcohol
337
How can steatosis be diagnosed in the liver?
With the naked eye, as the liver is golden yellow rather than the usual red.
338
What does advanced steatosis do?
Increases the size of the organ
339
What is advanced steatosis the first stage of?
Alcoholic liver disease
340
What is the problem with cholesterol?
It cannot be broken down in the body and is insoluble
341
How is cholesterol eliminated?
Only though the liver
342
How is excess cholesterol in the cells stored?
In membrane-bound droplets
343
Where does cholesterol accumulate?
Within smooth muscle cells and macrophages within atherosclerotic plaques
344
Why does cholesterol accumulate in atherosclerotic plaques?
Perhaps because the adjacent plasma contains mcuh cholesterol
345
How do macrophages containing cholesterol appear microscopically?
Have a foamy cytoplasm- therefore are called foam cells
346
Other than atherosclerotic plaques, where is cholesterol seen?
In macrophages within the skin and tendons of people with acquired and hereditary hyperlipidaemias
347
What do macrophages form in people with acquired and hereditary hyperlipidaemias?
Small masses called xanthomas
348
How are proteins seen in cytoplasm?
As eosinophilic droplets or aggregates in the cytoplasm
349
What is Mallory’s hyaline?
A damaged protein which is seen in hepatocytes in alcoholic liver disease
350
What is Mallory’s hyaline due to?
Accumulation of altered keratin filaments
351
What kind of disorder is α1-antitrypsin deficiency?
Genetics
352
What happens in α1-antitrypsin deficiency?
The liver produces a version of the protein α1-antitrypsin that is incorrectly folded, and so it cannot be packaged by the endoplasmic reticulum and accumulates within this organelle and is not secreted by the liver
353
What does the systemic deficiency of α1-antitrypsin mean?
Proteases within the lung can act unchecked
354
What do patients with α1-antitrypsin deficiency develop?
Emphysema as lung tissue is broken down
355
What are pigments?
Coloured substances
356
Give an example of a pigment that is a normal cellular constituent?
Melanin
357
Give an example of an exogenous pigment?
Soot (carbon)
358
What is soot?
An urban air pollutant
359
What happens once soot is inhaled?
It is phagocytosed by macrophages within lung tissue (alveolar macrophages)
360
How is soot seen in the body?
As blackened lung tissue or as blackened peribronchial lymph nodes
361
What is blackened lung tissue called?
Anthracosis
362
Why are the peribronchial lymph nodes blackened with soot inhalation?
Because they contain macrophages which have migrated from the lungs
363
How long are the tissues discoloured for in soot inhalation?
For life
364
What is the result of soot inhalation?
It is usually harmless, however if particularly high exposure occurs, e.g. in coal miners, the lungs can become fibrotic or emphysematous- this is called coal-works pneumoconiosis
365
Where is the accumulation of exogenous pigments intentional?
Tattooing
366
What happens in tattooing?
The pigments are pricked into the skin and phagocytosed by macrophages in the dermis, which remain their indefinitely
367
What happens to some of the pigments from tattooing?
They will reach the draining lymph nodes and remain their (as the lymph nodes act as a filter)
368
Give 3 examples of endogenous pigments
Lipofuscin
Haemosiderin
Bilirubin
369
What is lipofuscin known as?
Age pigment, or wear and tear pigment
370
What colour is lipofuscin?
Brown
371
Where is lipofuscin found?
In ageing cells
372
Does lipofuscin cause injury to the cells?
No
373
What is lipofuscin a sign of?
Previous free radical injury and lipid peroxidation
374
What does lipofuscin consist of?
A polymer of oxidised, indigestible, brownish, intracellular lipids
375
How does lipofuscin appear under the microscope?
As yellow-brown grains within the cytoplasm
376
What cells is lipofuscin found it?
Long lived cells, e.g. neurones, myocardium, hepatocytes
377
What is haemosiderin?
An iron storage molecule
378
What is haemosiderin derived from?
Haemoglobin
379
What colour is haemosiderin?
Yellow/brown
380
When does haemosiderin form?
When there is a systemic or local excess of iron
381
What is a common example of iron overload?
Haemorrhage into tissues including the skin subcutaneous tissues, i.e. a bruise
382
What happens if there is a systemic overload of iron?
Haemosiderin is deposited in many organs
383
What is the deposition of haemosiderin into many organs called?
Haemosiderosis
384
Where is haemosiderosis seen?
In conditions such haemolytic anaemias, blood transfusions and hereditary haemochromatosis
385
What is hereditary haemochromatosis?
A genetically inherited disorder which results in increased intestinal absorption of dietary ion
386
Where is iron deposited in haemochromatosis?
Skin, liver, pancreas, heart and endocrine organs
387
What is haemochromatosis associated with?
Scarring in the liver (cirrhosis) and pancreas
388
What are the symptoms of haemochromatosis?
Liver damage, heart dysfunction and multiple endocrine failures, especially of the pancreas
389
What is the treatment for haemochromatosis?
Repeated bleeding
390
What is bilirubin?
A bile pigment which is bright yellow
391
How is bilirubin produced?
Heme is broken down in biliverdin, which is broken down to bilirubin
392
What does bilirubin consist of?
A stock of porphyrin rings that have broken open and lost their iron
393
What happens once the porphyrin has been broken?
It can never be mended, and must be eliminated in the bile
394
What happens when bile flow is obstructed or overwhelmed?
Bilirubin levels in the blood rise, and jaundice results
395
Why might bile flow be obstructed or overwhelmed?
For example with impacted gallstones, in liver disease, or haemolytic anaemias
396
Where can bilirubin be formed?
Anywhere in the body, not just in the liver
397
Why can bilirubin be formed anywhere in the body?
Because all cells contain heme as cytochromes
398
Where is bilirubin deposited in tissues?
Either extracellularly or intracellularly (in macrophages)
399
What is the problem with bilirubin deposition?
It is very toxic
400
Where is bilirubin taken from the tissues?
To the liver
401
How is bilirubin taken to the liver?
By albumin
402
What happens to bilirubin in the liver?
It is conjugated with glucaronic acid and excreted into the bile
403
What is pathological calcification?
The abnormal deposition of calcium salts within tissues
404
What are the two roads to pathological calcification?
One local, dystrophic calcification
| One general, metastatic calcification
405
Which type of pathological calcification is more common?
Dystrophic
406
Where does dystrophic calcification occur?
In an area of dying tissue, in atherosclerotic plaques, in ageing or damaged heart valves, and in tuberculous lymph nodes
407
Is there any abnormality in calcium metabolism or serum calcium or potassium levels in dystrophic calcification?
No
408
What does a local change or disturbance in the tissue favour?
The nucleation of hydroxyapatite crystals
409
What can dystrophic calcification cause?
Organ dysfunction e.g. in atherosclerosis or calcified heart valves
410
Which valve never calcifies?
The pulmonary valve of the heart
411
Why does the pulmonary valve never calcify?
No one is sure. One theory is that the blood around the pulmonary valves is more acidic that that around the aortic valves, and the acidity prevents calcification
412
Where is the disturbance in metastatic calcification?
Body-wide
413
What happens in metastatic calcification?
Hydroxyapatite crystals are deposited in normal tissues throughout the body
414
When does metastatic calcification occur?
When there is hypercalcaemia secondary to disturbances in calcium metabolism
415
What is the effect of metastatic calcification?
It is usually asymptomatic, however it can be lethal
416
Can metastatic calcification regress?
Potentially, if the cause of the hypercalcaemia is corrected
417
What are the principal causes of hypercalcaemia?
Increased secretion of parathyroid hormone (PTH) resulting in bone resorption
Destruction bone tissue
418
What is a primary cause of increased secretion of PTH?
Due to parathyroid hyperplasia or tumour
419
What is a secondary cause of increased secretion of PTH?
Due to renal failure and the retention of phosphate
420
What is an ectopic cause of increased secretion of PTH?
Secretion of PTH-related protein by malignant tumours, e.g. carcinoma of the lung
421
What can cause destruction of bone tissue?
Primary tumours of bone marrow
Diffuse skeletal metastases
Paget’s disease of bone
Immobilisation
422
Give two examples of primary tumours of bone marrow
Leukaemia
| Multiple myeloma
423
What happens in Paget’s disease of bone?
Accelerated bone turnover occurs
424
Why does immobilisation of bone cause destruction of bone tissue?
It removes the stimulation to bone formation whilst resorption continues
425
What happens as cells age?
They accumulate damage to cellular constituents and DNA.
They may also accumulate lipofuscin pigment and abnormally folded proteins.
There is a decline in their ability to replicate
426
What is the decline in the ability of ageing cells to replicate called?
Replicative senescence
427
Can cells replicate indefinitely?
No- after a certain number of divisions they reach replicative senescene
428
What is replicative senescence related to?
The length of chromosomes
429
What are the end of chromosomes?
Telomeres
430
What happens with every replications?
The telomere is shortened
431
What happens when the telomeres reach a critical length?
The cell can no longer divide
432
Why can germ cells and stem cells continue to divide?
They contain an enzyme called telomerase, which maintains the original length of the telomeres
433
Pathologically, what cells contain telomerase?
Cancer cells, so they have the ability to replicate many times
434
What are the major effects of excessive alcohol intake on the liver?
Fatty change
Acute alcoholic hepatitis
Cirrhosis
435
How does excessive alcohol intake cause fatty change?
It affects fat metabolism within the liver, resulting in steatosis
436
What can fatty change in the liver cause?
Hepatomegaly
437
Is fatty change in the liver to due alcohol consumption reversible?
Yes
438
What are the symptoms of fatty change in the liver?
It is generally asymptomatic
439
Why does acute alcoholic hepatitis occur?
As alcohol and its metabolites are directly toxic, so a binge of alcohol can result in acute hepatitis
440
What is seen in acute alcoholic hepatitis?
Focal hepatocyte necrosis
Formation of Mallory bodies
A neutrophilic infiltrate
441
What are the symptoms of acute alcoholic hepatitis?
Fever
Liver tenderness
Jaundice
442
Is acute alcoholic hepatitis reversible?
Usually
443
How many alcoholics develop cirrhosis?
10-15%
444
What does cirrhosis result in?
Hard, shrunken liver
445
How does cirrhosis appear histologically?
As micro-nodules of regenerating hepatocytes, surrounded by bands of collagen
446
What is the long-term outcome of cirrhosis?
It is irreversible, serious and sometimes fatal
