POM3

Question 1

Causes of Cell injury

Answer 1

1. Oxygen deprivation
2. Chemical agents
3. Infectious agents
4. Immunological reactions
5. Genetic defects
6. Nutritional imbalances
7. Physical agents
8. Aging

Question 2

Cell injury

Answer 2

Cell injury can be lethal or sub-lethal.
Lethal - leads to cell death
Non-lethal - injury not amounting to death (may be reversible or progress to cell death)

Cellular response depends on

1) Type of injury
2) Duration of injury
3) Severity of injury

Consequence of injury depends on

1. Type of cell
2. Status of cell (eg. Is it dividing)

Intracellular systems are particularly vulnerable

1. Cell membrane integrity
2. ATP generation
3. Protein synthesis
4. The integrity of the genetic apparatus

The structural and biochemical components of a cell are so integrally related that multiple secondary effects rapidly occur

Cellular function is lost before cell death occurs which in turn occurs before the morphological changes are seen

Question 3

Atrophy

Answer 3

Shrinkage in the size of the cell (or organs) by the loss of cell substance

Eg. Brain shrinks in size in advanced dementia

Question 4

Hypertrophy

Answer 4

Increase in the size of cell and consequently an increase in the size of the organ
Can be physiological or pathological
It is caused either by increased functional demand or specific hormonal stimulation

Eg. Physiological hypertrophy - Hypertrophy of the uterus during pregnancy, small spindle shaped smooth muscle from a normal uterus vs large plump cells in gravid uterus
Pathological hypertrophy - Hypertrophy of heart muscle due to Hypertension

Question 5

Hyperplasia

Answer 5

An increase in number of cells in an organ
Can be physiological or pathological
Physiological hyperplasia can be either hormonal or compensatory
Pathological hyperplasia is usually due to excessive hormonal or growth factor stimulation

Eg. Physiological - During the first phase of the menstrual cycle, the oestrogenic phase, there is increased proliferation of the endometrial glands
Pathological - Cancer

Question 6

Metaplasia

Answer 6

A REVERSIBLE change in which one adult cell type is replaced by another.
May be physiological / pathological

Eg. Physiological - Cervix during pregnancy expands and opens up, becomes oedematous. Columnar epithelium of the endocervix which is normally in the canal becomes visible outside and due to the acidic environment of the vagina turns from columnar epithelium to squamous epithelium. These changes revert back after end of pregnancy
Pathological - Barrett’s (columnar lined) oesophagus

Question 7

Dysplasia

Answer 7

Precancerous cells which show the genetic and cytological features or malignancy but not invading the underlying tissue

Eg. Barrett’s oesophagus

Question 8

Light microscopic changes associated with reversible injury

Answer 8

• Fatty change
• Cellular swelling

These are examples of degenerative changes
i.e. changes associated with cell and tissue damage
Eg. Alcoholic fatty change
Ballooning degeneration

Question 9

Necrosis

Answer 9

Confluent cell death associated with inflammation
Different from apoptosis:
1. Apoptosis may be physiological
2. Apoptosis is a active energy dependent process
3. Apoptosis not associated with inflammation

Light microscopic changes associated with irreversible injury

1. Coagulation necrosis (turns/remains solid dead cells, coagulation proteins irreversibly bound to each other, seen in infarcts (except brain) due to loss of blood)
2. Liquefactive necrosis (turns into liquid, in infections + brain infarcts, neutrophils release toxic contents which liquefies tissue)
3. Caseous necrosis (turns into thick milky gooey substance, seen in TB, due to body trying to fight pathogen w/macrophages)
4. Fat necrosis (becomes fat/soap eg acute pancreatitis, seen in acute pancreatitis, damaged cells release lipases which split triglyceride esters within fat cells)

Question 10

Apoptosis

Answer 10

è programmed cell death, with no secondary inflammation around it, typically single cells, no release of cytoplasm as cell membrane remains intact. CAUSES:

o Embryogenesis

o Deletion of auto-reactive T cells in thymus

o Hormone-dependent physiological involution

o Cell deletion in proliferating populations

o Variety of mild injurious stimuli that cause irreparable DNA damage – triggers cell suicide pathway

Question 11

Necroptosis

Answer 11

Programmed cell death associated with inflammation, many causes such as viral infection

Question 12

Solutes

Answer 12

Cations:

• Na+ most plentiful in the plasma
• K+ most plentiful in the cell
• Extracellular Cl- much higher concentration in plasma than in cell
• Internally high concentration of anion neutralised by variety of anions, e.g. proteins, nucleic acid, phosphorylated proteins

Anions:

• Main one is organic phosphate -> ATP production, cell signalling, etc.
• Phosphorylation of proteins also key for activation and inactivation
• Proteins also anions, many have -ve net charge, although found in low concentrations
• pH inside cell more acidic than plasma
• Osmolarity between blood and intracellular compartment identical so not normally significant osmotic effect (except kidney w/concentrated fluids)

Question 13

Osmolarity

Answer 13

Osmosis = The movement of water down its own concentration gradient.
Osmosis moves water toward an area of higher osmolarity.
It can therefore change cell volume with consequences for cell function and survival.
Osmolarity = measure of concentration of all solute particles in a solution

Question 14

Tonicity

Answer 14

Tonicity defines the “strength” of a solution as it affects the final cell volume. Tonicity depends on both cell membrane permeability and the solution composition. 

H​ypertonic solutions
I​n a hypertonic solution, the osmolarity of the impermeant solutes outside the cell are greater than those inside the cell. The cell therefore shrinks in the solution.

H​ypotonic solutions
I​n a hypotonic solution, the osmolarity of the impermeant solutes outside the cell are less than those inside the cell. The cell therefore swells in the solution.

I​sotonic solutions
I​n an isotonic solution, the osmolarity of the impermeant solutes outside the cell is identical to those inside the cell. The cell volume therefore remains the same.

Differences in the concentrations of permeant solutes can result in transient changes to cell volume. If the difference is very large, it can result in cell damage.

Question 15

Maintenance of cell

Answer 15

The cells don’t burst because the Na+K+-ATPase maintains the concentration of Na+ ions (cyan squares) much lower inside the cell than outside.

The ATPase makes the membrane “effectively impermeable” to Na+ because any Na+ that diffuses in down the Na+ concentration gradient is actively pumped out again. Thus there is no net movement of Na+ across the membrane.

The intracellular osmolarity of impermeant solutes (mainly proteins at high concentration and low concentration Na+) balances the extracellular osmolarity of impermeant solutes (mainly high concentration Na+).

The cells don’t burst because the Na+K+-ATPase maintains the concentration of Na+ ions (cyan squares) much lower inside the cell than outside.

The ATPase makes the membrane “effectively impermeable” to Na+ because any Na+ that diffuses in down the Na+ concentration gradient is actively pumped out again. Thus there is no net movement of Na+ across the membrane.

The intracellular osmolarity of impermeant solutes (mainly proteins at high concentration and low concentration Na+) balances the extracellular osmolarity of impermeant solutes (mainly high concentration Na+).

Question 16

Tissue preservation

Answer 16

In transplantation, donated organs and tissues are commonly required to be transported to where the recipient is situated. When any tissue loses its blood supply, ischaemic changes occur, but these can be significantly slowed by rapid cooling of the tissue/organ to +4°C. Tissues are perfused with cold solutions via the arterial supply. Even when cooled, tissues/organs deteriorate.

The composition of the perfusion solution can reduce the deterioration in hypothermia, prolonging the time available to transport and keeping the organ viable.

Notably the Na+K+-ATPase stops functioning below 15°C which is compounded by the fact that without circulation there is little O2 and therefore little ATP to fuel the pump. Unless precautions are taken, Na+ will enter the cell (along with Cl-) and water will also enter as K+ exits. Cells are likely to swell and their membranes bleb, resulting in cell death.

One precaution is to perfuse the organ with a solution known as University of Wisconsin solution (UW). This is formulated to reduce hypothermic cell swelling and enhance preservation.

Three main factors serve to reduce cell swelling in UW-infused tissues:

Lack of Na+ or Cl- (therefore no influx possible).
Presence of extracellular impermeant solutes (lactobionate ions, raffinose).
Presence of a macromolecular colloid (starch)
Allopurinol and glutathione acts as an antioxidants, helping to protect the organs from damage from reactive oxygen species (ROS).



Question 17

How solutes exchange across blood vessels

Answer 17

A​ll blood vessels (e.g. arteries, capillaries, veins, lymphatics) are lined by endothelial cells which have pores. Each day, 8L of plasma leaks out of blood vessels.

M​olecules have several ways of traversing the endothelial cell layer:

N​.B. The blood-brain barrier (BBB) which separates the circulating blood from the brain is tightly sealed (to be discussed in the BRS module).

I​n a normal capillary, higher concentrations of plasma proteins inside the capillary than outside, generates an osmotic pressure known as the colloid osmotic pressure (COP). The flow of blood through the vessel also generates a hydrostatic pressure inside the vessel which is greater than that in the tissues though which it is passing. Thus, there is a tendency to “push” molecules though the capillary pores.

Solute and fluid movement across a vessel wall is determined by the balance between these opposing pressures.

In a normal capillary although the COP draws solute and fluid into the vessel, the slightly greater hydrostatic pressure results in net leakage from the capillary under normal conditions

Question 18

Oedema

Answer 18

The term​ oedema is used to describe the accumulation of fluids within tissues. Oedema results due to an imbalance in the normal cycle of fluid exchange in tissues causing fluid to accumulate in the interstitial spaces. A common cause of oedema is an increase in the permeability of capillary walls. I​n a leaky capillary, proteins are lost through an increase in pore size which reduces the COP and so fluids are more readily pushed out from the capillary.

Types of oedema :
1. Inflammatory oedema
Oedema is one of the cardinal signs of inflammation (MBC- Inflammation). Infectious and inflammatory stimuli often results in oedema.

In the figure below, inflammation can be observed around the sites of insect bites which has caused local blood vessels to become leaky. Swelling occurs because the rate of leakage from the vessels is greater than the rate at which the lymphatics can drain it.

2. Hydrostatic oedema

This individual is likely to have high blood pressure, which means increased hydrostatic pressure in vessels. This pushes more fluid out of the vessels, and can lead to accumulation of interstitial fluid.

3. Compromised function of lymphatic

The breast cancer survivor is likely to have had axillary (armpit) lymph nodes removed as part of her diagnosis or treatment. This can remove the pathway of drainage from the upper limb on the affected side, resulting in the accumulation of fluid.

In elephantiasis, parasitic worms can block lymphatic vessels, thereby preventing drainage of the lymph. In this case, the lymphatics in the right groin region has been blocked, preventing the drainage of interstitial fluid from the right lower limb.

Question 19

Lymphatic capillaries

Answer 19

T​o combat the loss of plasma fluids into tissues, lymphatic capillaries collect interstitial fluid that is destined for return to the blood circulation.

L​ymphatic capillaries are blind ended and have a low internal pressure which results into the net flow of fluids from tissues into the lymphatic capillaries.

Fluid is constantly being lost from blood vessels, passing into the interstitium to be drained by lymphatic vessels.

Lymph fluid returns to the circulation either via the lymphatic ducts in the subclavian region or via lymph nodes (Immune - Lymphoid tissues).

When the leakage of plasma into the interstitium exceeds the capacity of the lymphatics to collect and return it to the circulation, oedema will result as fluid accumulates in the interstitial space.

Question 20

Tumour

Answer 20

Any kind of mass forming a lesion

Question 21

Neoplasm

Answer 21

Autonomous (free) growth of tissue which have escaped normal constraints on cell proliferation

Benign - remain localised

Malignant - invade locally and/or spread to distant sites

Question 22

Teratomas

Answer 22

Tumour derived from germ cells and can contain tissue derived from all 3 germ cell layers -> may contain mature tissue and even cancers

Question 23

Hamartomas

Answer 23

Localised benign growths of one or more mature cell types - normal tissues organised abnormally - architectural but not cytological abnormalities

Question 24

Heterotopias

Answer 24

Normal tissues being found in parts of body where they are not normally present - normal tissues in wrong places

Eg. Pancreas cells in wall of large intestines

Question 25

Cancers

Answer 25

Malignant neoplasm (abnormal growth of cells which proliferate in a uncontrolled way and, in some cases, to metastatise)

Question 26

Metastasis

Answer 26

Spread of malignant tumour from its site of origin

Question 27

Carcinogen

Answer 27

Any substance that, when exposed to living tissues, may cause production of cancer

Question 28

How tumours spread

Answer 28

o Direct extension à tumour grows into surrounding tissue – fibroblastic proliferation, angiogenesis, immune response

o Haematogenous à via blood vessels (venules ,capillaries), most sarcomas metastatise this way first

o Lymphatic à via lymphatics to lymph nodes and beyond, most epithelial cancers metastatise this way first

o Transcoelomic à via seeding of body cavities, commonest = pleural and peritoneal cavities

o Perineural à via nerves

Question 29

How tumour cells differ from normal cells

Answer 29

o Larger nuclei – larger nuclear-cytoplasmic ratio

o More mitoses than normal derivative tissue

o Abnormal mitoses e.g. tripolar

o Marked nuclear pleomorphism – nuclear size and shape

Question 30

Differentiation of tumour cells

Answer 30

Stage à most important in terms of prognosis, how far disease has spread, TNM system

o T = tumour, how big is it?

o N = nodes, are lymph nodes involved and if so, how many?

o M = metastases, has it metastasized?

Grade à depends on degree of differentiation, how much does tumour look like original tissue

o High grade = nothing like original tissue, very different

o Low grade = similar to original tissue, not so differentiated

· Tumour spread is assessed by triple assessment:

o 1. Clinically à 2. Radiologically à 3. Pathologically

Question 31

Difference between Benign (can become malignant) and Malignant

Answer 31

Differentiation:
Benign - well differentiated
Malignant - ranges from poor to well

Rate of growth:
Benign - slow growing
Malignant - Rapid growing

Local invasion:
Benign - does not infiltrate basement membrane
Malignant - does infiltrate basement membrane

Metastasis:
Benign - does not metastasise
Malignant - can metastasise