POM3 Flashcards
Causes of Cell injury
- Oxygen deprivation
- Chemical agents
- Infectious agents
- Immunological reactions
- Genetic defects
- Nutritional imbalances
- Physical agents
- Aging
Cell injury
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
- Type of cell
- Status of cell (eg. Is it dividing)
Intracellular systems are particularly vulnerable
- Cell membrane integrity
- ATP generation
- Protein synthesis
- 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
Atrophy
Shrinkage in the size of the cell (or organs) by the loss of cell substance
Eg. Brain shrinks in size in advanced dementia
Hypertrophy
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
Hyperplasia
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
Metaplasia
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
Dysplasia
Precancerous cells which show the genetic and cytological features or malignancy but not invading the underlying tissue
Eg. Barrett’s oesophagus
Light microscopic changes associated with reversible injury
- 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
Necrosis
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
- Coagulation necrosis (turns/remains solid dead cells, coagulation proteins irreversibly bound to each other, seen in infarcts (except brain) due to loss of blood)
- Liquefactive necrosis (turns into liquid, in infections + brain infarcts, neutrophils release toxic contents which liquefies tissue)
- Caseous necrosis (turns into thick milky gooey substance, seen in TB, due to body trying to fight pathogen w/macrophages)
- Fat necrosis (becomes fat/soap eg acute pancreatitis, seen in acute pancreatitis, damaged cells release lipases which split triglyceride esters within fat cells)
Apoptosis
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
Necroptosis
Programmed cell death associated with inflammation, many causes such as viral infection
Solutes
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)
Osmolarity
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
Tonicity
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.
Hypertonic solutions
In 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.
Hypotonic solutions
In 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.
Isotonic solutions
In 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.
Maintenance of cell
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+).
Tissue preservation
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).
How solutes exchange across blood vessels
All 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.
Molecules 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).
In 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
Oedema
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. In 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.
- 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.
- 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.
Lymphatic capillaries
To combat the loss of plasma fluids into tissues, lymphatic capillaries collect interstitial fluid that is destined for return to the blood circulation.
Lymphatic 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.
Tumour
Any kind of mass forming a lesion
Neoplasm
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
Teratomas
Tumour derived from germ cells and can contain tissue derived from all 3 germ cell layers -> may contain mature tissue and even cancers
Hamartomas
Localised benign growths of one or more mature cell types - normal tissues organised abnormally - architectural but not cytological abnormalities
Heterotopias
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
Cancers
Malignant neoplasm (abnormal growth of cells which proliferate in a uncontrolled way and, in some cases, to metastatise)
Metastasis
Spread of malignant tumour from its site of origin
Carcinogen
Any substance that, when exposed to living tissues, may cause production of cancer
How tumours spread
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
How tumour cells differ from normal cells
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
Differentiation of tumour cells
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
Difference between Benign (can become malignant) and Malignant
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
