1. Cellular Adaptations in Disease
Faculty of Medicine & Health Sciences
Semester 3
Pathology Course P3
Cellular Adaptations in Disease
Prof. James Lowe
Welcome to the start of the Pathology course…
This session relates entirely to Chapter 2 in the recommended textbook
“PATHOLOGY” Stevens & Lowe
5th October 1999

2. Adaptability of cells to an altered environment
Overview
Adaptability of cells to an altered environment
Physiological and pathological stimuli
Changes in growth pattern
Hyperplasia, hypertrophy, atrophy, involution, metaplasia
Apoptosis
Growth factors
Role in altered environment
This is the range of topics that will be covered. It is importanat that you consolidate and extend the material presented in the lecture by reading the chapter in the textbook.
Some of the illustrations in this presentation are taken from another top book “BASIC HISTOPATHOLOGY” by Wheater Burkett Stevens & Lowe.

3. Extremely common responses in disease
Why is this important?
Extremely common responses in disease
Certain adaptations in growth act as a fertile ground for the later development of neoplasia - cancer formation…
Nomenclature is used in clinical work.
So pay attention...

5. Adaptability of cells to an altered environment
Cells are constantly exposed to changes in their environment
Cells can adapt to acceptable changes in their environment by modifying metabolism or growth pattern
Environmental changes can be physiological or pathological
Physiological stimuli - those which are within an acceptable range
Pathological stimuli - those that cause a severe disturbance to cell function

6. Examples of pathological stimuli
Nutritional
Immune
Endocrine
Physical agents
Chemical agents
Infections
Anoxia
Genetic
Some examples to read about…
Protein-calorie malnutrition
Diabestes mellitus
Allergy and hy[persensitivity reactions
Hypo and hyperthyroidism
Hypo and hyper parathyroidism
Heat, cold, irradiation, asbestos
Drugs, alkylating agents, PCPs
Protozoal, bacterial, vira andl parasitic infections
Vascular disease leading to poor bloof flow
Gene disorders, chromosomal disorders
Many of these areas overlap with other parts of the course

7. Cells may adapt by metabolic regulation
Induction of enzyme
Downregulation of enzyme
Increased synthesis of product
Reduced secretion of product
Metabolic adaptation is usually not associated with morphological changes
Enzyme induction:
Ethanol and liver microsomal enzymes
Anticonvusant drugs and liver microsomal enzymes
Increased/reduced synthesis
Parathyroid gland secrretion of calcitonin in response to serum calcium levels

8. The cell stress response allows cells to survive pathological stimuli
Housekeeping genes switched off
Cell stress genes switched on
Cells stress proteins are expressed in cells (also called heat shock proteins)
Cell stress proteins are cytoprotective
Cell stress response has great evolutionary conservation
Very fundamental response
Examples: hsp70 hsp20 (number refers to mol size)

9. Other groups of cell stress proteins have roles in the nucleus.
Small cell stress proteins act as molecular chaperones and prevent misfolding of proteins
Ubiquitin links to damaged proteins and flags them for elimination by the cell
Other groups of cell stress proteins have roles in the nucleus.
When proteins are damaged they misfold and are then damaging to the cell
Chaperone proteins transiently associate with other proteins and prevent misfolding or possibly allow correct refolding
If a damaged protein is present in the cell it is recognised as such and flagged for degradation by the ubiquitin-proteosome cytosolic proteolytic system.

10. Ubiquitin system Degraded protein proteosome Damaged protein
Free
ubiquitin
Degraded
protein
Activated
ubiquitin
proteosome
Damaged protein
The cell contains abundant free ubiquitin
Free ubiquitin is activated by a series of proteins and can then be covalently bound to damaged proteins by ubiquitin ligases.
The damaged protein, conjugated to ubiquitin, is termed a ubiquitinylated protein.
Such ubiquitinylated proteins are recognised by huge multicatalytic proteases in the cytosol termed proteosomes. They take in the ubiquitinylated proteins, release free ubiquitin (which is recycled) and degrade and eliminate the damaged protein.
Cells with an impaired ubiquitin system do not survive cell stresses and die.
Ubiquitinated protein

11. Calm...

12. Increased functional demand
Increased functional demand can be met by two main responses
Increase in cell size: hypertrophy
Increase in cell number: hyperplasia
These may occur independently or together.
Reflected by an increase in size and weight of an organ
If a stimulus that causes hypertrophy or hyperplasia is removed then the tissue reverts to its normal state.

13. Physiological hypertrophy
Skeletal muscle hypertrophy in response to exercise
Normal skeletal muscle fibres are all roughly the same size in cross section.
If you exercise the size and volume of individual fibres increases. The number of fibres does not increase.
This is the basis of the “You too can have a body like mine” advertisements for exercise devices designed to develop rippling biceps and a six-pack…
The metabolic basis involved increased synthesis of structural proteins by the cell.

14. Pathological hypertrophy
Myocardium in hypertensive heart disease
Inhypertension the heart muscle is called on to develop a sustained high blood pressure.
There is hypertrophy of myocardial cells, reflected in an increased mass of the left ventricle.
LV=left ventricle

15. Pathological hypertrophy
Myocardium in hypertensive heart disease
Normal cardiac muscle cells are all roughly the same size. In hypertrophy of the left ventricle cells increase dramatically in size with enlargement of nuclei.

16. Physiological hyperplasia
Endometrium in the menstrual cycle
At the start of the menstrual cycle there are few glands in the endometrium.
In response to oestrogenic stimulation these glands proliferate, such that towards the end of the cycle, at the secretory phase, there has been a trenemdous increase in number of cells and hence glands.
This is an example of hyperplasia - increase in cell number.

17. Physiological hyperplasia
Pregnant uterus
Normal uterus
Another good example of hyperplasia is seen in the uterus in pregnancy where there is a massive increase in the number of smooth muscle cells in the myometrium.
This is replected in a dramatic increase in the size of the uterus.

18. Pathological hyperplasia
Normal skin
Hyperplasia after trauma
In response to physical trauma, for example using a spade, the skin on the palm of the hand will thicken - an example of pathological hyperplasia.
This is reflected by a thicker kerating layer,thicker stratum spinosum, and more pronounced rete peges and ridges.
Similar epithelial hyperplasia can occur in the mouth in response to chronic dental trauma.
RP = rete peg
DP = dermal papilla

19. Hyperplasia may be nodular
Hyperplasia may occur in a non-uniform pattern in an organ or tissue - termed nodular hyperplasia
Examples include
hyperplasia of the prostate gland
hyperplasia of the breast
Not all hyperplasia is in a uniform pattern in a tissue.
Most examples relate to cyclical endocrine stimulation...

20. Nodular hyperplasia of prostate
From a young man showing uniform texture of gland
From an elderly man showing irregular hyperplastic nodules. This would cause obstruction
Prostatic enlargement due to nodular hyperplasia is believed to be the result of changes in testosterone stimulation with age.
It is very common in the elderly and causes obstruction to the urethra, leading to a poor urinary flow….

22. Reduced demand for cell activity
Reduction in the volume of a tissue is termed atrophy
reduction in cell volume
reduction in cell number
Cell loss is commonly replaced by either adipose tissue or fibrous tissue
Refelected in a reduced size and mass of an organ
There are three ways in which a tissue can respond to a reduction in functional demand
Get rid of cytoplasm and structural proteins: cells shrink
Eliminate whole cells
Mixture of the two
If cells are lost in an organ they are often replaced by collagen or fat. The collagen is dense and featureless, sometime called hyaline: hence the term hyalinisation of a tissue. This implies loss of functional speciialised cells and replacement by connective tissue.

23. Common causes of atrophy
Denervation
Immobilisation
Reduced endocrine stimulation
Ischaemia
Ageing

24. Pathological atrophy A= atrophic skeletal muscle fibres
In denervation atrophy there is atrophy of individual fibres which have lost their innervation.
This happens in motor neurone disease.
A= atrophic skeletal muscle fibres

25. Other causes of a small organ other than atrophy
Hypoplasia: incomplete growth of an organ
Agenesis: complete failure of development of an organ in embryogenesis
Examples:
Hypolastic lungs
Hypoplastic left ventricle
Renal agenesis
Agenesis of corpus callosum s
Another term, when an organ develops but its tissues are microanatomically badly put together, is dysgenesis. Thus a kidney may be termed dysgenetic if, developmentally, its tubules are cystic and there is an increase collagen in the parenchyma.

26. Physiological atrophy is termed involution
Most instances of involution are the result of withdrawal of an endocrine stimulus
Examples of involution
breast after cessation of lactation
uterus after parturition
thyroid after puberty
Involution demands removal of cells - mechanism is apoptosis (see later)

27. Cell components are removed by degradative systems
Events in cell atrophy
Cell components are removed by degradative systems
cytosolic proteolysis - ubiquitin system
autophagy: elements enwrapped by internal membrane systems and fused with the lysosomal system
Residual lipid material may remain in cells as a brown material termed lipofuscin
Lipofuscin is phospholipid material and is brown. Hence atrophic organs and the organs of old people are often brown-ish in colour.

28. To eliminate effete organelles

29. Reduction in cell number is through programmed cell death
Certain trophic signal to cells can lead to a specific form of cell death
Cell death is brought about by precise metabolic systems
The main type of programmed cell death is termed apoptosis

30. Apoptosis
Normal cells are closely anchored by cell junctions

31. Apoptosis: first stage...
Cells lose contact and round up. There is nuclear condensation.

32. Apoptosis next stage...
Apoptotic cell undergoes fragmentation to form apoptotic bodies

33. Apoptosis final event...
Apoptotic fragments are recognised by local cells and phagocytes, are internalised, and degraded.

34. Cell death pathways can be triggered by several factors….
Apoptosis biology
Cell death pathways exist in the cell metabolism controlled by the action of protease enzymes termed CASPASES
DNA is cleaved into fragments in between nuceosomes by endonucleases
Protein in cells is cross linked by transglutaminases
Cell death pathways can be triggered by several factors….

35. Apoptosis triggers….
Surface receptor activation
Surface membrane damage
Damage to mitochondrial membranes
DNA damage
Whether a cell lives or dies depends on the balance between pro-apoptotic and anti-apoptotic factors

37. Change in cell differentiation
Cells may respond to stimuli by a change in terminal differentiation
This process is termed metaplasia

38. Examples of metaplasia
Bladder transitional epithelium (T) with metaplasia to squamous epithelium (S) in response to a bladder stone…

39. Urothelium in response to stone
Example of metaplasia
Urothelium in response to stone
transitional epithelium to squamous
Respiratory mucosa in response to smoking
Ciliated columnar epithelium to squamous
Connective tissue in response to trauma
Collagenous tissue to osseous tissue

41. Growth factors
Growth factors and their receptors control cell growth
In disease, cell adaptations are controlled by the action of growth factors linking to nuclear transcription factors via secondary messenger systems.

43. Cells adapt to altered environment Metabolic adaptation
Summary
Cells adapt to altered environment
Metabolic adaptation
Cell stress response
Changes in growth pattern
Hyperplasia, hypertrophy, atrophy, involution, metaplasia
Growth factors, controlling proliferation or cell death, play a key role in cell adaptations in disease

44. Links to future work...
Cell biology of apoptosis will be continued when we consider neoplasia and in MM course
Cell biology of growth factors will be continued when we consider healing and repair and will also crop up in study of neoplasia.