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

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.

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...

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

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

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

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)

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.

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

Calm...

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.

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.

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

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.

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.

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.

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

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...

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….

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.

Common causes of atrophy Denervation Immobilisation Reduced endocrine stimulation Ischaemia Ageing

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

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.

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)

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.

To eliminate effete organelles

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

Apoptosis Normal cells are closely anchored by cell junctions

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

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

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

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….

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

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

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

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

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.

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

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.