Presentation on theme: "Cellular Adaptations in Disease"— Presentation transcript:
1Cellular Adaptations in Disease Faculty of Medicine & Health SciencesSemester 3Pathology CourseP3Cellular Adaptations in DiseaseProf. James LoweWelcome to the start of the Pathology course…This session relates entirely to Chapter 2 in the recommended textbook“PATHOLOGY” Stevens & Lowe5th October 1999
2Adaptability of cells to an altered environment OverviewAdaptability of cells to an altered environmentPhysiological and pathological stimuliChanges in growth patternHyperplasia, hypertrophy, atrophy, involution, metaplasiaApoptosisGrowth factorsRole in altered environmentThis 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.
3Extremely common responses in disease Why is this important?Extremely common responses in diseaseCertain 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...
5Adaptability of cells to an altered environment Cells are constantly exposed to changes in their environmentCells can adapt to acceptable changes in their environment by modifying metabolism or growth patternEnvironmental changes can be physiological or pathologicalPhysiological stimuli - those which are within an acceptable rangePathological stimuli - those that cause a severe disturbance to cell function
6Examples of pathological stimuli NutritionalImmuneEndocrinePhysical agentsChemical agentsInfectionsAnoxiaGeneticSome examples to read about…Protein-calorie malnutritionDiabestes mellitusAllergy and hy[persensitivity reactionsHypo and hyperthyroidismHypo and hyper parathyroidismHeat, cold, irradiation, asbestosDrugs, alkylating agents, PCPsProtozoal, bacterial, vira andl parasitic infectionsVascular disease leading to poor bloof flowGene disorders, chromosomal disordersMany of these areas overlap with other parts of the course
7Cells may adapt by metabolic regulation Induction of enzymeDownregulation of enzymeIncreased synthesis of productReduced secretion of productMetabolic adaptation is usually not associated with morphological changesEnzyme induction:Ethanol and liver microsomal enzymesAnticonvusant drugs and liver microsomal enzymesIncreased/reduced synthesisParathyroid gland secrretion of calcitonin in response to serum calcium levels
8The cell stress response allows cells to survive pathological stimuli Housekeeping genes switched offCell stress genes switched onCells stress proteins are expressed in cells (also called heat shock proteins)Cell stress proteins are cytoprotectiveCell stress response has great evolutionary conservationVery fundamental responseExamples: hsp70 hsp20 (number refers to mol size)
9Other groups of cell stress proteins have roles in the nucleus. Small cell stress proteins act as molecular chaperones and prevent misfolding of proteinsUbiquitin links to damaged proteins and flags them for elimination by the cellOther groups of cell stress proteins have roles in the nucleus.When proteins are damaged they misfold and are then damaging to the cellChaperone proteins transiently associate with other proteins and prevent misfolding or possibly allow correct refoldingIf a damaged protein is present in the cell it is recognised as such and flagged for degradation by the ubiquitin-proteosome cytosolic proteolytic system.
10Ubiquitin system Degraded protein proteosome Damaged protein FreeubiquitinDegradedproteinActivatedubiquitinproteosomeDamaged proteinThe cell contains abundant free ubiquitinFree 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
12Increased functional demand Increased functional demand can be met by two main responsesIncrease in cell size: hypertrophyIncrease in cell number: hyperplasiaThese may occur independently or together.Reflected by an increase in size and weight of an organIf a stimulus that causes hypertrophy or hyperplasia is removed then the tissue reverts to its normal state.
13Physiological hypertrophy Skeletal muscle hypertrophy in response to exerciseNormal 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.
14Pathological hypertrophy Myocardium in hypertensive heart diseaseInhypertension 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
15Pathological hypertrophy Myocardium in hypertensive heart diseaseNormal cardiac muscle cells are all roughly the same size. In hypertrophy of the left ventricle cells increase dramatically in size with enlargement of nuclei.
16Physiological hyperplasia Endometrium in the menstrual cycleAt 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.
17Physiological hyperplasia Pregnant uterusNormal uterusAnother 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.
18Pathological hyperplasia Normal skinHyperplasia after traumaIn 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 pegDP = dermal papilla
19Hyperplasia may be nodular Hyperplasia may occur in a non-uniform pattern in an organ or tissue - termed nodular hyperplasiaExamples includehyperplasia of the prostate glandhyperplasia of the breastNot all hyperplasia is in a uniform pattern in a tissue.Most examples relate to cyclical endocrine stimulation...
20Nodular hyperplasia of prostate From a young man showing uniform texture of glandFrom an elderly man showing irregular hyperplastic nodules. This would cause obstructionProstatic 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….
22Reduced demand for cell activity Reduction in the volume of a tissue is termed atrophyreduction in cell volumereduction in cell numberCell loss is commonly replaced by either adipose tissue or fibrous tissueRefelected in a reduced size and mass of an organThere are three ways in which a tissue can respond to a reduction in functional demandGet rid of cytoplasm and structural proteins: cells shrinkEliminate whole cellsMixture of the twoIf 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.
23Common causes of atrophy DenervationImmobilisationReduced endocrine stimulationIschaemiaAgeing
24Pathological 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
25Other causes of a small organ other than atrophy Hypoplasia: incomplete growth of an organAgenesis: complete failure of development of an organ in embryogenesisExamples:Hypolastic lungsHypoplastic left ventricleRenal agenesisAgenesis of corpus callosumsAnother 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.
26Physiological atrophy is termed involution Most instances of involution are the result of withdrawal of an endocrine stimulusExamples of involutionbreast after cessation of lactationuterus after parturitionthyroid after pubertyInvolution demands removal of cells - mechanism is apoptosis (see later)
27Cell components are removed by degradative systems Events in cell atrophyCell components are removed by degradative systemscytosolic proteolysis - ubiquitin systemautophagy: elements enwrapped by internal membrane systems and fused with the lysosomal systemResidual lipid material may remain in cells as a brown material termed lipofuscinLipofuscin is phospholipid material and is brown. Hence atrophic organs and the organs of old people are often brown-ish in colour.
29Reduction in cell number is through programmed cell death Certain trophic signal to cells can lead to a specific form of cell deathCell death is brought about by precise metabolic systemsThe main type of programmed cell death is termed apoptosis
30ApoptosisNormal cells are closely anchored by cell junctions
31Apoptosis: first stage... Cells lose contact and round up. There is nuclear condensation.
32Apoptosis next stage...Apoptotic cell undergoes fragmentation to form apoptotic bodies
33Apoptosis final event...Apoptotic fragments are recognised by local cells and phagocytes, are internalised, and degraded.
34Cell death pathways can be triggered by several factors…. Apoptosis biologyCell death pathways exist in the cell metabolism controlled by the action of protease enzymes termed CASPASESDNA is cleaved into fragments in between nuceosomes by endonucleasesProtein in cells is cross linked by transglutaminasesCell death pathways can be triggered by several factors….
35Apoptosis triggers….Surface receptor activationSurface membrane damageDamage to mitochondrial membranesDNA damageWhether a cell lives or dies depends on the balance between pro-apoptotic and anti-apoptotic factors
37Change in cell differentiation Cells may respond to stimuli by a change in terminal differentiationThis process is termed metaplasia
38Examples of metaplasia Bladder transitional epithelium (T) with metaplasia to squamous epithelium (S) in response to a bladder stone…
39Urothelium in response to stone Example of metaplasiaUrothelium in response to stonetransitional epithelium to squamousRespiratory mucosa in response to smokingCiliated columnar epithelium to squamousConnective tissue in response to traumaCollagenous tissue to osseous tissue
41Growth factorsGrowth factors and their receptors control cell growthIn disease, cell adaptations are controlled by the action of growth factors linking to nuclear transcription factors via secondary messenger systems.
43Cells adapt to altered environment Metabolic adaptation SummaryCells adapt to altered environmentMetabolic adaptationCell stress responseChanges in growth patternHyperplasia, hypertrophy, atrophy, involution, metaplasiaGrowth factors, controlling proliferation or cell death, play a key role in cell adaptations in disease
44Links to future work...Cell biology of apoptosis will be continued when we consider neoplasia and in MM courseCell biology of growth factors will be continued when we consider healing and repair and will also crop up in study of neoplasia.