Cellular Adaptations in Disease

1. Faculty of Medicine & Health Sciences Semester 3 Pathology Course P3 Cellular Adaptations in Disease Prof. James Lowe 5th October 1999

2. 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

3. 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.

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

6. Nutritional Immune Endocrine Physical agents Chemical agents Infections Anoxia Genetic Examples of pathological stimuli

7. Metabolic regulation • 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

8. Cell stress response • 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

9. Cell stress proteins • 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.

10. Ubiquitin system Free ubiquitin Degraded protein Activated ubiquitin proteosome Damaged protein Ubiquitinated protein

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

13. Physiological hypertrophy Skeletal muscle hypertrophy in response to exercise

14. Pathological hypertrophy Myocardium in hypertensive heart disease LV=left ventricle

15. Pathological hypertrophy Myocardium in hypertensive heart disease

16. Physiological hyperplasia Endometrium in the menstrual cycle

17. Pregnant uterus Normal uterus Physiological hyperplasia

18. Normal skin Hyperplasia after trauma Pathological hyperplasia 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

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

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

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

24. Pathological atrophy 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

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

27. 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

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

39. 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. 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.