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Think not disdainfully of death, but look on it with favor; for even death is one of the things that Nature wills. -

Golden lads and girls all must, As chimney-sweepers, come to dust. - William Shakespeare, Cymbeline (Guiderius at IV, ii). Think not disdainfully of death, but look on it with favor; for even death is one of the things that Nature wills. - Marcus Aurelius Antoninus

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Think not disdainfully of death, but look on it with favor; for even death is one of the things that Nature wills. -

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  1. Golden lads and girls all must, As chimney-sweepers, come to dust. - William Shakespeare, Cymbeline (Guiderius at IV, ii) Think not disdainfully of death, but look on it with favor; for even death is one of the things that Nature wills. - Marcus Aurelius Antoninus (121-180) Emperor of Rome 161–180, distinguished Stoic philosopher Meditations

  2. Death: Disaster or Design? Necrosis versus Apoptosis Dr Geoffrey Rowden Pathology Dept. Dalhousie University geoffr@dal.ca

  3. Outline • Cell damage and death - relationship to disease • Disastrous death – Swelling (Oncosis) followed by necrosis (Since 1870 or so) • Planned cell death – Apoptosis with or without necrosis (Since 1974 or so)

  4. Rudolf Virchow – (1821-1902) “All diseases are traceable to alterations in cells”

  5. Cells response to Stress • Adapt and live on at a lower or higher state of activity • Fail to cope with the stress and die

  6. Traditional cell death • Cells swell because they lose the ability to maintain salt balances across their membranes –”pump failure” • Mostly due to shutdown of energy generation by Mitochondria • Termed Necrosis – but should be called Oncosis

  7. Morphology of Swelling Death(Oncosis)

  8. Post-Oncosis Coagulative Necrosis • Commonest form • Main causes - Ischemia (no blood flow)/hypoxia (no oxygenation) • Protein denaturation with little initial enzyme activation - Lack of water • Cell outlines initially preserved • Eosinophilic (Pink stained) cytoplasm • EXAMPLE: Myocardial infarct

  9. Gross pathology – Myocardial Infarct

  10. Lesions in coronary arteries

  11. Critical Lesion - Atheroma Histology

  12. Normal - Dead cardiomyocytes

  13. Oncosis (Accidental Cell Death) • “Accidental death” is typified by cell swelling due to energy depletion and ion pump failure. Necrosis is the post mortem result. • Release of cell contents provokes an inflammatory response. Not seen in apoptosis.

  14. Apoptosis • First described in 1974 – John Kerr • Programmed cell death • Other names: Necrobiosis, Shrinkage necrosis, Single cell deletion. • Counterbalance to mitosis.

  15. Apoptosis – A helpful illustration of the term

  16. Oncosis Versus Apoptosis • Apoptosis is the defaultdisposal system to delete cells that have accumulated unrepairable DNA damage. Genomic integrity is protected . May have arisen in response to viral attack on cells. • Stereotyped morphologic pattern. • Linkage to DNA repair systems like p53 (Guardian of the genome).

  17. Apoptosis - Morphology

  18. Morphology of Swelling Death(Oncosis)

  19. Role in Tissue Homeostasis • Predictable developmental remodeling. e.g. tadpole tail, digits, soft palate kidney remodelling, brain development, etc. • Adult remodeling e.g.cyclical proliferation/atrophy as in the endometrium, breast or hair follicles. • Gene regulated.

  20. Apoptosis - Neural Development Surplus neurons deleted

  21. Hormone Deprivation -Prostate

  22. DNA Ladders DNA is chopped up in a controlled manner

  23. Genes of Cell Death • Caenorhabditis elegans (a nematode) deletes 131 cells by apoptosis during the development from egg to adult. • Mutations identify genes (ced 3/4 ) as necessary for cell death. (pro-apoptotic). • Ced 9 gene is anti-apoptotic and Bcl-2 is the mammalian homologue.

  24. Poison Cupboard of Caspases • The enzymes that do the controlled chopping • Cysteine proteases with preference for cleavage at an aspartate residue. • Activation of pro-caspases e.g. caspase 8 • Cascade of caspase activation. e.g. c10, c3, c7, c6, c2.

  25. Summary

  26. Must not all things at the last be swallowed up in death? Plato (427 BC - 347 BC), Dialogues, Phaed

  27. Phagocytic Disposal

  28. Mitochondria – An important target

  29. Bcl-2 Family • Anti-apoptotic - Bcl-2 , - mostly membrane associated, especially on mitochondrial outer membranes. • Pro-apoptotic - Bax, - cytoplasmic. Form competitive links to dimerize with Bcl-2. Inactivate the protective functions.

  30. Bcl-2/Bax and Cancer How the balance shifts to cause more or less cells surviving

  31. Summary

  32. Recap • Cell damage and death - relationship to disease • Disastrous death – Swelling (Oncosis) followed by necrosis • Planned cell death – Apoptosis with or without necrosis

  33. For three days after death hair and fingernails continue to grow but phone calls taper off. Johnny Carson

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