Cell Responses  3. Cell Death

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Cell Responses 3. Cell Death

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1. Cell Responses 3. Cell Death Dr.T.Krishna MD, www.mletips.com 1

2. Lecture Plan Cell death Apoptosis Necrosis Example of Cell injury & death Ischemia & Hypoxia Chemicals & Drugs 2 Dr.T.Krishna MD, www.mletips.com

3. Dr.T.Krishna MD, www.mletips.com 3 Cell InjuryCell Injury

4. Necrosis Definition: “ spectrum of morphologic changes that follow cell death in living tissue, largely resulting from the progressive degradative action of enzymes on the lethally injured cell ” Morphology LM (light Microscopy) Increased eosinophilia Myelin figures Calcification of dead cells EM (Electron Microscopy) Cytoplasm Membrane discontinuities large amorphous mitochondria densities Aggregates of fluffy material (denatured protein) Nucleus Pyknosis (nuclear shrinkage and increased basophilia also seen in apoptotic cell death) Karyorrhexis (fragmentation) Karyolysis (breakdown of DNA by DNase activity) 4 Dr.T.Krishna MD, www.mletips.com

5. Necrosis Types 1. Coagulative = preservation of the basic outline of necrotic cell Mechanism – protein denaturation characteristic of hypoxic cell death in all tissues (except Brain) Best example – MI 2. Liquefactive= Cell outlines are obscured & Replaced by yellow pus Mechanism – bacterial/fungal enzymatic digestion & inflammatory response Whatever is the stimulus – in brain it is always Liquefactive Gangrene – surgical term 5 Dr.T.Krishna MD, www.mletips.com

6. Necrosis Types 3. Caseous = distinctive form of Coagulative necrosis but tissue architecture is completely lost MC in TB (also in fungal) Meaning - cheesy white gross appearance of necrosis Microscopy - granulomatous reaction (what is granulomatous reaction?) 6 Dr.T.Krishna MD, www.mletips.com

7. Necrosis Types 4. Fat Necrosis = not a specific pattern Grossly - chalky white areas of calcium & fatty acids(fat saponification) Seen in acute pancreatitis & trauma of breast Ghost cells are seen in microscopy 7 Dr.T.Krishna MD, www.mletips.com

8. Examples of cell injury and death 1. Ischemia & Hypoxia MC type of cell injury in clinical medicine Ischemic injures faster than hypoxia Reperfusion injury – cell injury following restoration of blood flow to the ischemic cells Mechanism of cell death – predominately necrosis in ischemia ( apoptosis is important in reperfusion injury by reactive free radicals, complements, IgM) 2. Chemicals & drugs Mechanisms 1. Directly acting on cell structures Mercuric chloride – binds sulfhydral (SH) groups of membranes and proteins Cyanide – binds and inactivates mitochondrial cytochrome oxidase Anti- neoplastic and antibiotics- act on genetic material & proteins 8 Dr.T.Krishna MD, www.mletips.com

9. Examples of cell injury and death 2. Chemicals & drugs Mechanisms i). Directly acting on cell structures ii). Indirectly acting Convert into active toxic metabolites by p-450 oxidases Mechanisms – by reactive free radicals Examples – Carbon tetrachloride & Acetaminophen (Tylenol) Carbon tetrachloride (CCl4) = is converted into CCl3? CCl3 is a free radical ? inhibits apoprotein synthesis ? accumulation of Hepatic Lipoproteins (Fatty Liver) and causes auto – oxidation of polyenoic fatty acids of membranes Acetaminophen (Tylenol) = active toxic metabolites produced in liver ? binds and with reduced glutathione peroxidase (GSH) ; large doses of Tylenol depletes GSH and lead to free radical damage of liver (hepatic failure) 9 Dr.T.Krishna MD, www.mletips.com

10. Dr.T.Krishna MD, www.mletips.com 10

11. Apoptosis – Morphology LM- (H&E) Single cells or small clusters of cells Round or oval mass of intensely Eosinophilic cytoplasm with dense nuclear chromatin fragments EM Cell shrinkage, Chromatin condensation-most characteristic feature ,Phagocytosis, cytoplasmic blebs and apoptotic bodies Severity of stimulus determines the form of death 11 Dr.T.Krishna MD, www.mletips.com

12. Apoptosis – Molecular/Biochemical changes Protein Cleavage- By cysteine proteases / caspases First into larger pieces (50- 300 Kb) and later into Olig-onucleosomes (180 - 200 bp) In agarose gel electrophoresis Apoptosis is seen as DNA ladders (necrosis as smear pattern) Apoptotic cells express phosphatidylserine, thrombospondin ( adhesive glycoprotein) Macrophages recognize these cells early ? phagocytosis without inflammation 12 Dr.T.Krishna MD, www.mletips.com

13. Apoptosis – Mechanisms Apoptosis was studied in a Nematode Caenorhabditis elegans (C. elegans) C. elegans shows programmed cell growth followed by cell death specific genes (called ced genes, for cell death abnormal) – in mutant worms initiate or inhibit apoptosis Initiation phase- caspases activation 1. Extrinsic/ receptor-initiated pathway 2. Intrinsic/ mitochondrial pathway Execution phase- enzymes cause cell death 13 Dr.T.Krishna MD, www.mletips.com

14. Apoptosis – Mechanisms Extrinsic Pathway (Death Receptor- Initiated) initiated by involvement of cell surface death receptors (TNF-family ) on cells TNFR1, related protein - Fas (CD95) - cytoplasmic domain (death domain) 14 Dr.T.Krishna MD, www.mletips.com

15. Apoptosis – Molecular/Biochemical changes Intrinsic Pathway (Mitochondrial) No role for death receptors Growth factors & other signals stimulate Bcl2 family Anti-apoptotic members - Bcl2 and Bcl -x Pro-Apoptotic members - Bak, Bax, and Bim Present in mitochondrial membranes and the cytoplasm 15 Dr.T.Krishna MD, www.mletips.com

16. Dr.T.Krishna MD, www.mletips.com 16 Executioner caspasesExecutioner caspases

17. Apoptosis – Caspases Proteases present in the form of Pro-enzyme forms (Zymogens) C- cysteine protease (aspase- cleave after aspartic acid in the polypeptide chain) Types initiators- Caspases 8, 9 Executioners - Caspases 3, 6 >20 members Activated by other & own (autocatalysis) In nucleus, Caspases act on proteins involved in Transcription DNA replication DNA repair Example: Caspase 3 – DNAase activation (Inter nucleosomal cleavage) 17 Dr.T.Krishna MD, www.mletips.com

18. Apoptosis – Removal of Dead Cells Apoptotic cells release Soluble factors Marker molecules are expressed on surface of apoptotic cell or fragments Markers are immediately recognized by macrophages Macrophages also secrete substances which bind only to apoptotic cells Viable cells express molecules (CD- 31) and avoid getting phagocytosed 18 Dr.T.Krishna MD, www.mletips.com

19. Apoptosis – Examples 1. After growth factor deprivation Lymphocytes not stimulated by Ag/Cytokine Intrinsic pathway plays important role Mediated by Pro- Apoptotic Bcl2 family 2. DNA damage (Genotic stress) Chemicals Radiation P53 accumulation? trnscriptional activation of Bcl2 genes ?activation of Caspases 19 Dr.T.Krishna MD, www.mletips.com

20. Apoptosis- Examples contd.. 3. Apoptosis by TNF family of receptors TNF Cell death (apoptosis) Cell survival ( NFkB) Tumor necrosis by Thrombus formation of the Tumor vessels

21. Apoptosis- Examples contd.. 4. Cytotxic T- cell mediated Apoptosis FasL ?Fas + FasL ?Caspase activation ?Apoptosis Granzyme B ( serine protease) Perforin (Transmembrane pore forming molecule)Perforin (Transmembrane pore forming molecule)

22. Apoptosis – Deregulation ?Apoptosis Neuro degenerative disorders- Spino muscular dystrophies (SMA) Ischemic injury- MI Apoptosis of viral infected cells by CTLs ?Apoptosis Mutations/absence of p53 Hormone dependent Tumors- Breast, Ovary, Prostate Auto-immune diseases ( Auto-reactive Lymphocytes) 22 Dr.T.Krishna MD, www.mletips.com

23. Examples of cell injury and death 1. Ischemia & Hypoxia MC type of cell injury in clinical medicine Ischemic injures faster than hypoxia Reperfusion injury – cell injury following restoration of blood flow to the ischemic cells Mechanism of cell death – predominately necrosis in ischemia ( apoptosis is important in reperfusion injury by reactive free radicals, complements, IgM) 2. Chemicals & drugs Mechanisms 1. Directly acting on cell structures Mercuric chloride – binds sulfhydral (SH) groups of membranes and proteins Cyanide – binds and inactivates mitochondrial cytochrome oxidase Anti- neoplastic and antibiotics- act on genetic material & proteins 23 Dr.T.Krishna MD, www.mletips.com

24. Examples of cell injury and death 2. Chemicals & drugs Mechanisms i). Directly acting on cell structures ii). Indirectly acting Convert into active toxic metabolites by p-450 oxidases Mechanisms – by reactive free radicals Examples – Carbon tetrachloride & Acetaminophen (Tylenol) Carbon tetrachloride (CCl4) = is converted into CCl3? CCl3 is a free radical ? inhibits apoprotein synthesis ? accumulation of Hepatic Lipoproteins (Fatty Liver) and causes auto – oxidation of polyenoic fatty acids of membranes Acetaminophen (Tylenol) = active toxic metabolites produced in liver ? binds and with reduced glutathione peroxidase (GSH) ; large doses of Tylenol depletes GSH and lead to free radical damage of liver (hepatic failure) 24 Dr.T.Krishna MD, www.mletips.com

25. Dr.T.Krishna MD, www.mletips.com 25

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