cell injury handouts 14 9-2016
TRANSCRIPT
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Stages in cellular response to stress and injurious stimuli
Fig 1.1 (5)
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THE MORPHOLOGIC CHANGES INDICATIVE OF REVERSIBLE CELL INJURY
Fig 1.17 (18)
Fig 1.19 (19)
IRREVERSIBLE CELL INJURY
ATP DEFICIENCY SETS OFF THE CHAIN OF EVENTS
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THE MORPHOLOGIC CHANGES INDICATIVE OF REVERSIBLE CELL INJURY
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Example of Reversible Hepatocellular Injury:
Ballooning Degeneration• Swollen ; pale stained
hepatocytes• Clumped cytoplasm around
nucleus• Reversible cell injury
(corresponds to hydropic change)
• Often undergo lytic “spotty” necrosis (Permanent Cell Injury With Cell Death)
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Fig 1.19 (19)
Fig 1.18 (19)
I)ROLE OF Ca2+
IRREVERSIBLE CELL INJURY
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Fig 1.18 (19)
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IRREVERSIBLE CELL INJURY
II)ROLE OF FREE RADICALS
Fig 1.20 (21)
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Fig 1.21 (22)
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Fig 1.16 (18)
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Ischemia ↓↓ Mitochondrial Oxidative Phosphorylation (↓↓ ATP)
Failure of Na+/K+ ATPase Pump
Shift to Anerobic GlycolysisInflux of Na+ ; H2O →
-CELLULAR SWELLING-MICROVILLI LOSS-MEMBRANE BLEBBING-E.R. SWELLING-RIBOSOMAL DETACHMENT-MYELIN FIGURES
A) REVERSIBLE INJURY
FAILURE OF Ca2+ PUMPS (Resulting in ↑↑ Levels of Intracellular Ca2+ )
↓ pH ; ↓ Glycogen
CHROMATIN CLUMPING
REVERSIBLE INJURY
Release ; Activation of LYSOSOMAL ENZYMES
-LIPID BREAKDOWN (Membrane Phospholipid Loss)-CYTOSKELETAL ALTERATIONS (Protease Activation)-DNA DAMAGE
AND Reactive O2 Species
-RNAase Activation (↓ BASOPHILIA)-Endonuclease Activan
(NUCLEAR CHANGES)-Protease Activation (PROTEIN DIGESTION)
MITOCHONDRIAL INJURY-MPT → Loss of Proton Motive Force → Loss of Oxidative Phosphorylation → Cell Death (NECROSIS)
-cyt C. Leakage → APOPTOSIS
B) IRREVERSIBLE INJURY (CELL DEATH = NECROSIS & APOPTOSIS)
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Fig 1. 8 (13)
2nd Form Of Cell Death
APOPTOSISNECROSIS
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Fig 1. 24 (28)
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Fig 1. 25 (29)
A) INTRINSIC (MITOCHONDRIAL) PATHWAY OF APOPTOSIS
-Initiated by : Loss of Survival Signal (Growth Factor Deficiency) ; Radiation inuced DNA damage etc
-Results in :• Loss of Anti-apoptotic Proteins ( Bcl-2 ; BCL-x etc)• Activation of Apoptotic Sensors ( Bim ; Bid ; Bad)
- ACTIVATION OF APOPTOTICEFFECTOR PROTEINS ( Bax ; Bak)→ Bax/Bak CHANNELACTIVATION → CYTOCHROME C (cyt C) LEAKAGE
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cyt C → Combines with Apaf-1 → Activates PROCASPASE – 9 to CASPASE – 9 (Initiator Caspase) → Activates CASPASE – 3 ; CASPASE – 6(Executioner Caspase) → Activation of DNAase ( Nuclear Fragmentation) [APOPTOSIS : INTRINSIC]
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Fig 1. 25 (29)
B) THE EXTRINSIC (DEATH RECEPTOR–INITIATED) PATHWAY OF APOPTOSIS
-MEDIATED BY T-CELLS ( As in Thymic Involution ; Destruction of Virally Infected Cells / Tumour Cells by CD8-CTLs )-Mediated by 2 EXTRINSIC PROTEINS :1. FasL ( Binds on Fas Receptor on the
to- be- destroyed cell)2. TNF ( Binds to TNFR-1 on the to -be -
destroyed cell)
- Receptor Associated DEATH DOMAINbinds to ADAPTER PROTEIN DEATH DOMAIN ( Like FADD ; TRADD etc)
- ACTIVATION OF INITIATOR CASPASES FROM PRO-CASPASE ( Caspase-8 ; -10)→ ACTIVATION OF EXECUTIONER CASPASES ( Caspase-3 ; -6) ; Apoptosis
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Apoptosis. A viable leukemic cell (A) contrasts with an apoptotic cell (B) in which the nucleus has undergone condensation and fragmentation.
MORPHOLOGY OF APOPTOSIS : Cell shrinkage ; Chromatin condensation ; Fragmentation (into nucleosome size fragments) → Formation of Membrane blebs and apoptotic bodies→ Phagocytosis of apoptotic cells or cell bodies, usually by macrophages.
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Example of Apoptotic Hepatocellular Injury:Apoptotic (Acidophilic) Bodies
• Cells show apoptotic changes ; mummified
• Become shrunken ; angulated ; hypereosinophilic (with a densely stained pyknotic nucleus)
• Rounded remnants of such cells =Apoptotic Bodies
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TABLE 1-2 -- Features of Necrosis and Apoptosis Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis ➙
karyorrhexis ➙ karyolysis
Fragmentation into nucleosome-size fragments
Plasma membrane
Disrupted Intact; altered structure, especially orientation of lipids
Cellular contents
Enzymatic digestion; may leak out of cell
Intact; may be released in apoptotic bodies
Adjacent inflammation
Frequent No
Physiologic or pathologic role
Invariably pathologic (culmination of irreversible cell injury)
Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage
Table 1-2 (13)
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Fig 1. 29 (33)