cell injury handouts 14 9-2016

Stages in cellular response to stress and injurious stimuli

Fig 1.1 (5)

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

THE MORPHOLOGIC CHANGES INDICATIVE OF REVERSIBLE CELL INJURY

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)

Fig 1.19 (19)

Fig 1.18 (19)

I)ROLE OF Ca2+

IRREVERSIBLE CELL INJURY

Fig 1.18 (19)

IRREVERSIBLE CELL INJURY

II)ROLE OF FREE RADICALS

Fig 1.20 (21)

Fig 1.21 (22)

Fig 1.16 (18)

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)

Fig 1. 8 (13)

2nd Form Of Cell Death

APOPTOSISNECROSIS

Fig 1. 24 (28)

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

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]

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

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.

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

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)

Fig 1. 29 (33)