CELL ADAPTION AND INJURY

CELL COMPONENTS
NUCLEUS : “POWER HOUSE” – DIRECTS ALL PROCESSES IN THE CELL.
COMPRISED OF:
CHROMATIN
NUCLEOLUS
NUCLEAR MEMBRANE
MEMBRANE : TRANSPORT
PASSIVE DIFFUSION
ACTIVE TRANSPORT
BULK TRANSPORT (PINOCYTOSIS, PHAGOCYTOSIS)
SODIUM-POTASSIUM PUMP

CELLULAR ADAPTATION
• CELLS MAY ADAPT BY WAY OF
ATROPHY
HYPERPLASIA
HYPERTROPHY
METAPLASIA
NEOPLASIA ETC.
• ALL CELLS HAVE A RANGE OF ADAPTATION, TO WHICH THEY
REACT TO NORMAL PHYSIOLOGICAL STIMULI = HOMEOSTASIS
• IF THOSE LIMITS OF ADAPTATION ARE EXCEEDED, CELL INJURY
OCCURS

CELL INJURY
• REVERSIBLE
• IRREVERSIBLE
ADAPTATION  REVERSIBLE
CELL INJURY  IRREVERSIBLE
INJURY  CELL DEATH
CELL DEATH
APOPTOSIS: PROGRAMMED INDIVIDUAL CELL DEATH, INTERNALLY
CONTROLLED WITH MINIMAL DESTRUCTION TO ADJACENT CELLS
NECROSIS: DEATH OF A GROUP OF CELLS EXTERNALLY CONTROLLED i.e.
IN RESPONSE TO AN EXTERNAL STIMULUS - MARKED DISRUPTION OF
NORMAL ARCHITECTURE
CAUSES OF CELL DEATH
• ISCHAEMIA
• PHYSICAL AGENTS
• CHEMICAL AGENTS
• INFECTIOUS AGENTS
• IMMUNOLOGICAL REACTIONS
• GENETIC DERANGEMENTS
• NUTRITIONAL IMBALANCES
RESPONSE OF CELLS TO INJURY DEPENDS ON:
• TYPE OF INJURY
• DURATION OF INJURY
• SEVERITY OF INJURY
• TYPE, STATE AND ADAPTABILITY OF THE CELL, (i.e. NUTRITIONAL
OR HORMONAL STATUS & ITS METABOLIC NEEDS)
BIOCHEMICAL TARGETS OR SITES
• MAINTENANCE OF THE INTEGRITY OF CELL MEMBRANES (IONIC &
OSMOTIC BALANCE)
• AEROBIC RESPIRATION
• PROTEIN SYNTHESIS
• PRESERVATION OF THE GENETIC APPARATUS
• INJURY AT ONE SITE / LOCUS LEADS TO “RIPPLE EFFECT”
MORPHOLOGICAL CHANGES APPARENT AFTER ONE OF THE CRITICAL
BIOCHEMICAL SYSTEMS HAS BEEN DERANGED
BIOCHEMICAL EFFECTS RESULTING IN CELL INJURY
• ATP DEPLETION
• ATP REQUIRED AS A SOURCE OF ENERGY FOR MOST CELL
PROCESSES. PRODUCED BY: OXIDATIVE PHOSPHORYLATION
• GYCOLYSIS
OXYGEN DERIVED FREE RADICALS
• CELLS PRODUCE ENERGY BY REDUCING MOLECULAR OXYGEN TO
WATER BY-PRODUCT: REACTIVE OXYGEN SPECIES
• TOXIC TO NUCLEIC ACIDS, PROTEINS AND LIPIDS
• RADICAL SCAVENGING SYSTEMS ACT AS COUNTER-CHECK
INTRACELLULAR CALCIUM & LOSS OF CALCIUM HOMEOSTASIS
• N CYTOSOLIC CALCIUM  0.1μMOL EXTRACELLULAR 1.3 MMOL
• HI CYTOSOLIC CALCIUM after ISCHEMIA & SOME TOXIN DAMAGE
→INFLUX fm MITOCHONDRIA, ER & EXTRACELLULAR SPACE =
↑MEMBRANE PERMEABILITY
• HI CALCIUM TRIGGERS ENZYMES : PHOSPHOLIPASES, PROTEASES
AND ENDONUCLEASES
DEFECTS IN MEMBRANE PERMEABILITY
• MAY RESULT FROM ATP DEPLETION, CALCIUM INFLUX OR DIRECT
DAMAGE FROM TOXINS
• MAY AFFECT MITOCHONDRIA, PLASMA MEMBRANE & CELLULAR
MEMBRANES
MITOCHONDRIAL DAMAGE
• MAY BE DAMAGED BY HYPOXIA, INCREASED Ca
• RESULTS IN TOTAL LOSS OF OXIDATIVE PHOSPHORYLATION

EXAMPLES OF CELLULAR INJURY

• ISCHAEMIC & HYPOXIC INJURY
• ISCHAEMIA : REDUCTION IN THE BLOOD SUPPLY RESULTING IN
DECREASE OXYGEN
HYPOXIA: REDUCTION IN OXYGEN TENSION
INITIALLY DAMAGE IS REVERSIBLE, IF SUSTAINED BECOMES
IRREVERSIBLE

REVERSIBLE:
FIRST POINT OF ATTACK IS THE MITOCHONDRIA’S OXIDATIVE
PHOSPHORYLATION
• ACUTE CELLULAR SWELLING (CELL MEMBRANE)  ATP & ATPASE 
Na INTRACELLULARLY ISOSMOTIC GAIN OF WATER  CELL SWELLING 
DILATATION OF ER
• DETACHMENT OF RIBOSOMES FROM RER
• FUNCTIONAL CONSEQUENCES CAN OCCUR IN REVERSIBLE INJURY
IRREVERSIBLE
• THIS OCCURS WHEN ISCHAEMIA PERSISTS
• EXTENSIVE DAMAGE TO CELL MEMBRANES
• SEVERE VACUOLISATION OF MITOCHONDRIA AND PRODUCTION OF
DENSITIES
• SWELLING OF LYSOSOMES
• MASSIVE CALCIUM INFLUX
• LEAKAGE OF ENZYMES INTO CYTOPLASM FROM LYSOSOMES:
RNASES, PROTEASES
• LEAKAGE OF ENZYMES INTO THE EXTRA-CELLULAR SPACE
•  CELL DEATH
• POST DEATH : CELL COMPONENTS DEGRADED LEAKAGE OF
CELLULAR ENZYMES INTO EXTRACELLULAR SPACE AND MOLECULES
ENTER THE CELL.
• DEAD CELL IS REPLACED BY “MYELIN FIGURES”  PHAGOCYTOSED
BY OTHER CELLS OR DEGRADED INTO FATTY ACIDS  CALCIFICATION

CRITICAL EVENTS FOR “LETHAL HIT”

• INABILITY TO REVERSE MITOCHONDRIAL DAMAGE (LACK OF
OXIDATIVE PHOSPHORYLATION & ATP GENERATION
• PROFOUND DISTURBANCES IN MEMBRANE FUNCTION
MITOCHONDRIAL DYSFUNCTION:  CYTOSOLIC
Ca  UPTAKE BY MITOCHONDRIA  ACTIVATE PHOSPHOLIPASES
 DAMAGE TO MEMBRANE
LOSS OF MEMBRANE PHOSPHOLIPIDS
CYTOSKELETAL ABNORMALITIES : ACTIVATION OF PROTEASES
REACTIVE OXYGEN SPECIES : DAMAGE TO MEMBRANES LOW IN
ISCHAEMIA,  IN RE-PERFUSION
LIPID BREAKDOWN PRODUCTS : ACCUMULATE DUE TO PHOSPHOLIPASES
• LOSS OF INTRACELLULAR AMINO ACIDS
• FREE RADICAL-INDUCED CELL INJURY
• RESULTS FROM RADIATION, CHEMICAL INJURY, MICROBIAL
KILLING, TUMOUR DESTRUCTION AND INFLAMMATION
MORPHOLOGY OF REVERSIBLE CELL INJURY & NECROSIS
• REVERSIBLE INJURY:
CELLULAR SWELLING (HYDROPIC CHANGE / VACUOLAR DEGENERATION):
– RESULTS FROM LOSS OF IONIC & FLUID BALANCE
– FIRST MANIFESTATION OF CELL INJURY
– MACRO : PALLOR,  IN SIZE of ORGAN
– MICRO : SMALL CYTOPLASMIC VACUOLES
FATTY CHANGE:
– RESULTS FROM TOXIC, METABOLIC OR HYPOXIC INJURY
– SEEN IN CELLS DEPENDANT ON FAT METABOLISM I.E. HEPATOCYTE
OR MYOCARDIAL CELL
– MICRO: LIPID VACUOLES IN CYTOPLASM
ELECTRON MICROSCOPE CHANGES
- HYDROPIC SWELLING OF CELL
- CYTOPLASMIC BLEBS
- DISTORTION OF MICROVILLI
- “MYELIN FIGURES”
- MITOCHONDRIAL AMORPHOUS DENSITIES
- DILATATION OF ENDOPLASMIC RETICULUM
- LYSOSOMAL RUPTURE
- NUCLEAR ALTERATIONS
- NECROSIS
CELL DEATH OCCURING IN LIVING TISSUE RESULTING FROM
IRREVERSIBLE CELL INJURY.
ENZYMATIC DEGRADATION
• AUTOLYSIS
• HETEROLYSIS
• DENATURATION OF PROTEINS
•  EOSINOPHILIA (PINK)  BINDING OF EOSIN TO DENATURED
PROTEINS
• GLASSY HOMOGENEOUS CYTOPLASM  GLYCOGEN
• VACUOLATED CYTOPLASM (LYSOSOMAL ENZYMES DIGEST
ORGANELLES)
• CALCIFICATION
• NUCLEAR CHROMATIN CLUMPING
• PYKNOSIS
• KARYOLYSIS (DNASES)
• KARRYORHEXIS
TYPES OF NECROSIS
1. COAGULATIVE NECROSIS
– WHERE DENATURATION OF PROTEIN IS THE PREDOMINANT
PROCESS
– PRESERVATION OF BASIC ARCHITECTURE “GHOST OUTLINES”
– TISSUE MAINTAINS A FIRM TEXTURE i.e. MYOCARDIAL INFARCT
2. COLLIQUATIVE (LIQUEFACTIVE NECROSIS)
- WHERE ENZYMIC DEGENERATION IS THE DOMINANT PROCESS
- COMPLETE DISRUPTION OF ARCHITECTURE TO A LIQUID VISCOUS
MASS
- OCCURS IN THE CENTRAL NERVOUS SYSTEM OR IN PUTREFACTION
- MAY RESULT IN PUS
3. GANGRENOUS NECROSIS
– IN A LIMB OR HOLLOW VISCOUS
– “WET GANGRENE”
– “DRY GANGRENE”
4. CASEOUS NECROSIS:
- WHERE THERE IS BOTH ENZYMATIC DEGRADATION & PROTEIN
DENATURATION
- i.e. BOTH COLLIQUATIVE & COAGULATIVE NECROSIS
- OCCURS IN TUBERCULOSIS
- “CHEESY” WHITE APPEARANCE
5. FAT NECROSIS :
- OCCURS WHERE THERE IS FAT : CLASSIC EXAMPLES,
PANCREATITIS & BREAST

APOPTOSIS
GRK “FALLING OFF” PROGRAMMED CELL DEATH TO LIMIT
THE NUMBERS
OCCURS IN :
EMBRYOGENESIS
HOMEOSTASIS I.E. MENSTRUAL
CYCLE, BREAST FEEDING,
PROSTATE
DEFENSE MECHANISM IN IMMUNE REACTION
TO REMOVE DAMAGED CELLS IN DISEASE i.e. VIRAL HEPATITIS
TO LIMIT CELLS IN PROLIFERATING EPITHELIUM i.e. INTESTINAL CRYPTS
IN ATROPHY
IN AGEING
MORPHOLOGY OF APOPTOTIC CELLS
CELL SHRINKAGE
CHROMATIN CONDENSATION
FORMATION OF CYTOPLASMIC BLEBS & APOPTOTIC BODIES
PHAGOCYTOSIS OF APOPTOTIC CELLS BY ADJACENT CELLS
 APOPTOSIS DOES NOT ELLICIT INFLAMMATION
BIOCHEMICAL FEATURES OF APOPTOTIC CELLS
• PROTEIN CLEAVAGE : CASPASES

• PROTEIN CROSS-LINKING (RESULTS IN CYTOPLASMIC SHRINKAGE)

• DNA BREAKDOWN
PHAGOCYTIC RECOGNITION (BY EXPRESSING PHOSPHATIDLYSERINE &
THROMBOSPONDIN)
MECHANISMS OF APOPTOSIS
APOPTOSIS IS THE ENDPOINT OF AN ENERGY-DEPENDANT CASCADE
OF MOLECULAR EVENTS, INITIATED BY CERTAIN STIMULI & CONSISTING
OF :
1. SIGNALLING PATHWAYS : TRANSMEMBRANE SIGNALS, + OR –
2. CONTROL & INTEGRATION STAGE: ADAPTOR PROTEINS & BCL-2
PROTEIN (SUPPRESSES APOPTOSIS BY ACTING ON THE
MITOCHONDRIA
3. COMMON EXECUTION PHASE (PROTEOLYTIC CASCADE)
4. REMOVAL OF DEAD CELLS BY PHAGOCYTOSIS (BY EXPRESSING
SURFACE MARKERS)