CELLULAR INJURY - 1

Dr Ekta Bhutada Senior Lecturer

 Cellular injury occurs when a stress exceeds the cells ability to adapt
Stress cellular adaptation reversible injury irreversible injury cell death

 Factors affecting the severity of injury :

Type, length & severity of stress Type of affected cell Neurons & cardiac muscle > skeletal muscle Acute > chronic injury

Causes of cellular injury

Hypoxia & Ischemia Physical agents temperature, pressure Chemical agents poisons, metals Biological agents infections Genetic mutation Immunologic reactions

A 35 year old man meets with an accident & suffers severe blood loss.
What would be the sequence of events at cellular & subcellular levels? What is the fate of injured cells?

HYPOXIC ISCHEMIC INJURY

Very common clinical scenario
Hypoxia lack of O2 Causes Ischemia, anemia, severe blood loss

Ischemia Reduced blood flow Hence hypoxia + lack of other substrates; more harmful than hypoxia

Reversible injury
Hallmark sign cellular swelling
Mechanism ATP depletion
disruption of Na-K pump intracellular Na & water disruption of Ca pump intracellular Ca activated anaerobic glycolysis lactic acid accumulation enzymatic activity & protein denaturation

Normal kidney tubules

Reversible injury Cellular swelling

 Other reversible injury

Fatty change Mechanism Hypoxia,Metabolic & toxic injuries fatty change in organs involved with fat metabolism

Ultrastructural changes

Irreversible injury
Hallmark features Plasma membrane damage Mitochondrial damage
ATP, Ca & direct
injuries

Mechanism Plasma membrane damage cytosolic enzymes leak in serum diagnostic utility; further ATP depletion

 Mitochondrial damage ATP depletion & activation of apoptosis Massive Ca influx progression to cell death Final consequence of irreversible injury Cell death either by necrosis or apoptosis

Free radical Injury

Free radicals unstable due to single unpaired electron
Examples Reactive oxygen species(ROS), Fe2+, nitric oxide(NO)

Mechanism : Release energy damage cell membranes, proteins & DNA

 Free radicals removed by Antioxidants Vit A, C, E Ferritin, transferrin, lactoferrin Enzymes catalase, superoxide dismutase, glutathione peroxidase Excess of ROS (oxidative stress) reperfusion injury, cancer, neurodegenerative diseases

The End

CELLULAR INJURY - 2
Dr Ekta Bhutada Senior Lecturer

NECROSIS
Cell death due to lethal injury
Contents from irreversibly damaged cells leak out Inflammation elicited in the surrounding tissue

IRREVERSIBLE INJURY

Morphology
Increased eosinophilia due to denaturation of intracellular protein & enzymatic digestion of cell Nuclear changes in cell death: Pyknosis Karyolysis Karyorrhexis

Types of necrosis
Coagulative necrosis
Liquefactive necrosis

Caseous necrosis

Coagulative necrosis
Architecture of the dead tissue is preserved More eosinophilia & nucleus disappears
Mechanism : denaturation of proteins & destruction of enzymes Example ischemic infarction of any solid organ except brain

Coagulative necrosis

Kidney infarct

Liquefactive necrosis
Necrotic tissue gets liquefied due to enzymatic digestion of cells
Example ischemic infarction of brain, abscess

Brain infarct

Peritonsillar abscess

Caseous necrosis
Characteristic of tuberculosis
C/o caseous i.e. cheese like friable area of necrosis

Tuberculosis in lung & lymph node

Caseous necrosis

Other types
Gangrenous necrosis
Fat necrosis

Fibrinoid necrosis

Gangrenous necrosis
Black dead tissue Characteristic of ischemia of lower limb & intestine Dry gangrene coagulative necrosis Wet gangrene liquefactive necrosis due to supervening infection

Fat Necrosis
Focal areas of fat destruction Characteristic of pancreatitis
Mechanism Lipase activation fat breakdown FA + Ca chalky white deposits (saponification)

Fibrinoid necrosis
Necrotic damage to blood vessel wall & deposition of fibrin like material
Characteristic of vasculitis deposition of fibrinoid material in the blood vessel wall

APOPTOSIS
Suicide program Energy driven programmed cell death
Cells destined to die activate enzymes break the cell apoptotic bodies

No inflammation

 Physiologic & Pathologic

Physiologic during embryogenesis, endometrial breakdown during menstrual cycle Pathologic (crucial in removing damaged cells beyond repair) viral infections, degenerative diseases of CNS

Mechanism
intrinsic (mitochondrial)
Initiation phase extrinsic (death receptor)

Execution phase Removal phase

Disorders of dysregulated apoptosis

Defective apoptosis cancer, autoimmune diseases Increased apoptosis neurodegenerative diseases

FEATURES

NECROSIS

APOPTOSIS

CELL SIZE

Enlarged

Reduced

NUCLEUS

Pyknosis/karyorrhexis/k aryolysis Disrupted & contents may leak out Frequent

Fragmented

PLASMA MEMBRANE & CELLULAR CONTENTS ADJACENT INFLAMMATION

Intact & no leakage

No

PHYSIOLOGIC/PATHOLO GIC

Always pathologic

Physiologic /Pathologic

Autophagy
A process that triggers cell death which is distinct from necrosis & apoptosis
Cell eat its own contents Helps a cell to survive in various conditions like nutrient deprivation Exact mechanism not known

The End