Cell injury

Dr. Topesh Patle

Introduction

Cells are dynamic structures that constantly maintain internal balance (homeostasis). They adapt to stress through mechanisms such as hypertrophy, hyperplasia, atrophy, and metaplasia. However, when exposed to stress beyond their adaptive capacity, cellular injury occurs.

The severity and outcome of injury depend on:

  • Nature of the injurious agent

  • Duration of exposure

  • Intensity of the insult

  • Type of cell affected

  • Nutritional and hormonal status

  • Genetic makeup of the individual

Cell injury progresses along a spectrum:

  1. Adaptation → Reversible injury → Irreversible injury → Cell death

 

Causes of Cell Injury

Although causes are diverse, they can be grouped into major categories.

1. Hypoxia and Ischemia

Hypoxia is the most common cause of cell injury.

  • Hypoxia: Reduced oxygen availability

  • Ischemia: Reduced blood supply (oxygen + nutrients)

Common causes:

  • Myocardial infarction (coronary artery blockage)

  • Stroke (cerebral ischemia)

  • Severe anemia

  • Carbon monoxide poisoning

  • Shock

Oxygen is essential for oxidative phosphorylation in mitochondria. When oxygen supply decreases, ATP production falls, leading to energy failure.

2. Physical Agents

Physical injury may result from:

  • Mechanical trauma

  • Extreme heat (burns)

  • Extreme cold (frostbite)

  • Radiation exposure

  • Electric shock

  • Sudden pressure changes

Ionizing radiation damages cells by generating free radicals and causing DNA strand breaks.

3. Chemical Agents and Drugs

Many chemicals cause direct or indirect cellular damage.

Examples:

  • Industrial toxins

  • Pesticides

  • Heavy metals (lead, arsenic)

  • Alcohol

  • Chemotherapeutic drugs

Overdose of Paracetamol leads to accumulation of toxic metabolites that cause liver cell necrosis.

4. Infectious Agents

Microorganisms cause injury through toxin production, direct invasion, or immune-mediated mechanisms.

Examples:

  • Hepatitis B virus — causes liver cell injury

  • Mycobacterium tuberculosis — causes granulomatous inflammation

  • Fungal and parasitic infections

 

5. Immunologic Reactions

Immune responses may target self-tissues:

  • Autoimmune diseases

  • Hypersensitivity reactions

  • Chronic inflammatory disorders

Example: Autoimmune hepatitis causing hepatocyte injury.

6. Genetic Defects

Genetic mutations may lead to:

  • Abnormal enzyme function

  • Protein misfolding

  • Storage diseases

  • Metabolic imbalance

These defects predispose cells to injury even under normal conditions.

7. Nutritional Imbalance

  • Protein-energy malnutrition

  • Vitamin deficiencies

  • Obesity

  • Diabetes mellitus

Both deficiency and excess nutrients disturb metabolic processes.

Mechanisms of Cell Injury

Despite varied causes, most cell injuries follow common molecular pathways.

1. ATP Depletion

ATP is required for:

  • Sodium-potassium pump (Na⁺/K⁺ ATPase)

  • Protein synthesis

  • Lipid metabolism

  • Calcium transport

When ATP decreases:

  • Na⁺ accumulates inside cells

  • Water enters cells → swelling

  • Anaerobic glycolysis increases

  • Lactic acid accumulates

  • Intracellular pH decreases

Persistent ATP depletion leads to irreversible damage.

2. Mitochondrial Dysfunction

Mitochondria are the powerhouse of the cell.

Damage results in:

  • Reduced ATP production

  • Increased reactive oxygen species (ROS)

  • Release of pro-apoptotic proteins (e.g., cytochrome c)

Severe mitochondrial damage is a key event in irreversible injury.

3. Loss of Calcium Homeostasis

Normally, intracellular calcium levels are tightly regulated.

Injury causes calcium influx from:

  • Extracellular space

  • Endoplasmic reticulum

Elevated calcium activates:

  • Phospholipases → membrane damage

  • Proteases → cytoskeletal damage

  • Endonucleases → DNA fragmentation

  • ATPases → worsens ATP depletion

 

4. Oxidative Stress (Free Radical Injury)

Free radicals contain unpaired electrons and are highly reactive.

Common ROS:

  • Superoxide (O₂⁻)

  • Hydrogen peroxide (H₂O₂)

  • Hydroxyl radical (OH⁻)

Effects:

  • Lipid peroxidation of membranes

  • Protein oxidation

  • DNA damage

Excessive ROS overwhelms antioxidant systems and leads to cell death.

5. Membrane Damage

Membrane integrity is essential for cell survival.

Damage may affect:

  • Plasma membrane

  • Mitochondrial membrane

  • Lysosomal membrane

Consequences:

  • Enzyme leakage

  • Calcium influx

  • Release of lysosomal enzymes

  • Autodigestion of cell

 

6. DNA and Protein Damage

Severe DNA injury activates p53-mediated pathways.

If repair fails:

  • Apoptosis is triggered

Protein misfolding leads to:

  • Endoplasmic reticulum stress

  • Activation of apoptosis

 

Reversible Cell Injury

Reversible injury occurs when:

  • The insult is mild

  • Exposure is short

  • The cause is removed early

Cells can recover completely.

Morphological Features

https://ars.els-cdn.com/content/image/3-s2.0-B9780123704696000027-gr3.jpg

1. Cellular Swelling (Hydropic Change)

  • Most common early change

  • Due to failure of Na⁺/K⁺ pump

  • Cytoplasm appears pale and vacuolated

2. Fatty Change (Steatosis)

  • Common in liver and heart

  • Accumulation of triglycerides

  • Seen in alcohol-related liver disease

 

Ultrastructural Changes

  • Membrane blebbing

  • Mitochondrial swelling

  • Ribosomal detachment

  • Chromatin clumping

These changes are reversible if normal conditions are restored.

Irreversible Cell Injury

Irreversible injury leads to permanent damage and cell death.

Two principal forms:

  1. Necrosis

  2. Apoptosis

Hallmarks of Irreversible Injury

  • Severe mitochondrial dysfunction

  • Massive calcium influx

  • Extensive membrane damage

  • Lysosomal rupture

  • Nuclear destruction

Nuclear Changes

  1. Pyknosis — nuclear shrinkage

  2. Karyorrhexis — nuclear fragmentation

  3. Karyolysis — dissolution of nucleus

These are diagnostic features of irreversible injury.

Necrosis

Necrosis is uncontrolled cell death caused by severe injury.

Characteristics:

  • Cell swelling

  • Plasma membrane rupture

  • Inflammation

  • Leakage of enzymes

Clinical example: Myocardial infarction causing cardiac muscle necrosis.

Types:

  • Coagulative necrosis

  • Liquefactive necrosis

  • Caseous necrosis

  • Fat necrosis

  • Fibrinoid necrosis

 

Apoptosis

Apoptosis is programmed cell death.

Features:

  • Cell shrinkage

  • Chromatin condensation

  • Formation of apoptotic bodies

  • No inflammation

Occurs in:

  • Embryogenesis

  • Hormone withdrawal

  • Mild DNA damage

 

Comparison: Reversible vs Irreversible Injury

Feature Reversible Injury Irreversible Injury
ATP depletion Mild/moderate Severe
Membrane damage Repairable Irreparable
Nuclear changes Minimal Pyknosis, karyorrhexis
Outcome Recovery Cell death