MECHANISMS OF CELL INJURY AND DEATH

What is pathophysiology?

Study of disease mechanisms from cellular → tissue → organ level.

Where does disease begin?

At the cellular level, before clinical symptoms appear.

What is the cell fate continuum?

Homeostasis → Adaptation → Injury → Death

What is cellular adaptation?

Reversible change to meet increased demand (protective).

When does cell injury occur?

When stress exceeds adaptive capacity.

When does cell death occur?

After irreversible injury.

Types of cell death?

Physiological (normal) and pathological (disease).

What is hyperplasia?

Increased number of cells via mitosis.

Causes of hyperplasia?

Hormones, inflammation, trauma.

What is hypertrophy?

Increase in cell size (no increase in number).

Cause of hypertrophy?

Increased workload (e.g. exercise).

What is atrophy?

Decrease in cell size and/or number.

Causes of atrophy?

Nutrient deprivation, disuse, denervation, hormone loss.

What is metaplasia?

Replacement of one differentiated cell type with another.

Causes of metaplasia?

Chronic inflammation, hormones, vitamin deficiency.

What are features of reversible injury?

Cell swelling + loss of homeostasis.

Can reversible injury recover?

Yes, if stimulus is removed.

Most common cause of cell injury?

Hypoxia

Other common causes of cell injury?

• Physical injury

• Infection

• Nutritional imbalance

• Toxins/drugs

• Genetic defects

• Immune reactions

• Aging

Effects of ATP depletion?

• ↓ ion pumps → swelling

• ↑ anaerobic metabolism

• ↑ ROS

• Cytochrome C release → apoptosis

What happens in membrane damage?

• ↑ Ca²⁺ influx

• Loss of integrity

• ↓ phospholipids
  → Cell lysis

What are ROS?

Unstable free radicals.

What do ROS damage?

DNA, proteins, lipids.

Outcome of ROS?

Oxidative stress → cell injury.

Outcome of mild DNA damage?

Repair

Outcome of severe DNA damage?

Apoptosis

What happens with protein misfolding?

Toxic accumulation → disease (e.g. neurodegeneration).

Key concept of injury mechanisms?

They occur simultaneously.

Two main types of cell death?

Apoptosis and necrosis.

Other types?

Necroptosis, pyroptosis, ferroptosis, autophagy.

Define apoptosis.

Programmed, controlled cell death.

Key features of apoptosis?

• ATP-dependent

• Caspase-mediated

• Non-inflammatory

Morphological changes in apoptosis?

• Cell shrinkage

• Chromatin condensation

• DNA fragmentation

• Membrane blebbing

• Apoptotic bodies

What happens to apoptotic bodies?

Phagocytosed (no inflammation).

Triggers of apoptosis?

• DNA damage

• ROS

• Ca²⁺ imbalance

• Mitochondrial damage

Intrinsic pathway?

Mitochondrial → cytochrome C → Bcl-2 regulation.

Extrinsic pathway?

Death receptors (Fas, TNF).

Perforin/granzyme pathway?

Cytotoxic T cells induce apoptosis.

Final common pathway of apoptosis?

Activation of caspase-3

Define necrosis.

Uncontrolled cell death.

Key features of necrosis?

• ATP-independent

• Inflammatory

• Membrane rupture

Cellular changes in necrosis?

• Swelling

• Membrane breakdown

• Leakage of contents

Causes of necrosis?

• Ischaemia

• Hypoxia

• Toxins

• ROS

• Extreme temperatures

Outcome of necrosis?

Tissue damage + inflammation.

What is necroptosis?

Regulated necrosis (inflammatory, autoimmune-related).

What is pyroptosis?

Infection-driven, caspase-mediated, releases cytokines.

What is ferroptosis?

• Iron-dependent

• Lipid peroxidation

• No caspases

• Linked to cancer & neuroprotection

What is autophagy?

“Self-eating” process.

What is autophagy’s function?

• Degrades damaged components

• Recycles nutrients

• Supports survival

Mechanism of autophagy?

Lysosome-mediated (LC3 involved).

Is autophagy always cell death?

No — can promote survival or death.

Key difference in regulation between Apoptosis and Necrosis?

Apoptosis = controlled;
Necrosis = uncontrolled.

Energy use between Apoptosis and Necrosis?

Apoptosis = ATP-dependent;
Necrosis = ATP-independent.

Inflammation between Apoptosis and Necrosis?

Apoptosis = none;
Necrosis = yes.

Cell size between Apoptosis and Necrosis?

Apoptosis = shrink;
Necrosis = swell.

Membrane between Apoptosis and Necrosis?

Apoptosis = intact; Necrosis = ruptures.

What determines cell injury outcome?

• Type of stimulus

• Severity

• Duration

• Cell’s adaptive capacity

Most important injury mechanisms to remember?

• ATP depletion

• ROS

• Ca²⁺ influx

• DNA damage