Cells respond to injury through a series of adaptive, reversible, or irreversible changes, depending on the severity and duration of the insult, as well as the cell’s ability to adapt.
Types of Cellular Responses
| Response Type | Examples | Outcome |
|---|---|---|
| Adaptation | Hypertrophy, Atrophy, Hyperplasia, Metaplasia | Structural or functional adjustment to stress |
| Reversible Injury | Cellular swelling, fatty change | The cell recovers if the stimulus is removed |
| Irreversible Injury / Cell Death | Necrosis, Apoptosis, Necroptosis | Permanent loss of cell viability |
Mechanisms and Cellular Targets of Injury
- Damage by Oxygen-Derived Free Radicals
- Free radicals: Superoxide anion (O₂•−), Hydroxyl radical (•OH), Hydrogen peroxide (H₂O₂)
- Target damage: DNA, proteins, lipid membranes, and circulating lipids (e.g., LDL)
- ATP Depletion
- Disrupts Na⁺/K⁺ and Ca²⁺ pumps, causing:
- Ionic imbalance
- Cell swelling and ER dilation
- Decreased pH (due to increased anaerobic glycolysis)
- Chronic ATP depletion → Morphological and functional ER/ribosome changes
- Disrupts Na⁺/K⁺ and Ca²⁺ pumps, causing:
- Membrane Damage and Fluid Movement
- Mechanisms:
- Formation of the membrane attack complex (via the complement system)
- Breakdown of Na⁺/K⁺ gradients
- Effect:
- Cellular swelling (hydropic change)
- Mechanisms:
- Calcium Influx
- Elevated intracellular calcium activates destructive enzymes:
- Proteases: degrade proteins
- Phospholipases: damage cell membranes
- ATPases: worsen ATP depletion
- Endonucleases: damage DNA
- Elevated intracellular calcium activates destructive enzymes:
- Mitochondrial Dysfunction
- Oxidative phosphorylation → ↓ ATP production
- Formation of Mitochondrial Permeability Transition (MPT) channels
- Release of cytochrome c → triggers apoptosis
Reversible Cell Injury
Occurs when the injury is mild and transient.
| Feature | Mechanism/Effect |
|---|---|
| ↓ ATP synthesis | Reduced oxidative phosphorylation |
| Na⁺/K⁺ pump failure | Influx of Na⁺ and water → cell swelling |
| Anaerobic glycolysis | ↑ Lactic acid → ↓ pH |
| ↓ Protein synthesis | Ribosomal detachment from RER |
| Plasma membrane blebs | Early reversible change |
| Myelin figures | Indicative of membrane damage |
Irreversible Cell Injury
Occurs when cellular damage exceeds the capacity for repair.
| Feature | Mechanism/Effect |
|---|---|
| Severe membrane damage | Massive Ca²⁺ influx, enzyme leakage |
| Mitochondrial dysfunction | Irreversible ATP loss |
| Lysosomal rupture | Release of acid hydrolases → autolysis |
| Nuclear changes: | – Pyknosis: chromatin condensation – Karyorrhexis: nuclear fragmentation – Karyolysis: nuclear dissolution |
Protective Antioxidant Mechanisms
| Defense Mechanism | Function |
|---|---|
| Vitamins A, E, and C | Scavenge free radicals |
| Superoxide dismutase (SOD) | Converts superoxide → hydrogen peroxide |
| Glutathione peroxidase | Neutralizes hydroxyl ions or hydrogen peroxide |
| Catalase | Converts hydrogen peroxide → water + oxygen |
Clinical Correlation: Leakage of Cellular Enzymes
Loss of membrane integrity allows intracellular enzymes to leak into circulation — useful diagnostic markers of tissue injury.
| Organ/Tissue | Marker Enzymes in Blood |
|---|---|
| Heart (Myocardial injury) | Troponin (most specific), CPK-MB, LDH |
| Liver (Hepatitis) | AST, ALT |
| Pancreas (Pancreatitis) | Amylase, Lipase |
| Biliary system (Hepatobiliary injury) | Alkaline phosphatase, GGT |
Key Points to Remember
- Ischemia and hypoxia are the most common causes of cell injury.
- ATP depletion and membrane damage are central mechanisms.
- Calcium influx and free radicals amplify cell damage.
- Reversible → Irreversible injury is a continuous spectrum.
Learning Objective
Understand the cellular, biochemical, and molecular responses to injury — distinguishing reversible from irreversible changes — and correlate them with mechanisms of disease and clinical biomarkers of tissue damage.
