Cell Injury and Death Mechanisms

Local Reactions of the Organism

• Cell damage occurs when cells are stressed severely, unable to adapt, or exposed to damaging agents/intrinsic abnormalities
• Reversible cell injury—early/mild injury; functional & morphologic changes are reversible if the damaging stimulus is removed
• Cell death—continued damage; irreversible; two types: necrosis & apoptosis, which differ in mechanisms, morphology, and roles in disease and physiology
• Necrosis occurs when damage to membranes is severe; enzymes leak out of lysosomes, enter cytoplasm, digest the cell, resulting in necrosis.
• Cellular contents leak into extracellular space, causing an inflammatory reaction.
• Necrosis is always a pathologic process
• Apoptosis—when a cell lacks growth factors or has damaged DNA/proteins beyond repair; the cell kills itself.
• Apoptosis is characterized by nuclear dissolution, but without loss of membrane integrity, not always caused by pathologic cell damage
• Apoptosis does not elicit inflammation.

Causes of Cell Damage

• Oxygen deprivation (hypoxia)
• Chemical agents (e.g., CO, asbestos)
• Infectious agents (e.g., fungi, bacteria)
• Immunologic reactions (e.g., autoimmune reactions)
• Nutritional imbalances
• Physical agents (e.g., shock, temperature)
• Aging

Types of Cell Damage

• Reversible & irreversible cell damage
• The graph shows stages of reversible & irreversible cell injury, from cell function to stages of death, indicating the severity of changes as well.

Reversible Injury

• Two key changes: cellular swelling & fatty change
• Cellular swelling—result of pump failure; inability to maintain ionic/fluid homeostasis.
• Fatty change—occurs in hypoxic injury and other toxic/metabolic injuries; small or large lipid vacuoles in the cytoplasm appear
• Injurious insults induce changes in cellular organelles (e.g., endoplasmic reticulum, or ER)
• This may be an adaptive response with important functional consequences.

Cellular Swelling

• First manifestation of injury to cells
• Causes pallor (compression of capillaries), increased turgor, and increase in organ weight
• Clear vacuoles within cytoplasm (distended & pinched-off segments of endoplasmic reticulum (ER))
• Also called hydropic change or vacuolar degeneration

Fatty Change

• Manifested by appearance of lipids in the cytoplasm.
• Primarily found in fat-metabolizing cells (e.g., hepatocytes, myocardial cells), and is reversible
• Plasma membrane alterations (blebbing, blunting, distortion of microvilli)
• Endoplasmic reticulum (ER) dilation, ribosome detachment, and polysome dissociation
• Chromatin clumping noted.

Irreversible Cell Damage

• Necrosis—loss of membrane integrity & leakage of cellular contents, dissolution of injured cells.
• Enzymes from dying cells & leukocytes digest the cells.
• Associated with inflammation

Cytoplasmic Changes (necrosis)

• Necrotic cells show increased eosinophilia
• Nuclear changes occur; one of three patterns (due to DNA/chromatin breakdown): karyolysis, pyknosis, or karyorrhexis
• Fates of necrotic cells may persist, be digested, or disappear

Mechanism of Cell Damage

• Cellular response to injurious stimuli depends on injury type, duration, severity, status
• Consequences depend on the injured cell's type, adaptability, & genetic makeup.
• Cell injury results from abnormalities in several essential cellular components
• Multiple biochemical alterations can be triggered by a single injurious insult
• Examples: muscle tissues show different tolerance times to ischemia.

Mitochondrial Damage and Dysfunction

• Failure of oxidative phosphorylation leads to progressive ATP depletion
• Abnormal oxidative phos., leads to reactive oxygen species (ROS) formation

Influx of Calcium

• Cytosolic free calcium normally maintained at low levels by calcium transporters (ATP-dependent)
• Ischemia & certain toxins increase cytosolic calcium
• Increased cytosolic calcium activates enzymes: phospholipases & proteases
• These enzymes damage membranes and cytoskeletal proteins.

Oxidative Stress

• Free radicals (single unpaired electron)
• Reactive oxygen species (ROS)
• Role in cell injury.

ROS (Reactive Oxygen Species) in Inflammation & Host Defense

• Produced in phagocytic leukocytes (e.g., neutrophils, macrophages).
• Used to destroy ingested microbes/substances.
• NO (nitric oxide) is another reactive free radical.
• Protective mechanisms exist to remove ROS: superoxide dismutases (SODs) & glutathione peroxidases (GSH).

Defective Membrane Permeability

• Decreased phospholipid synthesis (due to low ATP levels)
• Increased phospholipid breakdown
• ROS (damaging effect)
• Cytoskeletal abnormalities
• Disturbances in membrane architecture, motility, and signaling resulting from changes.
• Lipid breakdown products

3 Main reactions that cause cell damage

• Lipid peroxidation of membranes
• Changes/Cross-linking in proteins
• DNA damage

Damage to DNA & Proteins

• Cells repair DNA damage, but severe damage triggers apoptosis

This quiz focuses on understanding local reactions of organisms related to cell injury and death. It covers topics such as reversible and irreversible cell injury, necrosis, and apoptosis. Test your knowledge on the differences between these processes and their implications in disease and physiology.