Cellular Adaptation, Injury, and Death

Cellular Adaptation, Injury, and Death

• Adaptation is essential for cells to survive stress
• Cell injury and cell death are major topics

Pathophysiology

• Pathology studies structural and functional changes in cells, tissues, and organs due to disease
• Physiology studies the functions of the human body
• Pathophysiology is physiology of altered health
• Pathophysiology deals with cellular and organ changes from disease and their effects on total body function
• Pathophysiology focusses on understanding disease mechanisms to prevent and treat diseases

Cellular Adaptation

• Adaptation is a protective mechanism to prevent cellular and tissue harm from stressors
• When stressed, cells undergo adaptive changes to survive and maintain homeostasis
• If a cell makes no changes or maladaptive changes, it will not survive
• An adapted cell is neither normal nor injured
• Cells adapt to internal environment changes in size, number, and type

Types of cellular adaptation

• Atrophy (size)
• Hypertrophy (size)
• Hyperplasia (number)
• Metaplasia (type)
• Dysplasia (size + number)

Atrophy

• Atrophy is a decrease in cell size, reducing tissue mass
• Occurs with decreased work demands or adverse conditions
• Allows survival at a lower, more efficient functioning level
• Reduces O2 consumption and cellular functions
• Common causes include disuse, insufficient nutrition, decreased neurological/hormonal stimulation, ischemia, and aging
• Shrinkage of skeletal muscle from immobilization is an example
• Brain atrophy can result from aging and reduced blood supply

Hypertrophy

• An increase in the size of individual cells, enlarging tissue mass
• Results from increased workload, affects cardiomyocytes and skeletal muscle
• Increases functional components of the cell for equilibrium between demand and capacity
• Common causes include physiological (exercise, pregnancy) and pathological reasons
• Adaptive and Compensatory hypertrophy are types of pathologicaly hypertrophy

Hyperplasia

• Hyperplasia is an increased number of cells, enlarging tissue mass
• Occurs in tissues with mitotic division capabilities like the epidermis
• Hypertrophy and hyperplasia can occur simultaneously, such as uterine enlargement during pregnancy
• Common causes include hormonal/compensatory physiological causes or non-physiological factors
• Excessive hormones or growth factors can cause non-physiological hyperplasia

Metaplasia

• One mature cell type is replaced by a different mature cell type
• The replacement cell is more suitable for the changed environment
• Reprogramming of undifferentiated stem cells is involved
• The cell type conversion does not cross primary tissue type boundaries
• Caused by chronic irritation/inflammation, and is often reversible when the irritant is removed

Dysplasia

• Dysplasia refers to abnormal changes in cell size, shape, and organization
• Not a true adaptive process, but related to hyperplasia
• Often called atypical hyperplasia
• Mostly found in epithelial tissues
• Common causes include chronic irritation/inflammation, infections (like HPV), carcinogen exposure
• It may not lead to cancer
• If it becomes cancerous, it is called neoplasia ("new growth")

Cell Injury

• Cells can be injured, leading to cell injury and death
• The extent of injury depends on intensity and duration, and cell type

Causes of cell injury

• Physical (mechanical forces, temperature extremes, electrical injuries)
• Radiation (ionizing, ultraviolet, nonionizing)
• Chemical (drugs, lead, mercury)
• Biologic agents (bacteria, viruses, parasites)
• Nutritional imbalances (excess/deficiency in fats, minerals, vitamins, amino acids)

Mechanisms of Cell Injury

• Free radical formation
• Hypoxia and ATP depletion
• Disruption of intracellular calcium homeostasis

Free Radicals and Reactive Oxygen Species

• Free radicals are chemicals with an unpaired electron in the outer shell
• Free radicals are extremely unstable and reactive
• Free radicals reaction with normal cell components causing damage
• Antioxidants remove free radicals
• Glutathione peroxidase is an example of an enzymatic antioxidant
• Vitamin C is an example of a non-enzymatic antioxidant

Reactive Oxygen Species

• Superoxide anion O2, hydroxyl radical OH, hydrogen peroxide H2O2
• Produced endogenously during metabolism or phagocytosis
• Exogenous causes include ionizing and UV radiation
• Oxidative stress happens when ROS generation exceeds body's neutralization capacity

Hypoxic Cell Injury

• Hypoxia is a lack of sufficient oxygen
• Hypoxia can result from ischemia, inadequate oxygen, respiratory disease, anemia, edema or cell's inability to use oxygen
• ATP depletion or "Power failure" results from hypoxia

ATP level reduction

• Anaerobic metabolism leads to lactic acid production, creating acidic conditions
• Acid damages membranes and affects biochemical reactions
• Na+/K+ ATPase declines, which increases intracellular sodium and cell swelling

Impaired Calcium Homeostasis

• Calcium ions are critical mediators of cell injury
• Increased calcium level inappropriately activates hydrolytic enzymes
• These enzymes can damage the cytoskeleton and membrane proteins
• Increased entrance or impaired efflux leads to increased calcium level
• Calcium/magnesium (Ca2+/Mg2+)-ATPase impairment is an example of impaired efflux

Cellular Death

• Reversible injury: Cell can revert to homeostasis if the agent is removed
• Two common patterns: Cellular swelling and fatty change
• Irreversible injury: Occurs if stress is too severe, cell fails to adapt
• Two types of irreversible injury: Apoptosis and necrosis

Apoptosis

• Cells that undergo apoptosis undergo an orderly process
• Programmed cell death or "cellular suicide"
• A highly selective process that eliminates injured and aged cells, controlling tissue regeneration
• Cells undergoing apoptosis have characteristic morphologic and biochemical features

Apoptosis Mechanisms

• Extrinsic (death receptor dependent) and Intrinsic (death receptor independent) pathways
• Execution in both pathways is carried out by cysteine-aspartic proteases (caspases)
• Caspases are activated by cleavage of an inhibitory portion of their polypeptide chain

Reasons for Apoptosis

• Needed for development
• Eliminates abnormal cells
• Maintains a balance

Diseases with Apoptosis

• Inhibition: Cancer, autoimmune and viral infections
• Hyperactivity: Neurodegenerative and hematologic diseases, tissue damage

Necrosis

• The death of cells or tissue portions from irreversible damage and not a cellular event
• Causes loss of cell membrane integrity, enzymatic breakdown, and inflammation
• Damaged cells release their cellular content and causes inflammation and further damage

Types of Necrosis

• Coagulative necrosis
• Liquefactive necrosis
• Caseous necrosis

Coagulative Necrosis

• Transformed to a gray, firm mass
• Acidosis develops and denatures enzymatic and structural proteins
• Characteristic of hypoxic injury, commonly seen in infarcted areas

Liquefactive Necrosis

• Causes the tissue to undergo liquefaction
• Occurs when some cells die, but their catalytic enzymes are not destroyed
• Cavities or ulcers may develop in the affected area
• Softening of the center of an abscess

Caseous Necrosis

• Distinct coagulation necrosis where dead cells persist indefinitely as soft, cheese-like debris
• Converted to cheesy material by fat-like substance infiltration
• Most commonly seen in tuberculosis

Gangrene

• The term is applied when a considerable mass of tissue undergoes necrosis

Dry Gangrene

• Caused by coagulative necrosis
• Lack of arterial blood supply
• Results in an area that dries, shrinks, and blackens

Wet Gangrene

• Liquefaction results
• Lack of venous flow allows fluid to accumulate in tissue
• Causes tissue that becomes cold, swollen, and black

Gangrene

• Caused by gas buildup within tissue, reducing blood supply
• Is from a Clostridium bacterial infection, commonly Clostridium perfringens
• Bacteria produce toxins that dissolve cell membranes, causing muscle cell death
• Hydrogen sulfide bubbles gas that form I nthe muscle

Cellular aging

• Cellular aging is the gradual decline in cell function and viability over time
• Cellular changes include atrophy, decreased function, and cell loss
• Accumulation of environmental and genetic damage
• Examples of genetic damage caused include DNA damage, free radicals, and glycation

Factors Affecting Aging

• Genetic Influences
• "Anti-aging' genes activities
• Mutations or gene expression changes
• Replicative senescence
• Telomeres become too short
• Cells can no longer divide

Genetic Influences and Premature Aging

• Hutchinson-Gilford progeria syndrome(早年衰老症候群) is an example
• mutation in the LMNA gene (lamin A, a scaffolding protein in nucleus)

Replicative Senescence

• A result of telomeres becoming too short, which result in cells are no longer dividing