Week 2 Flashcards: Cellular Injury & Death (Vocabulary)

Overview

• Week 2 content: Cellular Injury, Aging, and Death within Applied Pathophysiology & Pharmacology I.

• Objectives: understand etiology, pathogenesis, clinical manifestations, and treatment for cellular injuries; distinguish reversible vs irreversible injury; compare necrosis vs apoptosis; recognize cellular aging and adaptations.

• Emphasis on connections to foundational principles (energy metabolism, membrane integrity, oxidative stress) and real-world relevance (ischemia, trauma, toxins, infections).

Key Cell Structures and Functions

• Plasma membrane: transport nutrients and waste; generate membrane potentials; cell recognition and communication; growth regulation; sensor of signals for environmental adaptation.

• Cell membrane (plasma membrane) is the same structure referenced for transport and signaling.

• Cytoplasm: site of metabolic processes.

• Nucleus: largest cytoplasmic organelle; contains genetic information (DNA).

• Mitochondrion: ATP generator; powerhouse; converts energy to forms usable by cell reactions; requires oxygen; drives active transport pumps; source of reactive oxygen species (ROS) as a metabolic byproduct; central to metabolism and cell death signaling.

• Lysosomes: digestion; final products of lysosomal digestion include amino acids, fatty acids, sugars.

• Endoplasmic reticulum (ER) & Ribosomes: protein and lipid synthesis/assembly; rough ER + ribosomes for protein synthesis; smooth ER for lipid metabolism.

• Golgi apparatus: protein and lipid processing for transport; packaging and trafficking.

• Transport vesicles: shuttle molecules between ER, Golgi, and plasma membrane.

• Endocytotic vacuoles: vesicular transport during endocytosis.

• Cytoskeleton (microtubules, etc.): structural support and intracellular transport; important in maintaining cell shape and in injury responses.

• Nucleolus: substructure within nucleus involved in ribosome biogenesis.

• Nuclear envelope: encloses genetic material.

• Cilia: cellular appendages involved in movement and signaling.

• Lipid droplets: energy storage and lipid metabolism reservoirs.

• Other organelles mentioned: mitochondria, lysosomes, rough and smooth ER, Golgi apparatus, ribosomes.

Nucleus, Mitochondria, and Other Organelles (functional summary)

• Nucleus: stores DNA; coordinates gene expression and replication.

• Mitochondria: ATP production via oxidative phosphorylation; oxygen dependence; central to cellular energetics and death signaling; ROS generation as a byproduct.

• Lysosomes: enzymatic digestion; breakdown products feed back into metabolism.

• ER & Ribosomes: site of protein and lipid synthesis; ribosomes on rough ER enable secretory and membrane protein production.

• Golgi apparatus: post-translational modification and sorting for transport.

• Plasma membrane: maintains homeostasis, signaling, and recognition; participates in responses to environmental change.

Mitochondria & Cellular Metabolism

• Central role in cellular energetics and cell death signaling.

• ATP production via oxidative phosphorylation; requires oxygen.

• Powers active transport pumps \ via ATP hydrolysis.

• ROS (reactive oxygen species) are normal byproducts of mitochondrial metabolism.

• Mitochondrial metabolism is central to ischemic injury and reperfusion injury due to energy failure and oxidative stress.

Cellular Specialization and Function (Examples)

• Liver cells: respond to epinephrine by activating glycogenolysis, increasing blood glucose for rapid energy during fight/flight.

• Adrenal cortex cells: ACTH stimulation leads to cortisol production; cortisol drives muscle protein catabolism to release amino acids for resistance/adaptation.

• Muscle cells: amino acids and energy substrate mobilization under stress conditions to support function and repair.

Types of Cellular Injury: Framework

• Categories:

  • Reversible cellular injuries

  • Cellular accumulations

  • Cellular adaptations

  • Irreversible cellular injuries (necrosis, apoptosis)

  • Cellular aging

• Goal: differentiate outcomes and clinical implications of each pathway.

Extrinsic and Intrinsic Factors in Cellular Injury

• Extrinsic (external environment): toxins, mechanical trauma, radiation, infectious agents, toxins, drugs.

• Intrinsic (internal): genetics, hormonal changes/imbalances, immune dysfunction, structural defects, metabolic derangements.

• Contributors to injury span toxic, infectious, physical, and deficit (nutrients, oxygen, water, temperature, waste disposal).

Targets & Mechanisms of Cellular Injury

• Common mechanisms of injury:

  • ATP depletion

  • Altered ion concentrations (e.g., Ca^{2+} overload)

  • Inactivation of enzymes

  • Proteolysis of cytoskeleton

  • Increased ROS production

  • Detachment of ribosomes

  • DNA damage

  • Mitochondrial dysfunction and membrane (cell and organelle) damage

  • Impaired protein synthesis & transport machinery

  • Cytoskeleton disruption and genetic apparatus damage

  • ROS-mediated and mitochondrial signaling pathways drive injury progression

Types of Cellular Injury: A Taxonomy

• Stressor to tissues leads to:

  • Reversible cellular injuries

  • Cellular accumulations

  • Cellular adaptation

  • Irreversible cellular injuries (necrosis, apoptosis)

  • Cellular aging

Intracellular Accumulations

• Excess accumulation of substances within cells; can involve:

  • Fluids and edema-related material

  • Lipids and fats

  • Proteins (e.g., abnormal proteins)

  • Endogenous enzymes or substrates

  • Exogenous substances (pigments, environmental toxins)

• Consequences: disruption of cellular function, toxicity, and immune activation; overcrowding can impair processing and transport.

Hydropic Swelling and Edema (Reversible Injury)

• Hydropic swelling: first sign of reversible cellular injury.

• Mechanism: ATP depletion leads to Na^+-K^+ pump failure; Na^+ accumulates intracellularly; water follows; intracellular edema.

• Edema: abnormal accumulation of fluid in cells, tissues, and interstitial spaces; can affect organs and tissue function.

Intracellular Accumulations: Specific Examples

• Abnormal lipids/metabolism: Fatty liver disease due to abnormal lipid metabolism or accumulation.

• Abnormal proteins: Mallory-Denk bodies (cytoplasmic inclusions in hepatocytes) associated with liver injury; accumulation of misfolded proteins.

• Lack of enzyme: glycogen storage diseases due to enzyme defects causing abnormal glycogen accumulation.

• Indigestible materials and pigments: lipofuscin, cholesterol, cholestasis; pigments can indicate metabolic or excretory failure.

• Exogenous pigments/materials: inhaled or ingested materials that accumulate in tissues.

Organomegaly as a Result of Intracellular Changes

• megaly: Generalized enlargement of an organ (e.g., hepatomegaly, splenomegaly) due to edema or intracellular accumulations.

Reversible Cellular Adaptations (Page 25)

• Atrophy: decreased cell size; energy conservation.

  • Causes: disuse, denervation, ischemia, starvation, endocrine changes, injury.

• Hypertrophy: increased cell mass and functional capacity; caused by increased workload.

• Hyperplasia: increased cell number; caused by increased functional demand, hormonal stimulation, persistent injury, chronic irritation.

• Metaplasia: replacement of one cell type with another better suited to adverse conditions; fully reversible when injurious stimulus is removed.

• Dysplasia: disordered growth with variable cell size/shape; often pre-cancerous; may progress to cancer if stress persists (e.g., cervical dysplasia).

Irreversible Cellular Injury: Necrosis vs Apoptosis

• Necrosis: premature cell death due to external stress, commonly ischemia/oxygen deprivation; characterized by loss of membrane integrity and inflammation.

• Apoptosis: programmed cell death; regulated; often triggered by normal aging or controlled cellular processes; typically does not provoke inflammation.

Necrosis vs Apoptosis: Key Features (Comparison)

• Regulation: Necrosis is generally uncontrolled; apoptosis is a regulated genetic program.

• Triggers: Ischemia/ATP depletion vs extrinsic/intrinsic programmed signals.

• Cell shape: Necrosis—cell swelling; apoptosis—shrinkage/condensation.

• Plasma membrane: Necrosis—membrane rupture; apoptosis—membranes intact, fragmented into apoptotic bodies.

• Cellular content: Necrosis—leakage and inflammation; apoptosis—contained packaging into apoptotic bodies with minimal inflammation.

• Energy: Necrosis not ATP-dependent as a controlled process; apoptosis requires ATP.

• Inflammation: Present in necrosis; absent in apoptosis.

• Mediators: Necrosis—necrotic proteases; apoptosis—caspases (caspase-dependent).

Ischemia: Ischemia, Cascade, and Reperfusion

• Ischemia: most common cause of cell injury; insufficient blood supply leading to oxygen deficit and accumulation of metabolic waste (e.g., lactic acidosis); cellular proteins and enzymes become dysfunctional.

• Reversibility: Early ischemic injury can be reversible; damage progresses with continued ischemia.

• Ischemia-reperfusion injury: paradoxical additional injury when blood supply returns, due to calcium overload, reactive oxygen species, and inflammatory responses.

• Common causes: thrombosis, embolism, trauma, arterial insufficiency (e.g., aneurysm, constriction, hypovolemia, anemia).

• General signs: fever, malaise, tachycardia, leukocytosis, loss of appetite.

Ischemic Cascade and Cellular Damage

• Ischemia leads to nutrient and oxygen deficiency with waste accumulation.

• Damages cellular structures: plasma membrane, nucleus, mitochondrion, ER & ribosomes, Golgi, lysosomes.

• Progression to necrosis via autolysis of proteins and membranes; inflammation increases tissue damage.

Ischemia-Reperfusion Injury Mechanisms

• Calcium overload in cells.

• Formation of free radicals (ROS).

• Subsequent inflammatory response exacerbates tissue injury.

Types of Tissue Necrosis

• Coagulative necrosis: most common; solid tissues/organs; injured cells denature proteins forming a gel-like structure; general architecture preserved; proteolysis slowly dissolves tissue; example: heart.

• Liquefactive necrosis: tissue becomes liquid viscous mass due to digestive enzymes; often occurs in brain or in abscess formation; often associated with infection and lack of supportive connective tissue.

• Fat necrosis: injury to adipose tissue; typically associated with pancreatic enzymes during pancreatitis or breast trauma.

• Caseous necrosis: unique to tuberculosis; necrotic tissue is cell- and debris-rich with cheese-like appearance; incomplete proteolysis.

Gangrene

• Large area of tissue death due to interrupted blood supply.

• Types:

  • Dry gangrene: coagulative necrosis; tissue becomes blackened and dry; demarcation line develops between dead and healthy tissue; moist not involved.

  • Wet gangrene: liquefactive necrosis; often involves internal organs; can be rapidly fatal if unchecked.

  • Gas gangrene: infection by anaerobic Clostridium species; gas production (gas bubbles) and crepitus; associated with myonecrosis.

Treatments for Gangrene

• Removal of dead tissue: debridement; amputation where necessary; maggot debridement therapy (as adjunct).

• Antimicrobial agents.

• Revascularization: surgical transposition, angioplasty; promote blood flow to viable tissue.

• Hyperbaric oxygen therapy for gas gangrene in selected cases.

Cellular Aging

• Cumulative result of factors causing cellular and molecular damage.

• Progressive decline in proliferative and reparative capacity of cells with age.

• Responsible mechanisms:

  • DNA damage

  • Reduced proliferative capacity of stem cells

  • Accumulation of metabolic damage

• Physiologic aging features:

  • Age-related decrease in functional reserve

  • Decreased adaptability to environmental demands

Apoptosis and Programmed Cell Death

• Regulated or programmed cell death; can be triggered by extrinsic (external signals) or intrinsic (internal stress) factors.

• Not usually associated with systemic inflammation.

• Rate of apoptosis relative to cell replacement affects tissue/organ function.

Programmed Senescence Theory

• Intrinsic genetic program that limits cellular replication.

• Decline in telomerase production leads to shortened telomeres with each cell division.

• Cells die when telomere length reaches a critical threshold.

Somatic Death (Whole-Body Death)

• Death of the entire organism; no inflammatory or immune response precedes death.

• Typical features include cessation of respiration and heartbeat, temperature decline, pallor from blood pooling, rigor mortis, and postmortem autolysis.

• Brain death criteria: absence of brainstem reflexes, absence of electrical brain activity, and cessation of cerebral blood flow; used to determine somatic death.

Summary: Key Concepts to Remember

• Reversible vs irreversible injury hinges on membrane integrity, ATP availability, and the ability to restore normal function.

• Necrosis vs apoptosis differ in regulation, energetics, morphology, and inflammatory response.

• Ischemia drives most acute cellular injury; reperfusion can paradoxically worsen injury via calcium overload and ROS.

• Cells adapt to stress via atrophy, hypertrophy, hyperplasia, metaplasia, and dysplasia; these adaptations can be protective or pre-cancerous if stress persists.

• Intracellular accumulations reflect altered metabolism, enzymatic defects, or external substances, and can lead to organ dysfunction if extensive.

• Types of necrosis (coagulative, liquefactive, caseous, fat) have diagnostic implications for tissue injury etiology.

• Gangrene represents extensive necrosis with specific patterns (dry, wet, gas) and requires aggressive management.

• Cellular aging is driven by cumulative damage and telomere biology; apoptosis and senescence contribute to aging phenotypes and tissue function.

• Somatic death involves diagnostic criteria (e.g., brain death) and characteristic postmortem changes.

Next Week Preview

• Review chapters 3 & 4.

• Preview Banasik chapter 53 and Karch appendix B.

"For next week" reminders and study prompts:

• Integrate understanding of how energy failure links to membrane damage and cell death.

• Practice distinguishing necrosis vs apoptosis through morphology and regulatory pathways.

• Connect ischemia and reperfusion concepts to clinical scenarios (e.g., myocardial infarction, stroke).