Cell Injury and Death: Scientific Basis of Medicine

Cell Injury and Death

• Etiology: underlying causes and modifying factors responsible for the initiation and progression of disease (combination of environmental triggers and genetics)
• Pathogenesis: mechanisms of development and progression of disease, accounting for all changes that characterize a specific disease
• Cell Injury: variety of changes of stress that a cell suffers due to external and internal environmental changes (reversible or irreversible)
• Cell Death: event of a cell ceasing to carry out its functions (apoptosis, necrosis, autophagy)

Types of Cell Death

Necrosis

• Form of cell death in which cellular membranes fall apart, and cellular enzymes leak out and ultimately digest the cell
• Considered the inevitable end result of severe damage that is beyond repair
• Not thought to be regulated by specific signals or biological mechanisms
• Types of necrosis:
  • Coagulative
  • Liquefactive
  • Gangrenous
  • Caseous
  • Fat
  • Fibrinoid

Apoptosis

• Pathway of programmed cell death in which cells activate enzymes that degrade their own nuclear DNA, nuclear and cytoplasmic proteins
• Plasma membrane remains intact, but changes in a way that fragments (apoptotic bodies) break off and become readily digestible by phagocytes
• Phagocytes clear the dead cell and its fragments with little leakage of cellular contents, so no inflammatory reaction
• Causes of apoptosis:
  • Physiologic apoptosis (during normal development, in mature organisms)
  • Apoptosis in pathologic conditions (removes cells damaged beyond repair)

Autophagy

• Refers to lysosomal digestion of the cell's own components
• Survival mechanism during times of nutrient deprivation
• Allows starved cells to live by eating their own contents and recycling them for nutrients and energy

Mechanisms of Cell Injury and Death

• Cellular response to injurious stimuli depends on injury type, duration, and severity
• Consequences of injurious stimuli also depend on type, status, adaptability, and genetic makeup of injured cell### Cell Injury and Death
• Skeletal muscle can tolerate ischemia for 2-3 hours without reversible injury, but cardiac muscle can only tolerate 20-30 minutes.
• Genetic variations can contribute to differences in responses or pathways and lead to different outcomes.

Hypoxia and Ischemia

• Deficiency of oxygen leads to failure of many energy-dependent metabolic pathways, resulting in cell death by necrosis.
• Hypoxia and ischemia trigger compensatory mechanisms, including activation of VEGF, which stimulates uptake of glucose and glycolysis.
• Persistent or severe hypoxia/ischemia leads to failure of ATP generation, depletion of ATP in cells, and accumulation of reactive oxygen species.

Ischemia-Reperfusion Injury

• Restoration of blood flow to ischemic but viable tissue can result in cell injury, particularly after myocardial and cerebral ischemia.
• New damage may be initiated during reoxygenation by increased generation of ROS, which can cause additional tissue injury.

Oxidative Stress

• Refers to cellular abnormalities induced by ROS, which belong to a group of molecules known as free radicals.
• Free radicals readily react with inorganic and organic molecules, initiating reactions that can lead to cell injury.
• Oxidative stress can occur in various contexts, including chemical and radiation injury, hypoxia, cellular aging, and tissue injury caused by inflammatory cells.

Reactive Oxygen Species (ROS)

• ROS are generated normally in small amounts during redox reactions in mitochondrial respiration and energy production.
• ROS can also be produced by phagocytic leukocytes, mainly neutrophils and macrophages, as a weapon to destroy ingested microbes and other substances during host defense.
• Generation of ROS can be increased by absorption of radiant energy, enzymatic metabolism of exogenous chemicals, inflammation, and reperfusion of ischemic tissues.

Removal of Reactive Oxygen Species (ROS)

• Cells have mechanisms to remove free radicals and minimize injurious effects, including:
  • Enzymatic and non-enzymatic systems, such as superoxide dismutase, glutathione peroxidases, and catalase.
  • Endogenous or exogenous anti-oxidants, such as vitamins A, E, C, and beta-carotene.

Cell Injury

• Toxins, including environmental chemicals and substances produced by infectious pathogens, can induce cell injury that results primarily in necrotic cell death.
• DNA damage can trigger apoptotic death.
• Inflammation can elicit an inflammatory reaction, which can lead to cell injury.

Cellular Stress and Cellular Accumulation of Misfolded Proteins

• Accumulation of misfolded proteins in a cell can stress compensatory pathways in the ER and lead to apoptosis.
• Misfolded proteins can result from gene mutations, aging, infections, increased demand for secretory proteins, and changes in intracellular pH and redox state.
• Protein misfolding is thought to be the fundamental cellular abnormality in several neurodegenerative diseases, including Alzheimer's disease, Huntington disease, and Parkinson disease.

Intracellular Accumulations

• Cells may accumulate abnormal amounts of various substances, which may be harmless or cause varying degrees of injury.
• Examples of intracellular accumulations include:
  • Fatty change (steatosis)
  • Cholesterol and cholesteryl esters
  • Proteins
  • Glycogen
  • Pigments (e.g., melanin, hemosiderin)
  • Pathologic calcifications

Cell Injury and Death

• Cell Adaptation: a response to physiological stress or injury, which achieves a new steady state and preserves cell function
• Causes of Cell Injury: Hypoxia, Ischemia, Toxins, Infectious agents, Immunologic reactions, Physical agents, Genetic abnormalities, Nutritional imbalances, and Aging
• Reversible Cell Injury: Abnormal function and morphology of injured cells can return to normal if the damaging stimulus is removed
  • Two main morphological changes: Cellular Swelling and Fatty Change

Cell Death

• Necrosis: Accidental cell death, a spectrum of morphologic changes that follows cell death
  • Not regulated by specific signals or biological mechanisms
• Apoptosis: Programmed cell death, a pathway of cell death in which cells activate enzymes that degrade their own nuclear and cytoplasmic proteins
  • Triggered by genetic damage, growth factor deprivation, or accumulation of misfolded proteins
  • Phagocytes clear the dead cell and its fragments with little leakage of cellular contents
  • Does NOT trigger inflammatory reaction

Types of Necrosis

• Coagulative: Characteristic of infarcts (necrosis caused by ischemia) in all organs except the brain
• Liquefactive: Seen in focal bacterial/fungal infections
• Gangrenous: Not a distinctive pattern, commonly used in clinical practice
• Caseous: Found in tuberculous infection
• Fibrinoid: Occurs in immune reactions in which Ag-Ab complexes become deposited in the walls of blood vessels
• Fat: Focal areas of fat destruction

Autophagy

• Survival mechanism in times of nutrient deprivation
• Lysosomal digestion of the cell's own components
• Recycles contents for nutrients and energy
• Initiated by proteins in cytosol that sense nutrient deprivation
• Associated with atrophy of tissues

Ischemia-Reperfusion Injury

• Restoration of blood flow to ischemic but viable tissue can actually result in cell injury
• Clinically important – occurs after myocardial and cerebral ischemia
• Caused by the generation of reactive oxygen species (ROS) during reoxygenation

Oxidative Stress

• Cellular abnormalities induced by reactive oxygen species (ROS)
• ROS can initiate reactions that lead to chain of damage
• Caused by chemical and radiant injury, hypoxia, cellular aging, and tissue injury caused by inflammatory cells
• Accumulation of ROS determined by their rate of production and removal

Removal of ROS

• Cells have mechanisms to remove free radicals
• Enzymes: superoxide dismutase, glutathione peroxidases, and catalase
• Antioxidants: vitamins A, E, C, and beta-carotene

Protein Misfolding

• Causes disease by creating a deficiency of essential proteins or inducing apoptosis
• Misfolded proteins lose activity and are rapidly degraded, leading to loss of function and cellular injury
• Examples of diseases caused by protein misfolding include cystic fibrosis, Alzheimer's disease, Huntington disease, Parkinson disease, and possibly Type 2 diabetes

Intracellular Accumulations

• Cells may accumulate abnormal amounts of substances, which can be harmless or cause varying degrees of injury
• Accumulations can occur in the cytoplasm, organelles, or nucleus
• Causes of intracellular accumulations include inadequate removal and degradation of products, excessive production of endogenous substances, and deposition of abnormal exogenous materials

Examples of Intracellular Accumulations

Lipid Accumulations

• Fatty change (steatosis): accumulation of triglycerides within parenchymal cells, commonly in the liver
• Causes of fatty change include toxins, protein malnutrition, diabetes, obesity, anoxia, alcohol abuse, and diabetes associated with obesity
• Cholesterol and cholesteryl esters: associated with atherosclerosis

Protein Accumulations

• Less common than lipid accumulations
• Caused by excessive synthesis of proteins or presentation of excess proteins to cells (e.g., nephrotic syndrome)

Glycogen Accumulations

• Associated with abnormalities in glucose or glycogen metabolism
• Examples include glycogen storage diseases and diabetes, where glycogen accumulates in renal tubular epithelium, cardiac myocytes, and pancreas

Pigment Accumulations

• Melanin: brown-black pigment synthesized by melanocytes in the epidermis, acts as a screen against UV radiation
• Hemosiderin: golden yellow to brown pigment derived from hemoglobin, accumulates in tissues with local or systemic excess of iron

Pathologic Calcifications

• Common process in various disease states, resulting from abnormal deposition of calcium salts
• Associated with hypercalcemia, and occurs in disease states affecting parathyroid hormone, bone destruction, vitamin D, and renal failure

Protein Misfolding

• Causes disease by creating a deficiency of essential proteins or inducing apoptosis
• Misfolded proteins lose activity and are rapidly degraded, leading to loss of function and cellular injury
• Examples of diseases caused by protein misfolding include cystic fibrosis, Alzheimer's disease, Huntington disease, Parkinson disease, and possibly Type 2 diabetes

Intracellular Accumulations

• Cells may accumulate abnormal amounts of substances, which can be harmless or cause varying degrees of injury
• Accumulations can occur in the cytoplasm, organelles, or nucleus
• Causes of intracellular accumulations include inadequate removal and degradation of products, excessive production of endogenous substances, and deposition of abnormal exogenous materials

Examples of Intracellular Accumulations

Lipid Accumulations

• Fatty change (steatosis): accumulation of triglycerides within parenchymal cells, commonly in the liver
• Causes of fatty change include toxins, protein malnutrition, diabetes, obesity, anoxia, alcohol abuse, and diabetes associated with obesity
• Cholesterol and cholesteryl esters: associated with atherosclerosis

Protein Accumulations

• Less common than lipid accumulations
• Caused by excessive synthesis of proteins or presentation of excess proteins to cells (e.g., nephrotic syndrome)

Glycogen Accumulations

• Associated with abnormalities in glucose or glycogen metabolism
• Examples include glycogen storage diseases and diabetes, where glycogen accumulates in renal tubular epithelium, cardiac myocytes, and pancreas

Pigment Accumulations

• Melanin: brown-black pigment synthesized by melanocytes in the epidermis, acts as a screen against UV radiation
• Hemosiderin: golden yellow to brown pigment derived from hemoglobin, accumulates in tissues with local or systemic excess of iron

Pathologic Calcifications

• Common process in various disease states, resulting from abnormal deposition of calcium salts
• Associated with hypercalcemia, and occurs in disease states affecting parathyroid hormone, bone destruction, vitamin D, and renal failure