Necrosis-Apoptosis Lecture Notes PDF

Cell Growth/Proliferation Necrosis/Apoptosis Tissue Injury Kimberly Redding, M.D., M.P.H. HG #323 404-756-6672 [email protected] “The stability of th...

Cell Growth/Proliferation Necrosis/Apoptosis Tissue Injury Kimberly Redding, M.D., M.P.H. HG #323 404-756-6672 [email protected] “The stability of the structure is directly related to the security of the foundation” ― Blake Higginbotham  Lecture Outline Cell Growth/Proliferation Cell Injury/Death Reversible injury Irreversible injury Mechanisms of cell injury Mechanisms and morphologic features of cell death – Necrosis – Apoptosis  Define and use in proper context – Pyknosis – Karyorrhexis – Karyolysis – Ischemia – Infarct – Apoptosis – Necrosis Describe the morphologic and biochemical features of apoptosis – List examples of apoptosis under physiologic and pathologic Lecture conditions Describe the morphologic and biochemical features of necrosis Objectives Compare necrosis and apoptosis in terms of – Critical features of the definition – Common situations in which they occur and mechanisms for development Compare the types of necrosis (coagulation, caseous, fat, liquefaction and gangrenous) in terms of: – Gross and microscopic features – Common sites or tissues involved – Common causes or causative mechanisms – Examples  Cell Cycle Phases of the cell cycle: M phase- mitosis S phase- DNA replication G1/G2 During particular points in G1 and G2 the cell decides whether to move on to the next phase Cell cycle regulatory/control system Regulate DNA replication, mitosis, cytokinesis  Cell Growth/Proliferation Cellular requirements for growth and proliferation Nutrients Chemical signals from other cells Signal molecules are either Soluble proteins Proteins bound to the surface of other cells Proteins bound to the ECM Signal molecules can either stimulate or inhibit cellular function  Cell Signaling Hormones produced in endocrine glands are secreted into the bloodstream and are distributed widely throughout the body.  Cell Signaling Paracrine signals are released by cells into the extracellular fluid in their neighborhood and act locally.  Cell Signaling Neuronal signals are transmitted electrically along a nerve cell axon. When this electrical signal reaches the nerve terminal, it causes the release of neurotransmitters onto adjacent target cells.  Cell Signaling In contact-dependent signaling, a cell-surface-bound signal molecule binds to a receptor protein on an adjacent cell.  Cell Growth/Proliferation Stimulatory signal molecules classified into three major categories – Survival factors Suppress apoptosis – Mitogens Stimulate cell division – Growth factors Stimulate cell growth (increase in size and mass)  Cell Injury/Cell Death Cell death – Cell injury → Cell death Reversible vs. Irreversible cell injury Cell Injury/Cell Death  Hallmarks – Decreased oxidative phosphorylation (ATP formation) – ↓ Na+/ K+ ATPase pump (Na> outside cell; K > inside cell) Reversible – Membrane alterations Cell Injury – Changes in intracellular ion concentration – Cellular swelling – Alterations in intracellular organelles – Defects in protein synthesis – Cytoskeletal damage – DNA damage  Light microscopic features Cellular swelling Due to failure of energy dependent membrane ion pumps Fatty change Reversible Abnormal processing of fatty Cell Injury acids Ultrastructural features Plasma membrane blebbing, loss of microvilli, mitochondrial swelling, dilation of ER, detachment of polysomes, myelin figures, nuclear alterations Reversible Injury: Light Microscopic Changes Hydropic change (cellular swelling) Normal Liver Fatty change (steatosis) Reversible Injury: Ultrastructural Features Membrane blebbing Loss of microvilli Mitochondrial swelling Normal  Reversible vs. Irreversible Injury When does reversible injury become irreversible? – The “point of no return” still largely undefined – Two phenomena that characterize irreversibility Inability to reverse mitochondrial dysfunction Profound disturbances in membrane function  Irreversible Cell Injury Cell can no longer adapt- results in cell death Characterized by severe mitochondrial damage and severe loss of membrane integrity  Cellular Injury Normal Reversible Injury Irreversible Injury  Two main types of cell death – Necrosis “Unregulated” cell death Leakage of lysosomal enzymes into the cytoplasm Inflammatory reaction Irreversible Always a pathologic process Cell Injury – Apoptosis “Programmed” cell death Nuclear dissolution No inflammatory reaction Serves many normal cellular functions  Morphologic changes – Increased eosinophilia – Glassy appearance – Vacuolated appearance – Myelin figures – Dilated mitochondria with amorphous densities Necrosis – Nuclear changes Karyolysis-fading/loss of basophilia Pyknosis- nuclear shrinking; increased basophilia Karyorrhexis- nuclear fragmentation  Patterns of tissue necrosis Morphologic changes that occur in tissue when large numbers of cells die Several distinct patterns of tissue necrosis – Coagulative Necrosis – Liquefactive – Caseous – Fibrinoid Important to recognize; may provide clues as to the underlying cause  Morphologic Patterns of Necrosis Coagulative necrosis – Architecture of dead tissue is preserved (for a few days) – Injury denatures enzymes and proteins; proteolysis of dead cells is blocked – Tissue has firm texture – Cells are eosinophillic and anucleate – Example: ischemia due to vessel obstruction – Localized area of coagulative necrosis is an infarct  Coagulative Necrosis necrotic cells in the infarct preserved cellular outlines with loss of nuclei wedge-shaped kidney infarct inflammatory infiltrate  Gangrenous necrosis – Not a specific pattern of cell death – Refers to necrosis (usually coagulative) involving multiple tissue planes – Used in reference to necrosis of a limb that has lost its blood supply – Wet-gangrene- superimposed bacterial infection with more liquefactive necrosis  Patterns of Necrosis Liquefactive necrosis – Enzymatic digestion of dead cells – Tissue is transformed into a liquid viscous mass – Seen in bacterial infection (abscess formation); brain infarcts – Pus- creamy, yellow material formed from dead white blood cells Liquefactive Necrosis.  Morphologic Patterns of Necrosis Caseous necrosis – Most commonly seen with tuberculous infection – Caseous means “cheese-like”; area of necrosis appears white and friable – Characteristic microscopic appearance- collection of necrotic cells and debris surrounded by activated macrophages, mononuclear inflammatory cells→ granuloma Caseous Necrosis  Morphologic Patterns of Necrosis Fibrinoid necrosis – Usually seen in immune reactions involving blood vessels – Deposition of immune complexes in blood vessel – Immune complexes combine with fibrin; produce pink amorphous area of necrosis= fibrinoid Fibrinoid Necrosis  Morphologic Patterns of Necrosis Fat necrosis – Not a specific pattern of necrosis – Focal area of fat destruction; occurs in acute pancreatitis usually from release of lipases – Formation of calcium soaps (fat saponification); area appears white and chalky Fat Necrosis  Causes – Oxygen deprivation Hypoxia (deficiency of oxygen); ischemia (reduced blood flow) – Inadequate blood oxygenation- cardiorespiratory failure – Decreased oxygen carrying Cellular capacity of blood- anemia, CO poisoning Injury – Decreased blood volume- trauma – Physical agents Mechanical trauma Extremes of temperature (burns, deep cold) Radiation Electric shock  Cellular Injury Causes – Chemical agents and drugs Normal ions in high concentrations Poisons Pollutants, insecticides, herbicides Alcohol Therapeutic drugs – Infectious agents – Immunologic reactions Autoimmune reactions Reactions to microbes  Cellular Injury Causes – Genetic defects Defects in functional proteins – Enzyme defect – Accumulation of misfolded proteins – DNA damage – Nutritional imbalances Protein-calorie deficiencies Vitamin deficiencies Nutritional excess (cholesterol, caloric)  Cellular response to injury depends on the type of injury, the duration of injury, and the severity of the injury Consequences of injury depend the type, state, and adaptability of the Mechanisms injured cell Key cellular components most of Cell Injury frequently damaged: – Mitochondria – Cell membranes – Protein synthesis and packaging – DNA  Mechanisms of Cell Injury Key mechanisms of cellular injury – Decrease in ATP – Mitochondrial damage – Loss of calcium homeostasis – Oxygen derived free radicals (oxidative stress) – Defects in membrane permeability – Abnormal proteins Principal Mechanisms of Cell Injury  Key Features Tightly regulated pathway of cell death “Programmed cell death” Cells activate enzymes that degrade cells own DNA and nuclear and cytoplasmic proteins Apoptosis Plasma membrane remains intact but is altered such that it becomes target for phagocytic cells No leakage of cellular contents; does not elicit inflammatory reaction  Apoptosis Two distinct initiation phase apoptotic pathways – Intrinsic (Mitochondrial) pathway Most physiologic and pathologic situations – Extrinsic (Death Receptor Initiated ) pathway Eliminates self-reactive lymphocytes – Both pathways converge to a common activation pathway that initiates the execution phase of apoptosis Apoptosis Surface blebbing Formation of apoptotic bodies Membrane bound; composed of organelles +/- nuclear fragments Apoptotic bodies are ingested by phagocytes and degraded by phagocyte lysosomal enzymes  Apoptosis Morphologic features – Cell shrinkage Dense, deeply esosinophillic cytoplasm – Chromatin condensation- most characteristic feature Aggregates under nuclear membrane Nucleus may break into fragments Necrosis vs. Apoptosis Mechanisms of Cell Death