Cell Injury and Cell Death.Bendayan. Final. Jan 2024 Revised (1).pdf

Mechanisms of Cell Death Dr. Reina Bendayan, Leslie Dan Faculty of Phamacy January, 2024 Ref: Chapter 2, Robbins and Cotran Pathologic Basis of Disease, 10th edition, 2021 “Live as if you were to die tomorrow Learn as if you were to live forever”...

Mechanisms of Cell Death Dr. Reina Bendayan, Leslie Dan Faculty of Phamacy January, 2024 Ref: Chapter 2, Robbins and Cotran Pathologic Basis of Disease, 10th edition, 2021 “Live as if you were to die tomorrow Learn as if you were to live forever” M. Gandhi  OBJECTIVES Ø To discuss the general causes of disease Ø To know the types of cell injury Ø To discuss the mechanisms of cell injury and cell death Ø To review the causes and types of cell death Ø To contrast characteristics of apoptosis and necrosis PATHOLOGY: Pathos= Disease Pathology= Logos= study/knowledge Study of diseases Disease: 1) Loss of ease 2) Body’s reaction to injury may lead to disease 3) Body’s defense but with consequences  CATEGORIES OF PATHOLOGY Definitions Ø Etiology – causes and origins of a disease Ø Pathogenesis – mechanism of a disease Ø Morphology – gross and microscopic Ø Clinical manifestations – signs and symptoms Ø Prognosis – forecast as to the probable outcome of a disease Ø Management – treatment of the disease  Adaptations of Cellular Growth and Differentiation n Hypertrophy (increase in size of cells/organ) n Hyperplasia (increase in number of cells) n Atrophy (reduced size of cells/ organ) n Metaplasia (reversible change in which one differentiated cell type is replaced by another)  CAUSES OF DISEASE A. CONSTITUTIONAL FACTORS: Ø Hereditary – genetic abnormalities (haemophilia, down syndrome, etc) Ø Non-hereditary – age, gender, etc. (some diseases are more common in older people, (heart disease) and in women compared to men (breast cancer) B. ENVIRONMENTAL FACTORS: Ø Dietary deficiencies - deficiency of iron, vitamin, calcium, etc Ø Living external agents - infection by bacteria, virus, etc Ø Non-living external agents - physical agents (burn, chemical, radiation, etc) DISEASE STARTS FROM ‘CELL INJURY’ WHAT IS A CELL? ØThe word ‘CELL’ came from the Latin word, cellula meaning- a small room ØThe structural, functional and biological unit of all organisms ØAn autonomous self-replicating unit ØA semi-permeable membrane bound structure containing biomolecules, such as nucleic acids, proteins, etc CAUSES OF CELL INJURY n Oxygen deprivation n Physical agents n Chemical agents and drugs n Infectious agents n Immunologic reactions n Genetic alterations n Nutritional imbalances Causes of Cell Injury OXYGEN DEPRIVATION n Hypoxia – deficiency of oxygen n Ischemia – loss of blood supply (arterial flow or reduced venous drainage) Causes of Cell Injury PHYSICAL AGENTS n Mechanical trauma (an injury from a blow, crush, cut, or penetrating wound) n Extremes of temperature – burns, deep cold (liquid N2) n Radiation (X-rays, UV rays, etc.) n Electric shock Causes of Cell Injury CHEMICAL AGENTS AND DRUGS n Hypertonic concentration of salt – alteration of electrolyte homeostasis n Poisons – arsenic, cyanide, or mercuric salts n Insecticides and Herbicides n Air pollutant – carbon monoxide n Alcohol and Narcotic drugs Causes of Cell Injury INFECTIOUS AGENTS n Parasites n Fungi n Bacteria n Viruses Causes of Cell Injury IMMUNOLOGIC REACTIONS n Anaphylactic reaction to foreign protein and drug n Reactions to endogenous self- antigens – autoimmune diseases Causes of Cell Injury GENETIC Alterations n Congenital malformation – Down syndrome n Decreased life of red blood cell – Thalassemia, Sickle cell anemia n Inborn errors of metabolism Causes of Cell Injury NUTRITIONAL IMBALANCES n Protein-calorie deficiencies n Vitamin deficiencies n Excesses of lipids – Obesity, Atherosclerosis n Metabolic diseases – Diabetes  MECHANISMS OF CELL INJURY n Depletion of ATP n Influx of intracellular Calcium and loss of Calcium homeostasis n Mitochondrial damage (Causes: hypoxia, toxins, oxidative stress, etc) n Accumulation of Oxygen-derived free radical species (Oxidative stress, Causes: superoxide anion, hydrogen peroxide, etc) n Defects in membrane permeability (Causes: mitochondrial dysfunction, loss of membrane phospholipid, etc) Mechanisms of Cell Injury DEPLETION OF ATP Causes - Hypoxia, Ischemia Chemical Injury Membrane transport ATP Na+K+ATPase (Na-pump), Ca2+Mg2+ATPases (Ca-pump) Protein synthesis, Lipogenesis etc Mechanisms of Cell Injury Ischemia DEPLETION OF ATP Mitochondria Oxydative phosphorylation ATP Na pump Anaerobic glycolysis Other effects Ca++, H2O, Na+ influx Glycogen pH Ribosome detachment K+ efflux Clumping of Protein synthesis Nuclear ER swelling chromatin Cellular swelling Lipid deposition Blebs, etc TYPES OF CELL INJURY AND CELL DEATH Ø Cell Injury – Reversible – Irreversible Ø Cell Death – Necrosis – Apoptosis TYPES OF CELL INJURY/DEATH, AN OVERVIEW Normal cell Normal cell Normal cell Injury Chromatin Clumping cell injury Swelling of Reversible ER & MT Recovery Death Fragmentation of PM & nucleus Irreversible cell injury Swelling Necrosis of ER, lysozome Nuclear rupture, condensation PM blebs  NECROSIS Ø Necrosis is the premature death of cells caused by infection/interruption of blood supply. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death Ø Two essential concurrent processes that follow necrosis: Ø enzymatic digestion of cells Ø denaturation of proteins  APOPTOSIS OR PROGRAMMED CELL DEATH Ø The word came from a Greek word meaning falling/dropping off, like individual leaves from a tree. Ø Apoptosis is a naturally occurring, physiological form of cell death (i.e., cellular suicide) Ø It is induced and executed by a tightly regulated intracellular program CAUSES OF APOPTOSIS (PHYSIOLOGIC SITUATIONS) It is required for proper development - Example-1 Apoptosis during the metamorphosis of a tadpole into a frog Example-2 Sculpting the digits in the developing mouse paw by apoptosis CAUSES OF APOPTOSIS (PATHOLOGIC CONDITION) Destruction of cells that threaten an organisms’ integrity – For example: vcells infected by life threatening viruses vcells with DNA damage (i.e., exposure to UV radiation) vcells undergoing unregulated growth (i.e., prevention of oncogenesis) MORPHOLOGY OF APOPTOTIC CELL Cell shrinkage Chromosome condensation Formation of cytoplasmic blebs and apoptotic bodies Phagocytosis of apoptotic cells or cell bodies BIOCHEMICAL CHANGES IN APOPTOTIC CELLS ØProtein cleavage (i.e., hydrolysis of nuclear scafold and cytoskeletal proteins by activated caspases) ØDNA breakdown (i.e., activated Ca2+ and Mg2+ endonucleases breakdown DNA into oligonucleosomes in multiples of 180 to 200 bp) ØProtein cross-linking (i.e., activated transglutaminase converts cytoplasmic proteins into covalently linked shrunken shells that break into apoptotic bodies) ØPhagocytic recognition (i.e., phospatidylserine Øexpressed in the outer membrane of apoptotic cells is recognized by the macrophages for phagocytosis)  APOPTOSIS VS NECROSIS (MORPHOLOGICALLY) Apoptosis Necrosis Outset Shrinking of cytoplasm, Swelling of cytoplasm condensation of nucleus. and mitochondria Plasma Blebbing of PM without loss of Loss of membrane membrane integrity integrity (PM) Chromatin Aggregation of chromatin at the nuclear membrane Organelles Mitochondria become leaky due to Disintegration of pore formation organelles Vesicles Formation of apoptotic bodies No vesicle formation, complete lysis Terminal Fragmentation of cell into smaller Total cell lysis bodies APOPTOSIS VS NECROSIS (BIOCHEMICALLY) Apoptosis Necrosis Regulation Tightly regulated process Loss of regulation involving activation of enzymatic steps. Energy input ATP-dependent process Non energy-dependent process DNA Non-random mono & Random digestion of oligonucleosomal DNA (smear of DNA on fragmentation of DNA (ladder agarose gel) pattern on agarose gel) Timing Prelytic DNA fragmentation Postlytic DNA fragmentation (= late event in cell death) Biochemical Release of factors events (cytochrome c) into cytoplasm by mitochondria and activation of caspase cascade APOPTOSIS VS NECROSIS (PHYSIOLOGICAL EFFECT) Apoptosis Necrosis Extent Localized effect that Affects groups of contiguous destroys individual cells. cells. Induction Induced by physiological Evoked by non-physiological stimuli (lack of growth disturbances (viruses, factors, changes in hypothermia, hypoxia, hormonal environment) ischemia, poisons) Phagocytosis Phagocytosis by adjacent Phagocytosis by cells or macrophages macrophages Immune No inflammatory Significant inflammatory system response response.  REFERENCE: Robbins and Cotran Pathologic Basis of Disease, 10th edition, 2021