2024-2025 Northern Border University General Pathology 1st Semester PDF

Northern Border University Faculty of Applied Medical Sciences Department of Medical Laboratory Technology General Pathology 1st Semester 2024 – 2025  Cell Injury and Cell Death 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 2 ...

Northern Border University Faculty of Applied Medical Sciences Department of Medical Laboratory Technology General Pathology 1st Semester 2024 – 2025  Cell Injury and Cell Death 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 2  Overview of Cell Injury and Cell Death Reversible cell injury Irreversible injury and cell death 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 3  Stages in the evolution of cell injury and death 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 4 Schematic representation of a normal cell and the changes in reversible and irreversible cell injury 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 5  Causes of cell injury  The causes of cell injury range from the gross physical trauma of a motor vehicle accident to the single gene defect that results in a nonfunctional enzyme underlying a specific metabolic disease.  Most injurious stimuli can be grouped into the following categories: 1. Oxygen Deprivation 2. Physical Agents 3. Chemical Agents and Drugs 4. Infectious Agents 5. Immunologic Reactions 6. Genetic Derangements 7. Nutritional Imbalances 8. Aging 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 6  Mechanisms of Cell Injury 1. ATP depletion 2. Mitochondrial damage 3. Influx of calcium 4. Accumulation of reactive oxygen species 5. Increased permeability of cellular membranes 6. Accumulation of damaged DNA and misfolded proteins The most important targets of injurious stimuli are: 1. Aerobic respiration 2. Integrity of cell membranes 3. Protein synthesis 4. Cytoskeleton 5. Integrity of the genetic apparatus of the cell. Examples of cell injury and necrosis:  Ischemic and Hypoxic Injury  Ischemia-Reperfusion Injury  Chemical (Toxic) Injury 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 7  Cell death  There are two types of cell death: 1. Apoptosis 2. Necrosis Apoptosis:  Is a pathway of cell death in which cells activate enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins.  Fragments of the apoptotic cells then break off, giving the appearance that is responsible for the name (apoptosis, “falling off ”).  Causes of Apoptosis: 1. Apoptosis in Physiologic Situations:  Death by apoptosis is a normal phenomenon that serves to eliminate cells that are no longer needed and to maintain a constant number of cells of various types in tissues. 2. Apoptosis in Pathologic Conditions:  Apoptosis eliminates cells that are genetically altered or injured beyond repair and does so without eliciting a severe host reaction, thereby keeping the extent of tissue damage to a minimum. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 8  1. Apoptosis in Physiologic Situations  The programmed destruction of cells during embryogenesis.  Involution of hormone-dependent tissues upon hormone deprivation, such as endometrial cell breakdown during the menstrual cycle, and regression of the lactating breast after weaning.  Cell loss in proliferating cell populations, such as intestinal crypt epithelia, in order to maintain a constant number.  Elimination of cells that have served their useful purpose, such as neutrophils in an acute inflammatory response and lymphocytes at the end of an immune response.  Elimination of potentially harmful self-reactive lymphocytes, either before or after they have completed their maturation, in order to prevent reactions against the body’s own tissues.  Cell death induced by cytotoxic T lymphocytes, a defense mechanism against viruses and tumors that serves to kill virus-infected and neoplastic cells. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 9  2. Apoptosis in Pathologic Conditions  DNA damage.  Radiation, cytotoxic anticancer drugs, extremes of temperature, and even hypoxia can damage DNA, either directly or through production of free radicals.  Accumulation of misfolded proteins.  Improperly folded proteins may arise because of mutations in the genes encoding these proteins or because of extrinsic factors, such as damage caused by free radicals.  Cell injury in certain infections, particularly viral infections  Pathologic atrophy in parenchymal organs after duct obstruction, such as occurs in the pancreas, parotid gland, and kidney. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 10  Mechanisms of Apoptosis  Apoptosis results from the activation of enzymes called caspases  Two distinct pathways converge on caspase activation: 1. The Mitochondrial (Intrinsic) Pathway of Apoptosis  The choice between cell survival and death is determined by the permeability of mitochondria. 2. The Death Receptor (Extrinsic) Pathway of Apoptosis  Many cells express surface molecules, called death receptors, that trigger apoptosis.  Examples of Apoptosis: 1. Growth Factor Deprivation 2. DNA Damage 3. Accumulation of Misfolded Proteins: ER Stress 4. Apoptosis of Self-Reactive Lymphocytes 5. Cytotoxic T Lymphocyte - Mediated Apoptosis. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 11 The following morphologic features, characterize cells undergoing apoptosis: 1. Cell shrinkage. 2. Chromatin condensation. 3. Formation of cytoplasmic blebs and apoptotic bodies. 4. Phagocytosis of apoptotic cells or cell bodies, usually by macrophages. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 12  Necrosis  Refers to a spectrum of morphologic changes that follow cell death in living tissue, largely resulting from the progressive degradative action of enzymes on the lethally injured cell. in the setting of irreversible exogenous injury. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 13  Morphologic features, characterize cells undergoing Necrosis  Pyknosis: Characterized by nuclear shrinkage and increased basophilia.  Karyorrhexis: The pyknotic or partially pyknotic nucleus undergoes fragmentation.  Karyolysis: The basophilia of the chromatin may fade 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 14  Apoptosis and Necrosis Feature Necrosis Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis -> karyorrhexis -> Fragmentation into karyolysis nucleosome size fragments Plasma Membrane Disrupted Intact; altered structure, especially orientation of lipids Cellular Contents Enzymatic digestion; may Intact; may be released leak out of cell in apoptotic bodies Adjacent Inflammation Frequent No Physiologic pathologic Invariably pathologic Often physiologic, , role (culmination of irreversible means of or eliminating cell injury) unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 15  Necrosis  Under different conditions, necrosis in tissues may assume specific patterns: 1. Coagulative 2. Liquefactive 3. Caseous 4. Fat 5. Fibrinoid 6. Gangrenous 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 16  1. Coagulative necrosis  Coagulative necrosis is a form of necrosis in which the underlying tissue architecture is preserved for at least several days.  The affected tissues take on a firm texture. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 17  2. Liquefactive necrosis  Is seen in focal bacterial or, occasionally, fungal infections, because microbes stimulate the accumulation of inflammatory cells and the enzymes of leukocytes digest (“liquefy”) the tissue. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 18  3. Caseous necrosis  Is encountered most often in foci of tuberculous infection.  Caseous means “cheese- like,” referring to the friable yellow-white appearance of the area of necrosis.  On microscopic examination, the necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular pink appearance in the usual H&E-stained tissue. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 19 A tuberculous lung with a large area of caseous necrosis 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 20  4. Fat necrosis  Refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity.  This occurs in the calamitous abdominal emergency known as acute pancreatitis.  The released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification). 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 21  5. Fibrinoid necrosis  Is a special form of necrosis, visible by light microscopy, usually in immune reactions in which complexes of antigens and antibodies are deposited in the walls of arteries.  The deposited immune complexes, together with fibrin that has leaked out of vessels, produce a bright pink and amorphous appearance on H&E preparations called fibrinoid (fibrin-like). 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 22  6. Gangrenous necrosis  Is not a distinctive pattern of cell death, the term is still commonly used in clinical practice.  It usually refers to the condition of a limb, generally the lower leg, that has lost its blood supply and has undergone coagulative necrosis involving multiple tissue layers. When bacterial infection is superimposed, coagulative necrosis is modified by the liquefactive action of the bacteria and the attracted leukocytes (resulting in so-called wet gangrene). 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 23  Autophagy  Autophagy (“self-eating”) refers to lysosomal digestion of the cell’s own components. It is a survival mechanism in times of nutrient deprivation, such that the starved cell subsists by eating its own contents and recycling these contents to provide nutrients and energy. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 24  Intracellular accumulations 1. Depositions of lipids:  Fatty Change (Steatosis)  Cholesterol and Cholesteryl Esters 2. Proteins 3. Glycogen 4. Pigments: a. Carbon b. Lipofuscin c. Melanin d. Hemosiderin Pathologic calcification:  Dystrophic Calcification  Metastatic Calcification The major causes of hypercalcemia are:  (1) Increased secretion of parathyroid hormone  (2) Destruction of bone due to the effects of accelerated turnover  (3) Vitamin D–related disorders  (4) Renal failure. 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 25.. THANK YOU THANK YOU 8/17/2024 NBU, AMS, Dr.EIM & DMO, Histo 26