Lecture 1 Cell Injury (1) PDF

Cell Injury, Cell Death, and Adaptations  Introduction to Pathology Understanding changes to cells, tissues, and organs that are associated with disease and how the signs and symptoms develop for that disease  Why study Pathology Essential for un...

Cell Injury, Cell Death, and Adaptations  Introduction to Pathology Understanding changes to cells, tissues, and organs that are associated with disease and how the signs and symptoms develop for that disease  Why study Pathology Essential for understanding disease For diagnosis For following progression For developing treatment Must identify changes in cells, tissues, biochemical Gross Microscopic (Morphologic, molecular, biochemical)  Overview of cellular responses Cells interact with environment must change to maintain homeostasis Adaptation = achieve a new steady state and preserve viability and function Adaptive capacity exceeded or external stress inherently harmful = cell injury Cell damage is the basis of all disease  Classifications of Injurious Stimuli 1. Hypoxia and ischemia Oxygen deficiency and reduced blood flow Results in lack of oxygen and/or build up of waste and loss of nutrients 2. Toxins Air pollutants, insecticides, CO, smoke, ethanol, drugs etc. Glucose, oxygen, salt, water 3. Infectious agents Bacteria, viruses, parasites, fungi, etc 4. Immunologic Reactions Autoimmune, allergic reactions, excessive response to infectious agents 5. Genetic abnormalities Deficiency in functional proteins, accumulation in damaged macromolecules 6. Nutritional imbalances Protein deficiency, vitamin deficiency, excessive intakes 7. Physical agents Trauma, extreme temp, radiation, changes in atmospheric pressure 8. Aging Senescence  Cell Injury sequence of events Upon cell injury a specific sequence of events occur (causing type of stimulus does not matter) Reversible Cell Injury Cells and internal organelles swell plasma membrane blebs, and intercellular interactions reduced ER loses ribosomes Clumping of chromatin in nucleus Formation of myelin figures Color change – redder (eosinophilic)  Too much is too much If stimulus is not removed or becomes excessive, cells undergo cell death (Cells can not adapt) Three phenomena characterize the point of no return 1.Inability to restore mitochondria 2.Loss of plasma membrane structure and function (and intracellular membranes) 3.Loss of DNA and chromatin  Morphological changes visible Normal Early (Reversible) Injury Prolong (Irreversible) Injury  Cell Death Two types (depend on severity and nature of the insult) Necrosis - severe disturbances - rapid uncontrollable cell death (“accidental”) - ischemia, toxins, infections Apoptosis - less severe disturbances or normal cellular elimination - controlled by cellular pathways (“regulated”) - remove cells with intrinsic abnormalities (DNA or proteins unrepairable) Feature Necrosis Apoptosis Cell Size Enlarged Reduced Nucleus Pyknosis-> Karyorrhexis Framentation Plasma Mem Disrupted Intact but altered Cell Contents Enzyme Digestion Intact but reduced Inflammation Frequent No Physiologic or pathologic role Pathologic (Irreversible cell Physiologic (eliminated injury) unwanted or old cells)  Function-----Cell Death------Morphologic Changes - Cell Function is often lost before cell death has occurred - Morphological changes can occur well after death Example – Cardiomyocytes and ischemia -Stop contracting = 1 to 2 minutes -Cell death = 20 to 30 min -Visible morphologic changes = 2 to 3 hours (EM) -Visible morphologic changes = 6 to 12 hours (LM) -Serological changes = hours to days  Necrosis Cell death = cell membranes fall apart, digestive enzymes leak out, and the cell is digested -Inflammation occurs because of the materials released form the cell = the inflammation helps to clear the cellular debris and begin the healing process -Digestive enzymes are from the cells own lysosome or other cells responding to the inflammatory response -Mechanisms of necrosis vary - Failure to generate ATP - Damaged cell membranes - Damage to macromolecules -There are different types or patterns of necrosis - These patterns could give etiologic clues - Most have distinct apperances  Coagulative Necrosis - Tissue architecture is persevered for several days - Tissue becomes firm - All proteins are denatured during injury (including enzymes) - Anucleated dead cells persist and eventually destroyed by leukocytes - Cellular debris is then removed by phagocytes - Often seen in infarcts of solid organs except the brain  Liquefactive Necrosis -The result of bacterial and some fungal infections -Microbes stimulate rapid accumulation of inflammatory cells (leukocytes) which rapidly digest the tissue (liquefy) = Pus -Also seen in hypoxic death of brain tissue  Gangrenous Necrosis - Not a true pattern of necrosis but a combination of necrosises - Refers to limbs that have lost blood……. - Initially, it shows a coagulative pattern until a bacterial infection occurs - Changes to liquefactive necrosis  Caseous Necrosis - Site of tuberculous infection - Means “cheeselike” - Yellow-white visual appearance - Microscopic analysis shows fragmented of lysed cells. Might also observe the presence of inflammatory cells. (Giant Cells)  Fat Necrosis - Fat destruction - Pancreatic enzymes (lipases) are release into the pancreas or peritoneal cavity (acute pancreatitis) - Pancreatic enzymes lyse fat cells and breakdown the triglycerides - Fatty acids from triglycerides combine with calcium (white chalky areas) = essentially fat saponification  Fibrinoid Necrosis - Occurs often with immune reactions (antigen-antibody complexes deposit in walls of blood vessels - Severe hypertension also - Histology shows bright pink amorphous appearance called fibrinoid (immune complexes and plasma proteins in wall) - No gross morphological changes can be observed  Blood and Serum as Test Markers Necrosis leads to leakage of cellular content Some cells have specific proteins etc. Cardiac Cardiac creatine kinase and cardiac troponin Hepatic bile duct alkaline phosphatase Hepatocytes transaminases (ALT and AST)  Apoptosis Used in normal cellular degradation systems - Removes harmful or old cells - Normal physiological modifications Cell degrades its DNA, Nuclear and cytoplasmic proteins No inflammation because cellular content is not leaked Apoptotic bodies are formed which are degraded by phagocytes Intrinsic apoptotic pathway (Mitochondrial) Extrinsic apoptotic pathway Parts of each pathway can be shared  Other cell death pathways - Necroptosis Cellular signals like apoptosis but result in cell death like necrosis (can have inflammation) - Pyroptosis Apoptosis with a fever - Autophagy Done in response to nutrient deprivation Lysosomal degradation of its own cellular components  Mechanisms of cell injury and cell death - The response depends on type of injury, duration, and severity - Consequences depend on type of injury, duration, severity, and genetic make up  Hypoxia and ischemia One of the most frequent causes of cell injury and necrosis ATP production requires O2 ATP is needed for membrane transport, protein synthesis, lipogenesis, phospholipid turnover  Ischemia-reperfusion Restoring blood flow to ischemic tissues that were still viable can lead to increased cell injury - Increased reactive oxygen species (ROS) - Inflammation induction - Immune response  Oxidative Stress ROS production = free radicals Production from mitochondria Production from phagocytic leukocytes  Toxins Direct-acting toxins - Interact with important molecules or cellular organelles - Chemotherapeutics and bacterial toxins Latent toxins - Molecule converted to a reactive metabolite in the cell  ER Stress Result of accumulation of misfolded proteins  DNA Damage and Inflammation DNA Damage - Radiation, chemotherapeutics, ROS, and mutations - DNA damage is sensed and signals lead to p53 induced cell cycle arrest - DNA damage is repaired before S phase, if not = apoptosis Inflammation - Pathogens, cell death, autoimmune, allergies - Activation of inflammatory cells (neutrophils, macrophages, lymphocytes) which can damage host tissues  Cellular adaptations - Reversible changes to cell number, size, phenotype, metabolic state, of function - Physiologic adaptation = result of normal response to hormones or demands of mechanical stresses - Pathologic adaptation = result for changes to escape cell injury, but at the expense of normal function 1. Hypertrophy 2. Hyperplasia 3. Atrophy 4. Metaplasia  Hypertrophy - Increase in cell size = increase in organ size - No new cells, just bigger - Usually the result of increased functional demand or growth factor/hormonal stimulant - Physiologic example - Increase in uterus size during pregnancy - Increase in skeletal muscles from working out  Hypertrophy - Pathologic example - Increased heart because of hypertension or aortic valve disease  Hyperplasia - Increased cell number - Can only occur in tissue that has cells that can replicate - Cell number is increased because of growth factor stimulation - Physiologic hyperplasia - Hormonal hyperplasia = eg. Proliferation of breast tissue at puberty - Compensatory hyperplasia = eg. Liver regeneration - Pathologic hyperplasia - Formation of warts by viral infection (papillomaviruses)  Atrophy - Shrinkage in cell size by loss of cell substance - Cells will have diminished function but they are not dead - Caused by reduced workload, loss of innervation, decreased blood supply, decreased nutrients, loss of hormonal signaling, or aging - Usually the result of decreased protein synthesis and increased protein degradation (or perhaps autophagy)  Metaplasia - A change from one cell type to another - Change from a cell that is sensitive to a stress to a cell type that can handle that stress - Not usually the result of change in differentiated cells but rather the reprogramming of stem cells - Eg. Switch from columnar (ciliated) epithelium to squamous epithelium in smokers Often, the stimuli that induce metaplastic changes, if they persist, can predispose to malignant transformations  Intracellular Accumulations Cells can accumulate abnormal amounts of substances for a variety of reasons These substances can be stored in the cytoplasm, organelles, or specific granules Basis mechanism that lead to intracellular accumulations 1.Abnormal metabolism such as fatty accumulation in liver cells 2.Mutations that change protein folding such as prions, Alzheimer's, or sickle cell anemia 3.Enzyme deficiency such as Tay-sachs disease 4.Inability to digest phagocytized particles such as carbon pigment accumulation  Pathologic calcification - Common process in many diseases - Results from increase in calcium salt deposits as wells as iron or magnesium - Dystrophic calcification - Normal calcium metabolism but it deposits in injured/dead tissue - Eg. Advanced atherosclerosis - Metastatic calcification - Hypercalcemia in normal tissues - 1. increased secretions of parathyroid hormone - 2. destruction of bone - 3. vitamin D related disorders - 4. renal failure