Pathology Day 1 and 2a.pptx

Pathology: Cell Injury, Cell Death, and Adaptations Todd A. Nolan, Ph.D. 1 Pathology Understanding the causes of disease and the changes in cells, tissues, and organs that are associated with the development of disease. Etiology – origin of a di...

Pathology: Cell Injury, Cell Death, and Adaptations Todd A. Nolan, Ph.D. 1 Pathology Understanding the causes of disease and the changes in cells, tissues, and organs that are associated with the development of disease. Etiology – origin of a disease (the why?) Including underlying causes and modifying factors Pathogenesis – development of a disease (the how?) Includes from etiological trigger to cellular/molecular changes 2  Steps in the Developm ent of Disease 3 Cell Injury Hypoxia and ischemia – O2 deficiency or reduced blood supply. Among most common causes of cell injury Toxins – air pollutants, insecticides, CO, drugs (recreational and therapeutic) Infectious agents – viruses, bacteria, fungi, parasites 4 Cell Injury Immunologic reactions – autoimmune diseases Genetic abnormalities – sickle cell anemia, Huntington disease. Nutritional imbalances – vitamin deficiencies, obesity Physical agents – Trauma, radiation, sudden changes in pressure 5 Sequence of Events in Cell Injury and Cell Death 6 Reversible Cell Injury Defined as a derangement of function and morphology that cells can recover from if the damaging stimulus is removed 2 most consistent morphologic correlates Cellular swelling – also known as Hydropic change or vacuolar degeneration Fatty change 7 Necrosis 8 Apoptosis 9 Cell Death (Necrosis vs. Apoptosis) 10 Relationship between Function and Death 11 Morphology of Necrosis Cytoplasmic – increased eosinophilia Nuclear – 3 patterns Pyknosis – nuclear shrinkage and increased basophilia Karyorrhexis – nuclear fragmentation Karyolysis – digestion of DNA Fate of Necrotic cells – can persist, be digested, or become calcified (dystrophic calcification) 12 Types of Tissue Necrosis Coagulative Liquefactive Gangrenous Caseous Fat Fibrinoid 13 Coagulative Necrosis Affected tissues take on a firm texture. Dead cells are digested by the lysosomal enzymes of recruited leukocytes, and the cellular debris is removed by phagocytosis. Characteristic of infarcts (areas of necrosis caused by ischemia) in all solid organs except the brain. 14 Liquefactive Necrosis Found at sites of bacterial/fungal infections because microbes stimulate the accumulation of inflammatory cells and the enzymes of leukocytes digest (“liquefy”) the tissue. Produces “pus”. Localized collection of pus is an abscess. In the CNS, hypoxic cell death often causes liquefactive necrosis. In this form of necrosis, the dead cells are completely digested, transforming the tissue into a viscous liquid that is eventually removed by phagocytes. 15 Gangrenous Necrosis Not a distinctive pattern of cell death; the term is still commonly used in clinical practice. 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. In the presence of a bacterial infection, the morphologic appearance is often liquefactive because of destruction mediated by the contents of the bacteria and the attracted leukocytes (resulting in so-called wet gangrene). 16 Caseous Necrosis Caseous means “cheese-like,” referring to the friable yellow-white appearance of the area of necrosis. Unlike coagulative necrosis, the tissue architecture is obliterated, and cellular outlines cannot be discerned. Caseous necrosis is often surrounded by a collection of macrophages and other inflammatory cells; this appearance is characteristic of a nodular inflammatory lesion called a granuloma. 17 Fat Necrosis Refers to focal areas of fat destruction, which can be due to abdominal trauma or acute pancreatitis, in which enzymes leak out of damaged pancreatic acinar cells and ducts and digest peritoneal fat cells and their contents, including stored triglycerides. Released fatty acids combine with calcium to produce grossly identifiable chalky white lesions. 18 Fibrinoid Necrosis Special form of necrosis, visible by light microscopy. It may be seen in immune reactions in which complexes of antigens and antibodies are deposited in the walls of blood vessels, and in severe hypertension. Deposited immune complexes and plasma proteins that have leaked into the walls of injured vessels produce a bright pink, amorphous appearance on H&E preparations called fibrinoid (fibrin-like) by pathologists. Most often in certain forms of vasculitis and in transplanted organs undergoing rejection. 19 Causes of Apoptosis 20 Mechanisms of Apoptosis 21 Mechanisms of Apoptosis - Intrinsic Pathway Responsible for apoptosis in most physiologic and pathology situations Activation of Caspase- 9 causes activation of caspase cascade 22 Mechanisms of Apoptosis - Extrinsic Pathway Activation of a death receptor results in activation of Caspase-8 23 Mechanisms of Apoptosis 24 Autopha gy Lysosomal digestion of the cell’s own components Survival mechanism during periods of starvation May lead to apoptosis if starvation period is extensive 25 Mechanisms of Cell Injury and Cell Death Cellular response depends on the type of injury, duration, and severity Consequences of injury depend on cell type, cell metabolic rate, adaptability, and genetic makeup Skeletal muscle can survive complete ischemia for 2-3 hours. Cardiac muscle dies after 20-30 minutes Injury results from functional and biochemical abnormalities in one or more essential cellular components. 26 Mechanisms of Cell Injury and Cell Death 27 Mitochondrial Dysfunction and Damage Failure of oxidative phosphorylation, leading to decreased ATP generation and depletion of ATP in cells. 28 Oxidative Stress Cellular damage induced by the accumulation of reactive oxygen species (ROS), a form of free radical. ROS – produced in all cells in small amount during energy generation Produced in neutrophils to be used to destroy ingested microbed and other substances 29 Removal of Free Radicals Superoxide dismutases – converts superoxide into H2O2 Glutathione peroxidases – catalyzes the breakdown of H2O2 to H2O Catalase – found in peroxisomes. catalyzes the breakdown of H2O2 to H2O Antioxidants – block formation of free radicals or scavenge them once they have formed A, E, C, and beta-carotene 30 31 Cell Injury by ROS Peroxidation of membrane lipids Crosslinking of proteins Improper folding DNA damage Mutations and DNA breaks 32 Membrane Damage Mitochondrial Plasma Lysosomal membranes 33 Endoplasmic Reticulum Stress Accumulation of misfolded proteins in a cell can stress compensatory pathways in the ER and lead to cell death by apoptosis. 34 35 Hypoxia and Ischemia Persistent or severe hypoxia and ischemia lead to depletion of ATP. 36 Ischemia-Reperfusion Injury Paradoxically, restoration of blood flow to ischemic but viable tissues results in increased cell injury and necrosis. Increased ROS production may occur during reoxygenation, exacerbating damage. Some of the ROS may be generated by injured cells whose damaged mitochondria cannot completely reduce oxygen, and cellular antioxidant defense mechanisms may be compromised by ischemia, worsening the situation. 37 Cellular Adaptations to Stress Hypertrophy Hyperplasia Atrophy Metaplasia 38 Hypertrophy Hypertrophy refers to an enlargement of cells that results in increase in the size of the organ. Hypertrophy can be physiologic or pathologic and is caused either by increased functional demand or by growth factor or hormonal stimulation. 39 Physiologic Hypertrophy Physiologic hypertrophy of the uterus during pregnancy. 40 Pathologic Hypertrophy 41 Hyperplasia Hyperplasia is an increase in the number of cells in an organ that stems from increased proliferation, either of differentiated cells or, in some instances, progenitor cells. Physiologic Hormonal hyperplasia – proliferation of glandular epithelium of the female breast at puberty and during pregnancy Compensatory hyperplasia – residual tissue grows after removal or loss of part of an organ. Ex. – liver Pathologic Caused by hormonal imbalances. Ex. – benign prostatic hyperplasia 42  Atrophy Atrophy is reduced size of an organ or tissue caused by reduction in the size and number of cells 43 Metaplasia Change in which one adult cell type is replaced by another adult cell type. If the influences that induce metaplastic change persist, then there is a predisposition to malignant transformation of the epithelium. 44 Intracellular Deposits Steatosis – abnormal accumulation of triglycerides. Most commonly seen in the liver Caused by toxins, malnutrition, diabetes, obesity, anoxia Most common cause is alcohol abuse and diabetes associated with obesity Glycogen Associated with abnormalities of metabolism of glucose or glycogen Poorly controlled diabetes  glycogen deposits in renal tubular epithelium, cardiac myocytes, and β cells of the islets of Langerhans. 45 Intracellular Deposits Pigments Carbon – most common exogenous pigment Aggregates blacken the draining lymph nodes of the lungs (anthracosis) Lipofuscin – “wear-and-tear pigment” Heart, Liver, and Brain Complexes of lipid and protein caused by peroxidation of polyunsaturated lipids of intracellular membranes Hemosiderin – granular pigment which accumulates when there is a local or systemic excess of iron 46 Extracellular Deposits Dystrophic calcification – calcium deposits in injured or dead tissue Advanced atherosclerosis lesions, aging/damaged heart valves Metastatic calcification – associated with hypercalcemia due to: Increased parathyroid hormone Bone destruction due to disease (Paget disease, tumors Vitamin D intoxication Renal failure 47 Cellular Aging Result of decreased replicative capacity and functional activity of cells DNA damage Telomere dysfunction Epigenetic alterations Mitochondrial dysfunction Loss of stem cells Replicative senescence – occurs due to a progressive shortening of telomeres which ultimately results in cell cycle arrest. 48 Cellular Aging 49  Cellular Aging - Telomeres 50