Cell Injury and Death PDF

Cell Injury and Death Dr. Simon Kirby & Dr. Stephen Raab Normal thyroid follicles Hyperplastic thyroid  Causes of Cell Injury 1) Trauma 2) Physical agents (heat/cold) 3) Chemical agents 4) Drugs 5) Infectious agents (bacterial, viral, fungal, mycobacte...

Cell Injury and Death Dr. Simon Kirby & Dr. Stephen Raab Normal thyroid follicles Hyperplastic thyroid  Causes of Cell Injury 1) Trauma 2) Physical agents (heat/cold) 3) Chemical agents 4) Drugs 5) Infectious agents (bacterial, viral, fungal, mycobacterial, parasites) 6) Immunologic/autoimmune 7) Genetic 8) Nutrition 2  Causes of Cell Injury 9) Vascular 10) Neoplasia 11) Environmental (e.g., silica) 12) Metabolic (e.g., endocrine) 13) Iatrogenic 3 Cellular Responses to Stress and Stimuli Reversible only up to a point Functionally & structurally REVERSIBLE 4  Types of Cellular Adaptation: Hyperplasia and Hypertrophy  Cells respond to increased demand by hyperplasia or hypertrophy, or both Hyperplasia Cells respond with cellular proliferation Hypertrophy Cells respond with cellular enlargement 5  Hyperplasia and Hypertrophy Cells that are able to undergo mitosis respond with hyperplasia; cells (e.g. cardiac muscle cells) that cannot undergo mitosis respond with hypertrophy alone. 6  Two Types of Hyperplasia PHYSIOLOGIC HYPERPLASIA Hormonal: eg. uterus Compensatory: e.g. liver 7  Physiologic Hormonal Hyperplasia Pregnant uterus Normal uterus 8  Two Types of Hyperplasia PATHOLOGIC HYPERPLASIA  excessive hormonal stimulation  although these forms of hyperplasia are abnormal, the process remains controlled 9  Hypertrophy refers to an increase in the size of cells 10  Two Types of Hypertrophy PHYSIOLOGIC HYPERTROPHY AND PATHOLOGIC HYPERTROPHY  Both may be caused by increased functional demand or by specific hormonal stimulation.  Physiologic: Pregnant uterus (also undergoes hyperplasia)  Pathologic: Cardiac myocytes in response to pressure overload in a patient with essential hypertension 11  Left ventricular thickness > 1cm Left Ventricular Hypertrophy Secondary to Hypertension Cardiac muscle with scattered myocytes with enlarged nuclei 12  Types of Cellular Adaptation: Atrophy Shrinkage in the size of the cell by loss of cell substance Physiologic atrophy is common during normal development Pathologic atrophy depends on the underlying cause and can be local or generalized 13  Common Causes of Atrophy  Decreased workload (atrophy of disuse)  Loss of innervation (denervation atrophy)  Diminished blood supply  Inadequate nutrition  Loss of endocrine stimulation  Aging (senile atrophy)  Pressure 14  Senile atrophy Denervation atrophy Pressure atrophy Normal kidney 15  Types of Adaptation: Metaplasia Metaplasia is a reversible change in which one adult cell type is replaced by another adult cell type. 16  Examples of Metaplasia The most common epithelial metaplasia is columnar to squamous:  Bronchial epithelium in response to toxin exposure with cigarette smoking  Biliary tree epithelium in response to presence of stones Example of squamous to columnar: esophageal epithelium in response to repeated exposure to acidic gastric contents 17  Metaplasia E.g., Lung Metaplastic glandular Normal squamous epithelium epithelium: esophagus 18  Manifestations of Adaptation or Sub-lethal Cell Injury: Intracellular Accumulations (often linked with metaplasia) These substances (metabolites) may be:  Normal  Abnormal  Endogenous  Exogenous 19  Normal: lipid and protein Abnormal: mutated Alpha-1 antitrypsin Endogenous: Lipid storage disease Exogenous: pulmonary silicosis 20  Pathologic Calcification Nephrocalcinosis Dystrophic calcification: Metastatic calcification: Calcium deposits on previously Patient with hypercalcemia deposits injured tissue calcium in originally uninjured tissue 21  Cell Injury Cell injury result when no longer able to adapt or when cells are exposed to inherently damaging agents. 22  Reversible Cell Injury are reversible if the damaging stimulus is removed. The hallmarks of reversible injury are:  Reduced oxidative phosphorylation  Adenosine triphosphate (ATP) depletion  Cellular swelling caused by changes in ion concentrations and water influx. This level of detail not important ! 23  Two Major Microscopic Changes Seen With Reversible Cell Injury  Cellular swelling  Fatty change Important !! 24 Kidney With Reversible Injury Diffuse Cellular Swelling Pale, swollen cortex 25 Cellular Swelling Fatty Change 26  Causes of Cell Injury 1) Hypoxia due to ischemia, cardiorespiratory failure, severe blood loss, anemia, or CO poisoning 2) Physical agents 3) Chemical agents and drugs 4) Infectious agents 5) Immunologic reactions 6) Genetic derangements 7) Nutritional imbalances 27  Causes of Cell Injury 9) Vascular 10) Neoplasia 11) Environmental (e.g., silica) 12) Metabolic (e.g., endocrine) 13) Iatrogenic 28  Basic Cellular And Molecular Factors That Contribute To Irreversible Cell Injury And Death A common underlying process leading to cell death: Hypoxia  Two Types of Cell Death Necrosis Apoptosis  Severe plasma membrane  Cell DNA and/or proteins damage become damaged beyond  Plasma membrane dysfunction repair and eventual rupture  Genetic program for cell  Internal organelle membrane destruction is initiated and nuclear membrane  Nuclear dissolution dysfunction and rupture  Cell fragmentation  Lysosomal enzymes digest cell  Rapid removal of cellular  Extracellular injurious enzymes debris without an acute elicit an acute inflammatory inflammatory response response  Not necessarily associated  Always pathologic with cell injury (e.g., present during development ) Morphologic Changes With Necrosis Light Microscopy  Patterns of Tissue Necrosis When large numbers of cells undergo necrosis, the whole tissue or organ is described as necrotic Several morphologically distinct patterns of necrosis have been identified that may give clues about the underlying cause This is important !  Coagulative Necrosis Cardiac myocytes The basic architecture of the tissue is preserved for a few days. The injury denatures structural and enzymatic enzymes. Eosinophilic, anucleate cells may persist for days to weeks. Ischemia frequently leads to coagulative necrosis. A localized area of coagulative necrosis is an infarct.  Liquefactive Necrosis Digestion of the dead cells occurs, resulting in the replacement of tissue with a liquid, viscous mass. This type of necrosis is seen with bacterial and fungal infections, with transformation of the tissue into pus. This type of necrosis is also seen with ischemic damage to the brain, as shown above.  “Dry” Gangrenous Necrosis Term commonly applied in clinical practice for limbs or sections of bowel that have lost their blood supply and undergone coagulative necrosis. With infection and the formation of liquefactive necrosis, it is termed “wet gangrene”.  Caseous Necrosis Encountered most often with tuberculosis Infection. There is a friable white “cheese-like” area of necrosis containing foci of inflammation known as granulomas.  Fat Necrosis Focal areas of fat destruction. A common location for this to occur is in the inflamed pancreas (pancreatitis), where pancreatic enzymes leak from injured cells. Trauma to breast another example. Fat Necrosis With Dystrophic Calcification Patient with prior breast biopsy resulting in fat necrosis  Fibrinoid Necrosis Usually seen in immune reactions involving blood vessels