CellularResponsesAndCellInjury2023_James Lyons.pptx

Cellular Responses & Cell Injury Dr. James Lyons Associate Dean of Medical Education Professor of Pathology & Family Medicine Objectives • Describe pathologic versus physiologic processes • Describe cellular responses including atrophy, hypertrophy, hyperplasia, hypoplasia, aplasia, metaplasia, a...

Cellular Responses & Cell Injury Dr. James Lyons Associate Dean of Medical Education Professor of Pathology & Family Medicine Objectives • Describe pathologic versus physiologic processes • Describe cellular responses including atrophy, hypertrophy, hyperplasia, hypoplasia, aplasia, metaplasia, and dysplasia • Describe causes and mechanisms of cell injury • Describe key features of ischemic/hypoxic cell injury, free radical induced cell injury, and chemical injury Textbook Tenth edition, Chapter 2 Pathologic vs. Physiologic Processes • Physiologic processes are generally due to normal body function!! • Pathologic processes are generally due to disease!! Response of Cells to Stress • Adaptation - Cell undergoes changes that enable it to cope with excess stress; thus it escapes injury • Injury - Occurs if the cell is unable to adapt to stress - two types • Reversible injury - If injurious agent is removed, cell reverts back to normal state, both morphologically (appearance) and functionally • Irreversible injury - Cell will not revert to normal, even when agent of injury is removed, occurs in persistent or severe injury, death of cell is inevitable Response of Cells to Injury • Cell Death • End stage of irreversible cellular injury • Typically occurs either by necrosis or apoptosis • The response of the cell to injury depends, in part, on • Length of time of exposure to the injurious agent- E.g. brief exposure may induce only reversible injury, while prolonged exposure may cause irreversible injury • Dose of injurious agent -> Small dose = minimal changes, Large dose = cell death • Type of cell and its ability to adapt (e.g. Neurons less able to adapt to hypoxia than cardiac muscle cells) Cellular Adaptation vs. Cell Death Myocardial hypertrophy usually due to hypertension or valve problems Myocardial Infarction Cellular Responses • Atrophy • Hypertrophy • Hyperplasia • Hypoplasia • Aplasia • Metaplasia • Dysplasia Atrophy • Decrease in the size of an organ due to a decrease in the size of cells and a decrease in the number of cells • Results from increased protein degradation and decreased protein synthesis in cells • Physiologic (due to normal body function) or pathologic (due to disease) Atrophy • Physiologic • Atrophy of embryologic structures such as notochord and thyroglossal duct during fetal development • Atrophy of uterus after childbirth Atrophy • Pathologic • Caused by: • Decreased workload • Loss of innervation • Diminished blood supply • Inadequate nutrition • Loss of endocrine stimulation • Aging process • Pressure • End stage of an inflammatory process Atrophy • The cells shrink to a smaller size at which survival is possible • Atrophic cells have diminished function but are still viable Pathologic Atrophy The testis at the right has undergone atrophy and is much smaller than the normal testis at the left. Pathologic Atrophy Atrophy of right leg in patient after polio Hypertrophy • Increase in cell size resulting in an increase in organ size • Due to increased cellular protein production • DOES NOT imply an increase in the number of cells • Can be physiologic or pathologic • Often occurs in nondividing cells • In general their only response to stress is to enlarge • Example is cardiac hypertrophy due to chronic high blood pressure Chronic Hypertrophy • Persistent rather than transient • If the stress persists, organ failure may occur • Heart failure due to longstanding hypertension with associated hypertrophy Physiologic Hypertrophy Pathologic Hypertrophy Hearts, hypertrophied, normal (middle), and dilated - Gross, cross section Physiologic Hypertrophy Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (removed for postpartum bleeding) (left). B, Small spindle-shaped uterine smooth muscle cells from a normal uterus (left) compared with large plump cells in gravid uterus (right). Hyperplasia • Increase in the number of cells in an organ or tissue typically resulting in an increased size of the organ or tissue • Results from production of new cells that is typically driven by hormones and/or growth factors • May occur together with hypertrophy • Can be physiologic or pathologic • Occurs in cellular populations which are capable of mitosis • Physiologic hyperplasia is often divided into hormonal hyperplasia and compensatory hyperplasia • Pathologic hyperplasia is often due to excesses of hormones or growth factors Physiologic Hormonal Hyperplasia • Increases the functional capacity of a tissue when needed under hormonal influence • Example is breast hyperplasia during puberty and pregnancy Physiologic Compensatory Hyperplasia • Increases in tissue mass after damage or partial resection • Classic example is regeneration of the liver after a portion is removed Pathologic Hyperplasia • Most forms due to excessive hormonal stimulation or growth factors • Examples • Non-gestational endometrial hyperplasia • increased or unopposed estrogens • Benign prostatic hyperplasia • androgens • The hyperplasia typically regresses if the hormonal stimulation is eliminated • Cancers may arise from hyperplastic tissues Pathologic Hyperplasia The uterine lining above displays endometrial hyperplasia. the increase shown here is pathologic, because of continued abnormal hormonal stimulation. For comparison, uterus containing an IUD, but with normalappearing (NOT Hyperplastic) endometrium Pathologic Hyperplasia Thyroid gland with diffuse hyperplasia due to Graves disease. The gland is uniformly enlarged. This is an example of pathologic hyperplasia. Normal thyroid gland Hypoplasia • Incomplete development of an organ so that it fails to attain adult size • Examples: pulmonary hypoplasia as seen in newborns with oligohydramnios, streak ovary in Turner syndrome Streak Ovary Normal Ovary Pulmonary Hypoplasia Aplasia • Complete lack of development of an organ • Example: you can have thymic aplasia in DiGeorge syndrome Metaplasia • A reversible change in which one adult cell type is replaced by another adult cell type • The stimuli that induce the metaplastic change may also eventually lead to malignant transformation (cancer) in the metaplastic tissue Metaplasia • Examples • Squamous metaplasia in respiratory tract • Metaplastic transformation of esophageal mature squamous epithelium to mature columnar epithelium with goblet cells (Barrett’s esophagus) Metaplasia In Respiratory Tract Metaplasia of columnar to squamous epithelium in respiratory tract – can be due to chronic irritation/smoking Source: Robbins and Cotran Pathologic Basis of Disease 10th edition Metaplasia In Esophagus Metaplastic transformation of esophageal stratified squamous epithelium (left) to mature columnar epithelium with goblet cells (Barrett's esophagus), often caused by chronic heartburn (acid reflux) Dysplasia • Literally means “disordered growth” • This generally consists of an abnormal increase in immature cells, with a corresponding decrease in the number and location of mature cells • Results in a loss of uniformity of the individual cells as well as a loss in their architectural organization • Dysplastic cells often display hyperchromatic nuclei, high nuclear-to-cytoplasmic ratio, pleomorphism, and increased mitoses • Dysplasia may be reversible or may precede the development of cancer Oral Cavity Normal Dysplasia al Cervix Mild dysplasia Moderate dysplasia Severe dyspl Spectrum of cervical dysplasia Spectrum of cervical dysplasia: normal squamous epithelium for comparison; mild dysplasia with atypia and hyperchromasia limited to the lower third of the epithelium; moderate dysplasia with atypia and hyperchromasia limited to the lower two-thirds of the epithelium; severe dysplasia with atypia and hyperchromasia extending above the lower twothirds of the epithelium Causes of cell injury • Hypoxia - decreased oxygen delivery to tissue • Decreased blood flow or decreased oxygen content of the blood • Physical agents • Examples include trauma, excessive heat or cold, radiation, electric shock • Chemical Agents • Examples include poisons, insecticides, alcohol, and oxygen in high concentrations Causes of cell injury (continued) • Drugs • Infectious agents • viruses, bacteria, fungi, parasites • Immunologic reactions • anaphylaxis, autoimmune disease • Genetic derangements • chromosomal abnormalities • enzyme defects • Nutritional imbalances Reversible vs. Irreversible Injury • Reversible Injury • Typically early or mild changes that will revert back to normal if the underlying cause of the injury is stopped or removed • Irreversible • More severe changes that will result in cell death (usually by necrosis or apoptosis) Morphologic Changes in Reversible Injury • Cellular swelling • Fatty change (variable) • seen mainly in cells involved in and dependent on fat metabolism, such as hepatocytes and myocardial cells • Plasma membrane blebbing and loss of microvilli • Swelling of organelles (mitochondria, endoplasmic reticulum) • Eosinophilia (due to decreased cytoplasmic RNA) General mechanisms of cell injury • Role of oxygen • Ischemia/hypoxia -> Lack of oxygen within cell causes decrease in ATP production with resultant biochemical changes • Other injurious agents -> are capable of converting intracellular oxygen into oxygen-derived free radicals, very toxic • Reperfusion injury - when blood flow (and therefore oxygen) is restored to ischemic cells, large numbers of oxygen-derived free radicals may be generated • ATP depletion • Due either to activation of ATPases or decreased ATP synthesis • Leads to loss of integrity of cell membrane General mechanisms of cell injury • Injurious agents can interfere with membrane-bound calcium ATPases ("calcium pumps") and also affect organelles • This allows calcium that is normally sequestered within organelles (mitochondria and endoplasmic reticulum), as well as calcium that is outside the cell, to enter the cytosol • This increases cytosolic calcium concentration • Results in activation of calcium dependent enzymes that can injure cell • Denatures proteins General mechanisms of cell injury • Defects in membrane permeability • Due to direct damage by toxin • Indirectly through activation of calcium-dependent enzymes • Can involve cell's plasma membrane, as well as organellar membranes (e.g. membranes of mitochondria) Cell Injury • Ischemic/Hypoxic Cell Injury • Due to lack of oxygen • Free Radical Induced Cell Injury • Due to oxygen-derived free radicals • Chemical (Toxic) Injury • Due to chemicals/drugs/toxins • May involve generation of free radicals Early Ischemic/Hypoxic Injury • Reversible injury with key biochemical features • Decrease, or loss, of ATP within cell • Decrease in aerobic ATP production has consequences • Leads to increase in anaerobic glycolysis --> will generate lactic acid --> lowers intracellular pH --> results in decreased activity / inactivation of intracellular enzymes • Causes failure of calcium and sodium pumps of cell's membranes--> results in influx of calcium, sodium and water into cytosol and organelles--> impairs function • These are all early biochemical events--> if blood flow (and thus oxygen supply) is restored to the cell at this point in time, the cell would recover and return to normal Stent Placement Irreversible Ischemic/Hypoxic Injury • Irreversible Injury -Critical biochemical events • Inability to reverse mitochondrial dysfunction even upon reoxygenation--> ability to generate ATP is permanently lost • Major disturbances in plasma membrane function due to membrane damage • Membrane damage is caused by progressive loss of phospholipids from membrane due to degradation by calciumactivated phospholipases • Decrease in phospholipid synthesis due to lack of ATP • Loss of intracellular amino acids - certain amino acids (principally glycine) protect membrane from hypoxic damage--> loss of these leads to membrane injury • All of this profound membrane damage results in cell death Heart with myocardial infarction Free Radicals • Free radicals • chemicals with an unpaired electron • extremely reactive and unstable • will react with variety of intracellular molecules • Oxygen-derived free radicals (AKA reactive oxygen species) • generated from the oxygen within a cell • important ones include superoxide (O2- ), hydrogen peroxide (H2O2), hydroxyl radical (HO•), and hydroxyl ion (OH-) • normally present within cells Oxygen-Derived Free Radicals • Oxygen-derived free radicals --> normally kept in low concentrations by various biochemical mechanisms • Spontaneous decay into non-reactive elements. • Termination of free radical reactions by several mechanisms: • Antioxidants, e.g. vitamins A, C and E; glutathione (can block initiation of free radical formation, or directly inactivate free radicals) • Storage and transport proteins, e.g. ceruloplasmin and transferrin (they bind iron and copper, elements involved in the formation of oxygen-derived radicals) • Intracellular enzymes like superoxide dismutase, catalase, and glutathione peroxidase (convert radicals into inert substances, e.g. H2O and O2) Free Radical Induced Injury • Certain injurious agents can increase production of these free radicals --> large numbers of free radicals within the cell will lead to serious injury • Mechanisms of cell injury by O2-derived free radicals • Lipid peroxidation of membranes --> direct disruption of membrane lipids, with generation of peroxides, which further attack membrane lipids (chain reaction) • Oxidative modification of proteins --> degrades critical cytoplasmic enzymes • DNA damage (nuclear and mitochondrial) Ischemic/Hypoxic and Toxic/Free Radical Injury References • 1. Kumar V, Abbas A, Aster J, Robbins and Cotran Pathologic Basis of Disease, 10th edition, Elsevier Saunders, 2021 • 2. Kumar V, Abbas A, Aster J, Robbins and Cotran Pathologic Basis of Disease, 9th edition, Elsevier Saunders, 2014 • 3. Kumar K, Abbas A, Fausto N., Mitchell R., Robbins Basic Pathology, 8th edition, Elsevier Saunders 2007 • 4. Webpath: https://webpath.med.utah.edu/ • 5. Neuromuscular website: http://neuromuscular.wustl.edu/motor.html • Special thanks to Paul Murphy, M.D. - Department of Pathology, University of Kentucky, Lexington, KY Thank You! Questions?