Cellular adaptation, injury and deathv2.pdf

Cellular adaptation, injury and death Brianna Hanson, PA-C Intro to pathophysiology / Mechanisms of disease Summer, 2023 Cell adaptation Atrophy Hypertrophy Hyperplasia Metaplasia Dysplasia Cellular stressors Cells are regularly exposed to stressors, such as: Exposure to toxins Infections Temperatur...

Cellular adaptation, injury and death Brianna Hanson, PA-C Intro to pathophysiology / Mechanisms of disease Summer, 2023 Cell adaptation Atrophy Hypertrophy Hyperplasia Metaplasia Dysplasia Cellular stressors Cells are regularly exposed to stressors, such as: Exposure to toxins Infections Temperature changes Mechanical damage Physiologic changes (i.e., blood supply, nutrition…) Cell adaptation Adaptation is a response to stress or other type of stimulus: Atrophy Hypertrophy Hyperplasia Metaplasia Dysplasia Cell adaptation – atrophy either not making or too protein enough much Decrease in size of cells, and subsequently, the organ. Leads to decreased protein synthesis and/or increased protein catabolism. Caused by Decreases in workload or use Decrease in blood supply, nutrition, nerve stimulation Physiologic atrophy Can be physiologic (normal) or pathologic. Cell adaptation – atrophy Pathologic atrophy Cell adaptation – hypertrophy Increase in size of cells and, subsequently, the organ. Increase in size is due to increase in cellular components (plasma membrane, ER, etc.) and not cellular fluid. Happens in several cell types, but predominantly muscle cells Caused by increase in work Can be physiologic or pathological Physiologic hypertrophy Cell adaptation – hypertrophy Pathologic atrophy Cell adaptation – hyperplasia Increase in number of cells secondary to increased cell division, otherwise cells appear normal. Typically occurs in tissues with stem cells Can be physiologic or pathological Physiologic hyperplasia Cell adaptation – hyperplasia Pathologic hyperplasia Cell adaptation – metaplasia Replacement of one mature cell by another less mature cell type. (Typically) caused by chronic irritation of cells Can be physiologic or pathologic Physiologic cervical metaplasia occurs at points during menstruation Pathologic cervical metaplasia can occur due to HPV infection Cell adaptation – metaplasia Pathologic metaplasia Cell adaptation – dysplasia Abnormal changes in size, shape, and organization of mature cells; immature cells with unexpected odd shape and/or configurations. Cellular pleomorphism – cells are uneven in size Nuclear pleomorphism – variation in size or shape of nucleus Hyperchromatism – darkly staining nuclei due to an abnormal abundance of nuclear chromatin Increased number of cells with mitotic figures – an unusually great amount of cells undergoing mitosis Not a true adaptive change (referred to as atypical hyperplasia) Generally considered precancerous Cell adaptation – dysplasia Dysplastic cervical tissue Cervix typically lined with glandular epithelium. Dysplastic cervical tissue can resemble immature squamous or epithelial cells of various shapes and sizes that multiply faster than normal cells. Not cancer…but concerning that it could progress to cancer. Cell adaptation Anaplasia – bonus! Poor cellular differentiation. Cells lose their mature morphological characteristics. Loss of cellular orientation relative to each other and to basement membrane. Seen in many cancers. Knowledge Check #1 Draw a picture representing the five (5) types of cellular adaptations. TL:DR; cell adaptation Atrophy - Decrease in size of cells Hypertrophy - Increase in size of cells Hyperplasia - Increase in number of cells Metaplasia - Replacement of one mature cell by another less mature cell type Dysplasia - Increase in number of cells Cell injury Reversible vs. irreversible injury Mechanisms of injury Systemic manifestations of cellular injuries Cell injury Cellular injury leads to injury of tissues and organs Up to a certain point, a cell can compensate for the injuries if the stimulus resolves (reversible) There is a point of no-return, where even if the stimulus abates, irreversible damage is done and cell will die (irreversible) Cell injury Responses to injurious stimuli is highly variable and depends on The type of stimuli The duration of stimuli The severity of injury Consequences of injury depend on Characteristics of the injured cell (type, adaptability, nutritional status, metabolic needs, function) Example: skeletal muscle versus cardiac muscle Cell injury – general mechanisms Cellular targets of injurious stimuli: Disruption of aerobic respiration and ATP production Genetic integrity Synthesis of proteins Cytoskeletal structure Integrity of cell membranes Calcium homeostasis Injurious disrupts ATP DNA direct momostatis Cell injury – causes Chemical agents – poisons, pollution, occupational exposures (asbestos), alcohol, tobacco, drugs Pathogens – direct injury via production of toxins or indirect injury via host inflammatory response poisons pollution chemical Cell injury – causes Heavy metals Lead can metals Heavy RINA DNA damage Mimics calcium (and other metals); it can behave as chemical messenger, disrupt normal calcium homeostasis Disrupts oxidative phosphorylation Interferes with enzymatic reactions (like the production of heme) Leads to production of reactive oxygen species O O O O Cell injury – causes Physical / mechanical factors – trauma, burns, frostbite, radiation, pressure changes Immunologic reactions – hypersensitivity reactions and autoimmune diseases Genetic factors – inborn errors of metabolism Nutritional imbalances – inadequate calorie/protein intake, vitamin deficiencies Cell injury – causes Lack of oxygen (hypoxia), caused by Not enough oxygenated air reaching the lungs (hypoventilation, high altitude, airway obstruction…) Dysfunction in lungs ability to oxygenation blood (interstitial lung disease) Not enough blood getting to the lungs in order to receive oxygen (shock, cardiac arrest) Dysfunctional hemoglobin or lack of sufficient hemoglobin (anemia, carbon monoxide poisoning) Not enough oxygenated blood reaching the tissues (ischemia secondary to hemorrhage, vascular blockage) Cells unable to utilize oxygen (methanol poisoning) Reperfusion of oxygen after prolonged hypoxia Free radicals Cell injury causes – free radicals Free radical is missingelectron steel electrons makes them unstable Atom, ion or molecule with an unpaired electron in its outer orbital Unstable and highly chemically reactive Can steal electrons from other atoms or molecules Can donate its free electron to other atoms or molecules Free radicals are of cell by products respiration Cell injury causes – free radicals Free radicals are generated physiologically and pathologically Electron transport chain in cellular respiration makes free radicals, more specifically, reactive oxygen species (ROS) ROS include Superoxide Hydrogen peroxide Hydroxyl radical ymissing Cell injury causes – free radicals Not all ROS are free radicals electron pair Not all free radicals are ROS Cell injury causes – free radicals Free radicals cause injury by initiating autocatalytic reactions Any molecules with which free radicals react are themselves converted into free radicals Targets of free radical injuries: Lipid peroxidation of membrane causing membrane instability Oxidative modification of proteins causing damage to the active sites of enzymes, disrupting the conformation of structural proteins Lesions in DNA caused by single and double stranded breaks Cell injury causes – free radicals Sources of free radicals / ROS Hypoxia leads to production of ROS, as does reperfusion of hypoxic tissues with oxygen Phagocytes produce superoxide (that can then be made into hydrogen peroxide) Ionizing radiation (UV or x-rays) cause water to lose an electron causing hydroxyl radical Cell injury causes – free radicals Sources of free radicals / ROS Heavy metals like iron and copper Ethanol metabolite (acetaldehyde) and byproducts (ROS) Cell cycle inhibitors Cell injury causes – free radicals Free radicals are neutralized by anti – oxidant enzymes and substances like: Superoxide dismutase – present in cytoplasm and produced by mitochondria Catalase – produced by peroxisomes Glutathione peroxidase – produced by mitochondria and present in cytoplasm Vitamin C in cytoplasm Vitamins E, A and β Carotene in the plasma membrane and cell membrane of organelles Storage molecules (ferritin and transferrin hold iron in storage) An imbalance between free radical generating & radical scavenging systems results in “oxidative stress” Toomuchfree radical Knowledge Check #2 Answer the following questions: What is a free radical? What is a reactive oxygen species? Why are free radicals so reactive and unstable? Why does this make them dangerous to cells? What are the main sources of free radicals and ROS? Cell injury Cellular changes associated with reversible cell damage Cellular swelling Membrane blebbing ER swelling Ribosomal detachment Mitochondrial swelling Nuclear chromatin clumping Cell injury – hypoxic injury Sodium-potassium pump stops working, and this interferes with the sodium-calcium exchanger (which is important in keeping calcium out of the cell) ATP gets broken down Creation of ROS Membrane damage Denaturation of proteins Decreased efficacy of some enzymes Cell injury – reperfusion injury Reoxygenation leads to Large influx of oxygen Oxygen reacts with product of the breakdown of ATP to make superoxide (and subsequent other ROS) Calcium overload occurs and leads to damage of integrity of mitochondria membrane, increasing its permeability ROS further attack membranes Cell injury Cellular changes associated with irreversible injury: Those changes seen in reversible injuries plus… Extensive damage to all cellular membranes Swelling or rupture of lysosomes Vacuolization (formation of vacuoles) of mitochondria, further reducing capacity to generate ATP Further influx of extracellular calcium and release of intracellular calcium  activation of intracellular enzymes that catabolize proteins, membranes, ATP and nucleic acids. Cell injury Mitochondrial vacuolization Systemic manifestations of cellular injury Manifestation Cause Fever Release of endogenous pyrogens as part of the acute inflammatory response Increased heart rate Increased metabolic/oxygen demand in response to fever Increased number of leukocytes Response to infectious etiologies Pain Release of bradykinins, physical pressure Cellular enzymes in ECF Lactate dehydrogenase (LDH) Creatine kinase (CK) Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Alkaline phosphatase (ALP) Amylase Systemic manifestations of cellular injury Clinically, enzymes can be used to tell us about cell injury Myocardial infarction – CK Pancreatitis – amylase Hepatitis – ALT, AST, LDH, ALP Knowledge Check #3 Jot down as much as you can recall about the mechanisms of cell injury associated with hypoxia. TL;DR: cell injury #1 Reversible injury: if stimuli is removed, cell can recover from injury (changes associated with this: swelling of the cell, ER and mitochondria; membrane blebbing; ribosomal detachment; nuclear clumping Irreversible: even if stimuli removed, the cell is committed to death. Exact point of no-return is unknown but inability to restore calcium homeostasis is a hallmark (changes associated with this: extensive membrane damage; swelling/rupture of lysosomes; vacuolization of mitochondria; destruction of proteins, ATP, and nucleic acids). Main cellular targets: disruption of respiration; genetic integrity; synthesis of proteins; cytoskeleton, membrane integrity; calcium homeostasis Free radical is an atom, ion, or molecule with an unpaired electron in outer orbital and this makes it extremely unstable and reactive such that it easily steals electrons from or donates electrons to other molecules. TL;DR: cell injury #2 ROS are created through natural metabolic processes; some ROS are free radicals. Our body has developed methods for handling ROS so that they don’t cause too much damage but when those defense mechanisms are overwhelmed, oxidative stress is the result Free radicals / ROS damage cell membranes, structural configurations of proteins, and cause lesions in DNA Hypoxia, reperfusion, radiation, heavy metals, ethanol are sources of free radicals / ROS. Hypoxia leads to decrease in ATP production, failure of membrane pumps and increased intracellular calcium, decreased protein synthesis, lower intracellular pH which interferes with enzymatic reactions, increase ROS production. Reintroduction of oxygen causes huge influx of oxygen and super production of ROS as well as large increase in intracellular calcium. Cell death Cellular necrosis vs. apoptosis Features and appearances of tissue necrosis Cell death Cell death follows two pathways Apoptosis – programmed cell death, can be normal or pathological Necrosis – always pathological Cell death - apoptosis Apoptosis Controlled destruction regulated by molecular signals which either inhibit or promote the process Cellular components become more compact DNA fragmentation Plasma membrane remains intact but undergoes blebbing Release of fragments that contain digested cell components (called apoptotic bodies)  cell shrinkage Apoptotic bodies are engulfed and destroyed by immune cells, resulting in no inflammatory response apopotic bodies Cell death - apoptosis Intrinsic pathway Intracellular stimuli DNA damage Ischemia Free radicals Disruption of the mitochondrial membrane  release of cytochrome c into the cytoplasm  where it forms with Apaf1 to form an apoptosome  activates caspase-9  activates “executer” caspases-3/6/7. C Cytochrome Cell death - apoptosis Extrinsic pathway Extracellular stimuli Usually a cytokine like TNF Exposure to toxins High temperature Radiation Signal binds to death receptor transmembrane protein  cleavage of procaspase-8 into caspase-8  procaspase-3 is cleaved by caspase-8 and becomes caspase-3 Cell death - necrosis Necrosis Swelling of cell DNA dissolution, condensation, and finally fragmentation Cellular components are digested Plasma membrane ruptures Expulsion of digestive enzymes and ROS in ECF activates inflammatory response Cell death – necrosis Liquefactive necrosis Typically caused by infection (as seen in abscesses) Seen in ischemic injury to the brain Pathogenesis: Enzymatic digestion of cellular debris in dead or dying tissues. Enzymatic digestion of surrounding tissues. Denaturation of cellular proteins. Macroscopic appearance of tissue: liquid-like, sometimes creamy-yellow secondary to presence of pus Cell death – necrosis Coagulative necrosis Typically caused by ischemia, but also trauma and toxins Predominant form of necrosis in every organ but the brain Pathogenesis: Normal architecture of necrotic tissue is maintained for several days after cell death because proteolytic enzymes are damaged during initial injury Macroscopic appearance: starts out pale and dry, but can become red due to inflammatory response Cell death – necrosis Gangrenous necrosis (subcategory of coagulative) Caused by prolonged ischemia, typically of limbs and digits. Pathogenesis: Similar to coagulative but reduced arterial perfusion causes arteriolar dilation which leads to swelling and damage to tissues Superimposed infection causes wet type Gas gangrene caused by saprophytic bacteria in muscle tissue Macroscopic appearance: Severely darkened skin (dry) with varying degree of putrefaction (wet). seeresford Cell death – necrosis Caseous necrosis Caused by fungal and mycobacterial infections Pathogenesis: Macrophages wall off infection Partially digest cells as a byproduct of immunologic response to infectious agent Macroscopic appearance: white, soft, cheesy-looking material Cell death – necrosis Fat necrosis Caused by disruption of oxygen to fat cells Seen in organs with high adipose tissue; pancreas, breast Pathogenesis: acute inflammation resulting in damaged cells releasing digestive enzymes which break down lipids to generate free fatty acids Macroscopic appearance: whitish deposits as a result of the formation of calcium soaps Cell death – necrosis Fibrinoid necrosis Caused by deposition of fibrin within blood vessels. Associated with vascular damage (autoimmunity, immune-complex deposition) Knowledge Check #4 Find a partner. Person #1 – explain to your partner what you can recall about the cell changes associated with necrosis. Partner #2 – explain to your partner what you can remember about the cell changes associated with apoptosis. TL;DR: cell death Apoptosis is controlled, purposeful destruction that can be a normal or pathological response. Cellular components become more compact, DNA fragments, the plasma membrane remains intact but blebs called apoptotic bodies are released and destroyed by immune cells, cell shrinks in size, no inflammation. Apoptosis pathways consist of intrinsic (which is mediated by mitochondrial release of cytochrome C) and extrinsic (which is mediated by receptor binding to death receptor on the cell membrane). Both processes culminate in activation of caspase-3. Necrosis is always pathological. The cell swells, DNA undergoes dissolution, condensation and eventually fragments, cell components are digested, plasma membrane ruptures and spills contents into the ECF where spilled digestive enzymes cue an inflammatory reaction. There are several types of necrosis: liquefactive, coagulative, gangrenous, fat, and fibrinoid.