BMS 100 Pathology Concepts 1 – Types of Cell Injury Fall 2022 PDF

Pathology Concepts 1 – Types of Cell Injury BMS 100 Week 8 Overview Introduction to Pathology Reversible and Irreversible Cellular Injury Causes Morphologic Characteristics Necrosis Discrete Mechanisms Convergence of Mechanisms Morphologic Characteristics Apoptosis Intrinsic vs. Extrinsic Pathways I...

Pathology Concepts 1 – Types of Cell Injury BMS 100 Week 8 Overview Introduction to Pathology Reversible and Irreversible Cellular Injury Causes Morphologic Characteristics Necrosis Discrete Mechanisms Convergence of Mechanisms Morphologic Characteristics Apoptosis Intrinsic vs. Extrinsic Pathways Initiation vs. Execution Phases Mechanisms and Signaling Concepts Necroptosis Overview cont… Cellular adaptations to Stress Hypertrophy, Atrophy, Hyperplasia Patterns of Long-Term Extracellular Damage Calcification Cellular Inclusions (post-learning) Definition of Terms Reversible cell injury: ▪ A cell/tissue has been stressed, but overcomes this stress and resumes normal physiologic function No notable long-term morphologic or physiologic changes Irreversible cell injury ▪ A cell/tissue has become damaged and will eventually die due to the severity of the damage Adaptation – there is a change in cellular/tissue structure or function that is almost always due to long-term stresses ▪ Examples: hypertrophy, hyperplasia, atrophy, metaplasia ▪ These changes are usually somewhat reversible Types of Insults to Tissues or Cells Hypoxia and ischemia ▪ Definitions: Infection, inflammation, and immune-mediated disorders Toxins/chemical agents Trauma, compression, thermal injuries Deficiencies in nutrients or growth factors Mechanisms of Cell Injury In general: The cellular response to injury depends on: ▪ Type of injury Ischemic? ROS? Physical? Chemical? Inflammatory? Microbial? ▪ Duration of the injury ▪ Severity of the injury ▪ The adaptability and the metabolism/phenotype of the cell Big difference between cardiac cells and skeletal muscle cells re: vulnerability to ischemia Reversible Cell Injury If the insult/stress is resolved, then the cell resumes normal function and appearance Sometimes the pathophysiologic consequences of the insult is clearly visible under the microscope: ▪ Cellular swelling - why? ▪ Non-specific nuclear changes ▪ Ribosomal detachment, membrane abnormalities due to cytoskeletal disassembly, accumulation of lipids Lipid vacuoles enlarge, collections of damaged membranous components (myelin figures) loss of mRNA → a more eosinophilic cytoplasm Small “blebs” – bubble-like outpouchings in the membrane Sometimes changes are more difficult to observe: ▪ Damage to proteins (including misfolding), DNA, subtle changes in organelle function and size due to damaged membranes Reversible Injury – key features What you can’t see under the light microscope: ▪ Changes in calcium concentrations ▪ Unfolded proteins ▪ Damage to DNA or cytoskeletal elements ▪ Loss of membrane potentials or abnormal distribution of molecules across cell membranes ▪ ATP depletion Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-8, p. 41 Irreversible Cellular Injury These changes will be discussed in more depth as we explore necrosis and apoptosis Typical findings under the microscope: ▪ Serious loss of integrity – plasma membrane, lysosomal membranes, mitochondrial membranes, ER membranes ▪ Destruction of cytoskeletal elements ▪ DNA and nuclear “disruption” Karyolysis – chromatin fades Pyknosis – chromatin condenses, more basophilic, nucleus shrinks Karyorrhexis – nucleus fragments (late) Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-8, p. 41 Cell Death – two major categories Necrosis ▪ The agents that have injured the physiology/biochemistry of the cell → immediate loss of cellular viability ▪ If cellular signaling is involved in this process, it is disorganized and unregulated Programmed cell death ▪ Cell death is delayed and requires protein synthesis ▪ Cellular signaling is always involved and the cell proceeds through an orderly series of steps → death ▪ This can be due to long-term, irreparable cellular damage or loss of cell use ▪ Best examples – apoptosis and necroptosis Necrosis – mechanisms of injury: ▪ ▪ ▪ ▪ ▪ ▪ ▪ Depletion of ATP Mitochondrial damage Calcium accumulation Oxidative stress / free radicals Membrane damage Denatured proteins DNA damage Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-16, p. 45 ATP depletion and cell injury Reduction (5 – 10% of normal) in ATP levels results in: Na+/K+ pump dysfunction and swelling ▪ Eventually leads to membrane damage Anaerobic metabolism decreases pH (lactic acid, inorganic phosphate) Increased production of free radicals Failure of calcium pumps Reduction in protein synthesis, detachment of ribosomes, misfolding of proteins Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-17, p. 45 Calcium accumulation in the cytosol Extracellular calcium: 1 – 2 mmol Intracellular calcium – 0.0001 mmol (at rest) High overall levels of cytosolic calcium: ▪ Activate a variety of destructive enzymes ▪ Directly activate caspases ▪ Cause calcium release from mitochondria Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-19, p. 47 Calcium accumulation in the cytosol We already know calcium is a “special” ion ▪ Only ion that is a ubiquitous second messenger Interacts with a number of intracellular proteins (i.e. calmodulin) that can activate or inactivate intracellular processes ▪ Enzymes that are particularly relevant to necrosis: Proteases Phospholipases Endonucleases (DNA, chromatin fragmentation) Cytosolic calcium is highly regulated ▪ Loss of regulation → nonspecific overall activation of the enzymes specified above ▪ ATP deficiency disrupts appropriate calcium sequestration ▪ Cytosolic calcium accumulation opens the mitochondrial permeability transition pore (MPTP) Mitochondrial damage Mitochondrial membranes can be damaged by free radical attack if levels of cytosolic calcium increase too high in the cell, the MPTP can open ▪ Loss of mitochondrial membrane potential ▪ Releases H+ ▪ Further increase in cytoplasmic calcium Mitochondrial calcium “dumped” into cytosol ▪ Inability to generate ATP and ultimately necrosis ▪ This channel is poorly understood.. But important Increased cytosolic calcium → MPTP opens → leakage of H+ and calcium Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-18, p. 46 Membrane damage Phospholipids are both broken down and not synthesized during ischemic injury ▪ Cytoskeletal damage increases physical stresses on the membrane Lipid breakdown can result in: ▪ Leaky membranes ▪ Lipid breakdown products that can have a detergent effect on cellular membranes Detergent-like effects: unesterified free fatty acids acyl carnitine lysophospholipids Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-21, p. 49 Membrane damage and the cytoskeleton Cytoskeletal abnormalities ▪ Activation of proteases by increased cytosolic calcium may cause damage to elements of the cytoskeleton Lose the “anchoring” and stabilizing effect of the cytoskeleton on cell membranes ▪ cell swelling → detachment of the cell membrane from the cytoskeleton → membrane susceptible to stretching and rupture A “broken” cytoskeleton compounds this process Membrane damage and lysosomes Injury to lysosomal membranes results in: ▪ Direct enzymatic damage to cellular components ▪ activation of enzymes by lysosomal enzymes Enzymes include RNases, DNases, proteases, phosphatases, glucosidases and cathepsins Unregeulated enzymatic degradation of cell components → loss of DNA, RNA, glycogen, cytoskeletal proteins → death by necrosis ▪ ?? What needs to happen to the intracellular mileiu before lysosomal enzymes can be activated? Free radicals and cellular damage Generated by: ▪ Normal metabolic processes Oxidation reactions during cellular respiration ▪ In ischemic/low oxygen conditions, free radical production increases ▪ Metabolism of drugs or toxins Acetaminophen, alcohol are good examples ▪ Radiation – UV light, x-ray ▪ Fenton reaction – metals receive or donate electrons (copper, iron) ▪ Leukocytes – to kill pathogens in inflammatory reactions Free radicals damage: ▪ Lipids – leading to membrane damage ▪ Proteins – especially at disulfide bonds ▪ DNA – can cross-link and break strands Free radical formation and effects Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-20, p. 48 Useful free radical knowledge Superoxide Hydrogen peroxide Hydroxyl Peroxynitrite O 2- H2O2 OH- ONOO- Formed: -Incomplete reduction of O2 during oxidative phosphorylation; By phagocyte oxidase in leukocytes Generated by SOD from O2- and by oxidases in peroxisomes Generated from H2O by hydrolysis, e.g., by radiation; from H2O2 by Fenton reaction; from O2- Generated by O2and NO synthase in many cell types (endothelial cells, leukocytes, neurons, others) Eliminated Conversion to H2O2 and O2 by SOD Conversion to H2O and O2 by catalase (peroxisomes), glutathione peroxidase (cytosol, mitochondria) Conversion to H2O by glutathione peroxidase Conversion to HNO2 Pathologic effects Production of degradative enzymes in leukocytes and other cells; may directly damage lipids, proteins, DNA; acts close to site of production Can be converted to OHand OCl-, which destroy microbes and cells; can act distant from site of production Most reactive Damages lipids, oxygen-derived proteins, DNA free radical; principal ROS responsible for damaging lipids, proteins, and DNA Free radical generation and elimination The Fenton reaction: ▪ H2O2 + Fe+2 →.OH + OH- + Fe+2 ▪ Because most of the intracellular free iron is in the ferric (Fe+3) state, it must be reduced to the ferrous (Fe+2) form to participate in the Fenton reaction ▪ This reduction can be enhanced by O2 sources of iron and O2- may cooperate in oxidative cell damage Iron accumulation in cells can be toxic Mechanisms to remove free radicals include: ▪ Antioxidants: i.e. Vitamin E, A, C ▪ Enzymes Catalase – breaks down H202 Superoxide dismutase – converts 02- to H202 Glutathione peroxidase – decomposes H202 Apoptosis Overview Tightly regulated intracellular program ▪ Requires synthesis and activation of signaling and effector proteins If you block protein synthesis, apoptosis is blocked ▪ Plasma membrane remains intact However, it is altered → better phagocytosis of cell remnants Dead cell remnants rapidly cleared → no inflammation ▪ Inflammation is prominent after necrotic damage to tissue ▪ Inflammation = Infiltration of immune cells (specifically neutrophils) to either: ▪ Kill pathogens ▪ Clean up dead or dying cells Accompanied by typical vascular changes – vasodilation and increased “leakiness” of capillaries Causes of apoptosis - physiologic Programmed destruction of cells during embryogenesis ▪ The embryo forms many structures that are no longer required in the fetus Hormone-dependent involution in adult ▪ Endometrial cell breakdown during the menstrual cycle ▪ Ovarian follicular atresia in menopause ▪ Regression of lactating breast after weaning ▪ Prostatic atrophy after castration Cell deletion in proliferating cell populations ▪ intestinal crypt epithelia in order to maintain a constant number Causes of apoptosis – apoptosis as an adaptive response to pathology Death of host cells that served their purpose ▪ Neutrophils in acute inflammatory response ▪ Lymphocytes at the end of an immune response Cells undergo apoptosis because deprived of necessary survival signals, e.g. growth factors Elimination of potentially harmful self-reactive lymphocytes ▪ Before or after they have completed their maturation Cell death induced by cytotoxic T cells ▪ Defense mechanism against viruses and tumors - serves to eliminate virus-infected and neoplastic cells Same mechanism responsible for cellular rejection of transplants Causes of apoptosis – apoptosis as an adaptive response to pathology Cell death produced by a variety of injurious stimuli ▪ Radiation and cytotoxic anticancer drugs damage DNA If repair mechanisms cannot cope with injury - cell kills itself by apoptosis Elimination better than risking mutations and traslocations → malignant transformations ▪ Injurious stimuli, heat and hypoxia Induce apoptosis if mild but still irreversible Necrotic cell death if large doses of insult Have ER stress and unfolded proteins triggering apoptosis Apoptosis as the “problem”, not the “solution” Pathological apoptosis occurs during: ▪ Accumulation of misfolded proteins – free radical damage or genetic disease can result in accumulation of misfolded proteins As these proteins accumulate in the ER, this is known as ER stress Proteins can misfold because of free radical damage, ATP depletion, of viral infection ▪ Pathologic atrophy/involution of secretory tissues in parenchymal organs after duct obstruction ▪ (pancreas, parotid, kidney all good examples) Microscopic pathology of apoptosis Cell shrinkage ▪ Cytoplasm dense, organelles tightly packed Chromatin condensation ▪ aggregates peripherally, close to the nuclear membrane, into dense masses ▪ Nucleus eventually fragments Formation of cytoplasmic blebs and apoptotic bodies ▪ Bleb = spherical membrane protrusion → a small body with a membrane containing organelle/organelle fragments = apoptotic body Phagocytosis of apoptotic cells or cell bodies by macrophages ▪ Degraded by lysosomes and adjacent healthy cells migrate or proliferate to replace the space left over Microscopic pathology of apoptosis Very difficult to visualize: ▪ not all cells in a tissue at risk undergo apoptosis at once ▪ no inflammation ▪ apoptotic bodies are quite small Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-8, p. 41 Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-22, p. 54 Biochemistry and signaling of apoptosis Two major concepts: ▪ There are two basic stages to apoptosis: Initiation – the sequence of events involving recognition of apoptotic signals or cellular damage and activation of intracellular “initiator” caspases Execution – “executioner” caspases are activated by the “initiator” caspases and cause the cellular changes of apoptosis ▪ There are two major types of apoptosis: Intrinsic (mitochondrial) pathway Extrinsic (death-receptor) pathway Pick out the steps and the types! Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-13, p. 44 Intrinsic (Mitochondrial) Pathway The intrinsic pathway is results from cellular damage or from lack of growth factors ▪ Results from increased permeability of the mitochondrial outer membrane with consequent release of death-inducing (pro-apoptotic) molecules into the cytoplasm ▪ Release of pro-apoptotic proteins is tightly controlled by the BCL2 family of proteins These proteins are composed of varying numbers of BH4 domains It’s a good name → 4 X “BH” proteins Intrinsic Pathway - initiation Bcl-2, Bcl-X, and Mcl-1 are anti-apoptotic – they are at high levels in the presence of growth factors and other signals that indicate a viable cell ▪ They keep the mitochondria from “spilling its guts” prevent mitochondrial pore formation and leakage of cytochrome c and other pro-apoptotic proteins into the cytosol ▪ BH4 proteins - they are located in the mitochondrial membrane, in the cytosol, and in the ER membrane Bax and Bak are pro-apoptotic - can form channels in the mitochondria and allow leakage of their contents ▪ They’re formed from 3 “BH” domains – called BH1-3 ▪ When activated → pores in the outer mitochondrial membrane Bim, Bad, and Bid, Puma, and Noxa are increase when the cell is “stressed” or should undergo apoptosis ▪ Only one “BH” domain – called BH3 proteins (have the 3rd domain) Intrinsic Pathway - initiation What increases Bim, Bid, and Bad, Puma, Noxa (BH3 only)? ▪ ER stress ▪ Lack of growth signals ▪ DNA damage What activates the mitochondrial leak channel (Bax/Bak)? ▪ Lack of BH4 molecules ▪ BH3-only molecules What happens if you open the mitochondrial leak channel? ▪ Cytochrome C leaks into the cytosol ▪ Cytochrome C directly activates a protein known as apoptosis-activating factor (APAF) → activation of caspases The anti-apoptotic and pro-apoptotic BH families counteract each other – the balance between the two determines whether a cell will pursue apoptosis Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-14, p. 45 Remember this? Alberts et. Al., Molecular Biology of the Cell, 6th ed. p. 860, fig 15-53 Apoptosis Activating Factor Key executioner caspases – 3, 6 Yes, it does look like a snowflake. A deadly snowflake. Alberts et. Al., Molecular Biology of the Cell, 6th ed. p. 1026, fig 18-7 Extrinsic Pathway - initiation Initiated by activation of plasma membrane death receptors on a variety of cells ▪ Part of the TNF family of receptors ▪ Fas receptor is best known/studied Intracellular death domains of these receptors then activate caspases 8 and 10 Caspases 8 and 10 then activate other caspases that are involved in the execution phase Extrinsic Pathway Fas is a death receptor expressed on many cell types The Fas ligand (FasL) is expressed on T cells that recognize self antigens and some cytotoxic T cells When FasL binds to Fas, they form a binding site called Fasassociated death domain (FADD), which activates Caspases 8 and 10 Caspases 8 and 10 then activate the executioner caspases Kumar et. al., Robbins and Cotran Pathologic Basis of Disease 9th ed. Fig 2-15, p. 46 Intrinsic and Extrinsic Pathways – Execution Phase Both intrinsic and extrinsic pathways converge in the execution phase Caspases 8, 9, and 10 can all activate executioner caspases, such as caspase 3 and 6 Executioner caspases can: ▪ Cause cleavage of DNA (via DNAse enzyme activation) ▪ Destroy the nuclear matrix ▪ Cause cytoskeletal changes ▪ Activated flippases The end–result of the execution phase DNA is cut into discrete lengths (about the size of nucleosomes) by endonucleases activated by caspases Phosphatidylserine “flips” to the outer envelope of the cell membrane (flippase) ▪ Normally present in the inner envelope of the cell membrane – during apoptosis it flips to the other side ▪ This allows macrophages to recognize and phagocytose apoptotic bodies Phagocytosis of apoptotic cells is so efficient that dead cells often disappear within minutes without leaving a trace ▪ Known as efferocytosis Apoptotic Pathways Growth factors increase synthesis of Bcl-2 and Bcl-x ▪ Lack of growth factor signal (i.e. hormone) triggers apoptosis via intrinsic (mitochondrial) pathway DNA damage leads to the synthesis of p53 ▪ P53 stimulates Bax/Bak (pro-apoptotic) Misfolded proteins that accumulate in the ER (ER stress) cause production of caspases and apoptosis ▪ Feature prominently in alpha-1 antitrypsin deficiency, a number of other disorders Protein misfolding and ER stress Chaperone proteins seem to be ATP-dependent and need to be constantly produced As poorly-folded proteins accumulate, cells usually increase their production of chaperone proteins and increase activity of proteasomes As soon as the misfolded protein “burden” becomes too great → caspase activation Necroptosis Morphologically resembles necrosis: ▪ loss of ATP, cell/organelle swelling, generation of free radicals, etc ▪ Does not involve caspase activation However, unlike necrosis it is triggered by genetically programmed signal transduction ▪ Sometimes called ‘programmed necrosis’ Mechanism of activation is similar to extrinsic pathway, i.e. binding of ligand to a receptor ▪ Example – TNF (tumour necrosis factor) binds to its receptor → RIP-kinase activation → MLKL phosphorylation → pokes holes in the plasma membrane Necroptosis – when does it happen? Seems to be linked to physiologic development (calcification) of the growth plate Cell death in steatohepatitis, pancreatitis, ischemia-reperfusion injury Maybe Parkinson’s disease A backup mechanism for cells infected by viruses that inhibit the activation of caspases i.e. cytomegalovirus (CMV) prevents the activation of caspase 8 by FADD…. but can’t prevent necroptotic pathways Long-term Adaptations to Cellular “Stress” Hypertrophy – increase in size of cells → increase in size of the organ ▪ Can be physiologic or pathologic ▪ Causes: increased functional demand, hormonal stimulation ▪ Example – the heart Mechanical stresses across the cardiomyocyte, growth factors, and constant neuroendocrine stimulation result in: ▪ Induction of different proteins/contractile elements ▪ Increased contractile proteins ▪ (hopefully) increased vascular development Cardiac Hypertrophy Robbins & Cotran (9th ed) – pg 58 Long-term Adaptations to Cellular “Stress” Hyperplasia – increase in the number of cells in an organ ▪ Physiologic or pathologic, again i.e. growth, regeneration, adaptation to mechanical stresses, hormones, growth factors ▪ Long-term, non-physiologic hyperplasia is a known risk factor for many different types of malignancies Can be due to increased division of tissue-resident stem cells or mature cells can be stimulated to enter the cell cycle and divide (more next week) Long-term Adaptations to Cellular “Stress” Atrophy – decrease in the number and/or size of cells ▪ Physiologic or pathologic, again Usually pathologic – disuse, loss of growth factors, compression, loss of nerve supply, reduction of blood supply ▪ Autophagy can be a mechanism for the development of atrophy As the name suggests – cells “eat” or digest unused components Three major types: ▪ Chaperone-mediated lysosomal digestion of old proteins + lysosomes that “surround” old cellular components ▪ Highly regulated “macro-autophagy” Autophagy Figure 2-17 - Autophagy Cellular stresses, such as nutrient deprivation, activate an autophagy pathway that proceeds through several phases: ▪ Initiation ▪ Nucleation ▪ Elongation of isolation membrane Leads to creation of a double-membranebound vacuole (autophagosome) ▪ Surrounds cellular component → fuses with a lysosome → digestion → recycling of metabolites Macroautophagy – the autophagosome The isolation membrane (phagophore) is thought to be derived from the ER ▪ Initiating and nucleating complex cause this phagophore to form and surround cellular components Inhibitory genes mTOR and MAPK prevent the activation of the initiating/nucleating complexes ▪ These are often activated by RTK growth factor receptors Phagophore elongates and surrounds the cell materials destined for digestion Autophagosome Autophagosome docks with a lysosome Autophagy is implicated in: ▪ ▪ ▪ ▪ Destruction and recycling of malfunctioning organelles Both cancer cell death and survival Destruction and rebuilding of muscle in response to activity Destruction of intracellular pathogens Pathologic Calcification Abnormal tissue deposition of calcium salts ▪ Can also include smaller amounts of magnesium and iron salts There are two forms: Calcification in dying tissue = dystrophic calcification ▪ No abnormalities in serum calcium or calcium metabolism Calcification in viable tissue = metastatic calcification ▪ Almost always due to hypercalcemia Dystrophic Calcification Localized in areas of necrosis Usually present in atherosclerotic plaques ▪ Also commonly seen in aging or damaged heart valves that have undergone long periods of stress due to hypertension Whatever the site of deposition, the calcium salts appear macroscopically as fine, white granules or clumps, often felt as gritty deposits Final common pathway is the formation of crystalline calcium phosphate Dystrophic Calcification Dystrophic calcification of aortic valve Dystrophic calcification Calcium is concentrated in membrane-bound vesicles in cells by a process that is initiated by membrane damage and has several steps: (1) Calcium ion binds to the phospholipids present in the vesicle membrane (2) Phosphatases associated with the membrane generate phosphate groups, which bind to the calcium (3) The cycle of calcium and phosphate binding is repeated, raising the local concentrations and producing a deposit near the membrane (4) A microcrystal is formed which can then propagate and lead to more calcium deposition Metastatic Calcification Occurs in normal tissues/cells due to diseases that cause increased levels of serum calcium (hypercalcemia) Tends to affect interstitial tissues of the gastric mucosa, kidneys, lungs, pulmonary veins ▪ Although quite different in location, many of these tissues secrete acid at one surface of the cell (or are acidic at that surface for other reasons) ▪ At the opposite surface of the cell, the fluid is more alkaline → calcium precipitates in a more alkaline environment Exacerbated by high calcium concentrations Usually causes limited clinical dysfunction, relatively rare Morphologic Patterns of Necrosis 1.Coagulative - architecture of dead cells preserved 2.Liquefactive - dead cells digested 3.Caseous - “cheese-like” necrosis, usually seen in TB 4.Fat Necrosis Morphologic Patterns of Necrosis Coagulative Necrosis ▪ Preservation of the basic outline of the coagulated cells Eosinophilic “cell ghosts” with no nuclei may persist for weeks ▪ Affected tissue has a firm (cooked) texture ▪ Injury and increasing intracellular acidosis denature structural proteins and enzymes → blocks proteolysis ▪ Necrotic cells eventually removed by fragmentation and phagocytosis of cellular debris = inflammation ▪ Typical of necrosis in most solid organs, with the exception of the brain ▪ Typical of ischemic damage – i.e. myocardial infarct Coagulative Necrosis Morphologic Patterns of Necrosis Liquefactive necrosis ▪ Characteristic of focal bacteria or fungal infections → accumulate inflammatory cells → completely digests dead cells → liquid viscous mass Microbes stimulate the accumulation of leukocytes and the liberation of enzymes from these cells ▪ Typical of necrosis within the brain… although usually not due to infectious processes In acute inflammation → creamy yellow material accumulates because of dead white blood cells = pus ▪ In some cases, coagulative necrosis may progress to a liquefactive picture over time Morphologic Patterns of Necrosis Caseous Necrosis ▪ Distinctive form of coagulative necrosis ▪ Found in foci of tuberculosis (TB) infection ▪ Cheesy white appearance of area of necrosis, found in the centre of the granuloma Under the microscope, the necrotic area is a structure-less collection of debris enclosed within a distinctive inflammatory border The entire structure is known as a granuloma ▪ Tissue architecture completely obliterated, replaced by the granuloma Figure 1-20 A tuberculous lung with a large area of caseous necrosis. The caseous debris is yellow-white and cheesy. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 17 March 2009 07:33 PM) © 2007 Elsevier Caseous Granuloma Morphologic Patterns of Necrosis Fat Necrosis ▪ Not a specific pattern of necrosis, but refers to a focal area of fat destruction ▪ Typically occurs as a result of release of activated pancreatic lipases into the pancreas and the peritoneal cavity i.e. acute pancreatitis ▪ Activated pancreatic enzymes escape from acinar cells and ducts to liquefy fat cell membranes and split the TG esters contained within fat cells ▪ Released FA combine with calcium to produce grossly visible chalky white areas Figure 1-21 Foci of fat necrosis with saponification in the mesentery. The areas of white chalky deposits represent calcium soap formation at sites of lipid breakdown. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 17 March 2009 07:33 PM) © 2007 Elsevier Morphologic Patterns of Necrosis Note: Most necrotic cells and debris disappear by a combination process of enzymatic digestion and fragmentation, followed by phagocytosis of debris by leukocytes If not destroyed and reabsorbed, tend to attract calcium salts and other minerals → dystrophic calcification