cell pathology 11

8/6/2019 Cell Pathology 11

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Pathology of the cell

Stephen J. Hess DDS


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Terminology

Cellular PathologyHistopathology(tissue)Organ (systemic)PathologyMolecular Pathology

(in the future)


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Structure andfunction of the

human cell

Nucleus

Cytoplasm

CellMembrane


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Nucleus

Nuclear envelope

Nucleolus

Nuclear pore


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Nucleus

Consists of nucleic acids and nuclearproteinsAll human cells except RBCs and plateletsneed a nucleusNucleic acids arranged in aggregates calledchromatin during resting states and intochromosomes during mitosisNucleolus specialized organelle composedprimarily of RNA


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Genetic material is identical for allcells of an individual; however, it is

expressed differently in varioustissues of the body:

Differentiated cells(perform specialized functions)

Undifferentiated cells (embryonicstem cells)


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Differences

Differentiated cells Specialized Abundant cytoplasm

Low N:C ratio Many organelles Examples: liver and

kidney cells

Undifferentiated cells Embryonic Scant cytoplasm

High N:C ratio Few organelles Examples: Many tumor

cells


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Cytoplasmic structures


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Cytoplasm

Consists of amorphous matrix calledhyaloplasm and fibrillar meshwork(framework) called cytoskeleton .Organelles in the cytoplasm: Mitochondria Ribosomes Endoplasmic reticulum Golgi bodies Lysosomes Specialized organelles


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Cytoplasmic Organelles

Mitochondria Generate energy---rich in oxidative enzymes More mitochondria in cells with complex

functions

Ribosomes Free---synthesize proteins and enzymes for use

within the cell RER ribosomes synthesize products for export


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Cytoplasmic Organelles

Endoplasmic reticulum Rough (RER) protein synthesis for export Smooth (SER) complex functions--catabolism

of drugs, hormones, nutrients; synthesis ofsteroid hormones. Most prominent in liver andgonadal cells

Golgi bodies Process proteins into secretory granules or

lysosomes


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Cytoplasmic OrganellesLysosomes Rich in lytic enzymes such as acid hydrolases Primary lysosomes originate from Golgi

bodies can give rise to secondary lysosomescalled autophagosomes and heterophagosomeswhen they fuse with cytoplasmic vesicles.Maximally active at low ph

Exocytosis extrusion of undigested material (residual

bodies) from the cell


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Cytoskeleton in the Hyaloplasm(ground substance of the cytoplasm)

3 types of filaments: Microfilaments (composed of actin and myosin) Microtubules (tubulin) defects in this can

cause ciliary motility problems Intermediate filaments

Used in immunohistochemistry to aid in tumor

identification---5 classes: Epithelial-keratins Mesenchymal-vimentin Muscle-desmin Glial GFAP (Glial fibrillary acid protein in astrocytes) Nerve-neurofilaments


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Cellular integration at single celllevel and beyond

Autocrine stimulation: secretions from cellattach to cell membrane surface receptorsand provide stimulation (self-stimulation)

Paracrine stimulation: adjacent cells act oneach otherEndocrine stimulation: hormones

transported by vascular system act ondistant cellsSee figure 1.5 in text


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Homeostasis=maintaining steady state with

environmentEssential minerals= sodium,

chloride, potassium, calcium,& iron


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Cellular injury

ReversibleIrreversible


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Cellular Changes to injuryAcute injury typically involves changes in cell shape(cellular swelling or so-called hydropic swelling--influxof NA+ and water)Chronic injury causes adaptation in the cell--the most

important are: atrophy hypertrophy hyperplasia

dysplasiaAll these changes are potentially reversible onelimination of the cause---if not the cell may bepermanently changed or transform into a neoplastic cell


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Reversible cell injuryTypically a mild or brief injury

First sign is usually cellular swelling ( hydropicchange or degeneration )---influx of Na+, Ca2, andwater into cell due to altered permeability of cellmembrane

Blebs form at the cells surface Loss of microvilli in endoplasmic reticulum Chromatin clumping


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Reversible cell injury

Less energy is generated due to switch toanaerobic glycolysis; ph becomes moreacidic due to lactic acid buildup; organelles

tend to disintegrate and curl up formingmyelin figuresIf oxygen is restored and nucleus isundamaged and source of injury removed,the cell will revert to its normal state


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Reversible cell injury

Functional changes associated withreversible cell injury: Reduced energy production Decreased protein synthesis Increased autophagy (sequestering of damaged

proteins and potentially toxic products formed

during cell injury)


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Irreversible cell injury

1. Nuclear changes due to damage: Pyknosis (condensation of chromatin or

shrinkage of nucleus) Karyorrhexis (fragmentation of nucleus into

nuclear dust) Karyolysis (dissolution and lysis of chromatin

and nuclear structure)2. Loss of cell integrity3. Rupture of cell membrane central factor

in pathogenesis of irreversible cell injury


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Slide 1.7


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Cytoplasmic enzymes releasedfrom dying/dead cells:

AST (aspartate aminotransferase)ALT (alanine aminotransferase)

LDH (lactic dehydrogenase)CK (creatine kinase)


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Causes of cellular injury (seetable 1-2)

Hypoxia / anoxiaToxins Direct toxicity (mercury, heavy metals) Indirect toxicity (carbon tetrachloride)

Microbes

Inflammation and immune reactionsGenetic and metabolic disordersPhysical


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Hypoxia / anoxia

CAUSES:1. O2 supply interrupted (suffocation)

2. Inadequate pulmonary transfer of O2 (pneumonias)3. Inadequate transport of O2 in blood (anemia)4. Inability of cell to use O2 (cyanide poisoning)

Some cells can survive hypoxia much longer

than others Brain-minutes; heart 1-2 hours; kidney-several hours;fibroblasts-24 hours ( connective tissue cells are themost resistant to anoxia)


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Re-oxygenation

Can completely repair a short-livedreversible cell injuryOversupply of O2 can lead to the formationof free oxygen radicals (hydrogen peroxideH2O2, hydroxyl radical OH, and superoxideO2-which cause additional tissue damagewhich is termed reperfusion injury


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Free radicals

Unstable, highly reactive atoms ormolecules with an unpaired electron in theirouter orbitHighly reactive, tend to self propagateCan cause cell damage by lipid peroxidation(affects cell membrane); inactivation ofenzymes, and by causing mutations through

blocking of DNA transcriptionNormally these are formed in smallquantities and neutralized by anti-oxidantssuch as catalase (scavenger enzyme)


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Free radicals may be initiated incells by:

Absorption of radiant energy (UV, radiation)Enzymatic metabolism of exogenouschemical or drugsSmall amounts of toxic intermediates suchas superoxide generated during normalmetabolic processes

Transition metals (copper, iron) to donate oraccept free electronsNitric oxide (which can act as a free radical;also acts as a chemical mediator


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Toxic injury

Directly toxic to cell: Heavy metals such as mercury that inactivatecellular enzymes

Indirectly toxic: carbon tetrachloride upon ingestion it is

changed to CCl3 which acts as a free radical

and damages cell membranes


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Other causes of cell injury

Microbial Bacterial toxins Viral---kill from within cell or induce immune

responseMediators of inflammation/ immunereactions---see chapters 2 and 3Genetic/ metabolic disturbancesPhysical temperature; radiation


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Cellular adaptations to injury


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Cellular adaptations to injury

AtrophyHypertrophy and hyperplasia

Metaplasia/dysplasiaIntracellular accumulationsAging


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AtrophyDecrease in size of a cell, tissue, organ, or entirebody and reduced metabolismAtrophic cells contain a brown pigment,lipofuschin (called the wear and tear pigment),

which imparts a brown color to an organPhysiologic atrophy -occurs with age andessentially involves the entire bodyPathologic atrophy due to inadequate nutrientsand stimulation Vascular insufficiency Muscle-wasting

Spinal cord injury


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Atrophy

Dr. Hess-age 24 Dr. Hess-age 63


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Hypertrophy

Increase in the size of tissues or organs due to anenlargement of individuals cells bodybuilding

Pure hypertrophy occurs only in the heart and

striated muscles cells contain moremyofilaments which allow them to contract moreefficiently Example: Heart under strain of hypertension increases

in size because individual cardiac muscle cells increasein size (i.e.,: left ventricular hypertrophy with HBP)

**Often occurs in conjunction with hyperplasia **


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Hypertrophy

Hypertrophy of the left ventricledue to hypertension


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Hyperplasia

Increase in the size of organs or tissues dueto increase in the numbers of cellsOccurs in response to: Hormonal stimulation (pregnancy)---more

endometrial cells (endomertrial hyperplasia) Chronic injury (denture induced papillary

hyperplasia) Idiopathic factors ( example polyps)


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Hyperplasia


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MetaplasiaChange of one mature celltype into another maturecell type usually causedby irritation

Example: Bronchioles change from columnarrespiratory type epitheliumto stratified squamousepithelium in response to

smoke irritation


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Dysplasia

Premalignant conditionCharacterized by disorderly arrangement of cells andnuclear atypia

Can be reversible or progress to neoplasia


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Intracellular accumulations

May result from an overload of metabolitesor exogenous material, phagocytosis, orfrom blocked excretion of the material


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Intracellular Accumulations

Examples: Anthracosis (coal particles) Hemosiderosis (blood derived brown pigment) Lipid (fat) accumulation

ObesitySteatosis (fatty deposits) secondary to alcohol abuse ordiabetes

Cholesterol (most damaging of intracellular category)

Lipofuschin (mixture of lipids and proteins with goldenbrown pigment called ceroid; also called the wear andtear pigment ---seen with organ atrophy)

Glycogen


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Anthracosis

H id i


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HemosiderinGolden yellow to brown hemoglobin-derived pigmentwhich accumulates in tissues where there is a local orsystemic excess of iron. Example: bruiseSystemic overload is called hemosiderosis --- Iron overload due to blood breakdown; usually young

patients May be due to frequent transfusions or due to intra-

alveolar bleeding in the lungsHereditary Hemochromatosis Genetic defect in iron uptake regulation; extensive

buildup of iron leading to joint pain, liver fibrosis, heart failure,

pancreatic problems (can result in diabetes) Treatment: phlebotomy


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Hemosiderin


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Lipofuschin

Brownish pigment; represents complexes oflipid and protein derived from free radical-catalyzed peroxidation of polyunsaturatedlipids of subcellular membranesAlso called the aging pigment ---functionof age or atrophy (marker of past free

radical injury)Found in the heart, brain, liver, and smoothmuscle

C ll l A i


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Cellular Aging


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Theories of Aging

Wear and tear hypothesis Organs with cells that do not regenerate decline

in function brain and heart

Some cells in tissues are replaced bymultipotential stem cells

Genetic hypothesis

Aging is predetermined processProbably a blend of theories


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Cellular aging

Results from: Accumulating cellular damage by free radicals

or defective DNA repair

Reduced capacity to divide (replicativesenescence)Progressive shortening of chromosomal ends(teleomeres)

Reduced ability to repair damaged DNA Other factors

Accumulation of metabolic damagePossible role of growth factors that promote aging


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Cellular Death

All humans cells have a finite life spanCellular death occurs in several differentforms: Necrosis (from external source) Apoptosis (programmed cell death

internal source--requires energy-involvesgene activation and enzyme action)

Autolysis (cessation of oxygenation andblood flow in a dead organism lead todissolution of the cells and tissues)

Post-mortem process


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The histological signs of

necrosis are the same as thoseof irreversible cell injury: cell

membrane rupture and nuclearchanges


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Forms of necrosis

CoagulativeLiquefactiveCaseousFat

Fibrinoid


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Necrosis

Coagulative Necrosis Most common Tissue looks like solid mass of boiled meat

Sudden cessation of cell function due toblockage/inactivation of most enzymes Outline and architecture of dead tissue is

preserved (very little autolysis). city of thedead. Necrotic tissue appears paler thannormal

Examples: MI, infarcts of solid organs such askidney


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Coagulative necrosis


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Coagulative necrosis

Loss of cross-striations and nuclei


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Liquefactive necrosis

Characterized by the dissolution of tissues,transforming it into paste-like or waterydebris

Due to the action of hydrolytic enzymesreleased from dead cells most commonlyin a brain infarctCan be due to lysosomal action frominflammatory cells such as seen in anabscessExamples: brain infarct, abscess, wet

gangrene


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Caseous necrosis

Soft, yellow-white, and cheesyStructure-less necrosisTypically seen with tuberculosis and deepfungal infectionsGranulomatous appearance with amorphouscentral section surrounded by epithelioid

histiocytes, lymphocytes, and some giantcells.

Caseous necrosis tuberculous lung


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W.B. Saunders Company items andderived items Copyright (c) 1999 by

W.B. Saunders CompanySlide 1.17

Granuloma


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Epithelioid macrophage

T lymphocyte

Multinucleated giant cells form from coalescing macrophages

Granuloma


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(Enzymatic) Fat necrosisForm of liquefactive necrosis of fat tissuecaused by lipolytic enzymes---involves fataround pancreas usually and develops inthe course of acute pancreatitis. As

triglycerides are digested, free fatty acidsare released and precipitate as calcium saltsGrossly fat tissue appears soft andgelatinous initially, but later has chalkygritty white patches composed of calciumsoaps/salts ( a type of dystrophiccalcification)---formation of these soaps is

called saponification


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Fibrinoid necrosis

Limited to small blood vessels, usuallysmall arteries, arterioles, glomeruli affectedby autoimmmune disease

Walls of vessels and also kidney glomeruliare impregnated with fibrin and appear redmicroscopically

Fibrinoid necrosis


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Fibrinoid necrosis


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Fibrinoid necrosis


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Outcomes of cellular necrosis

Repair by regeneration (liver/kidney)Repair by fibrous scarring (heart)Calcification (dystrophic)

Resorption of necrotic tissue with formation of apseudocyst (brain)Secondary complications

gangrene

Gangrene


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GangreneWet gangrene ---superimposed bacterial infectionof tissue which has undergone ischemiccoagulative necrosis, leading to inflammation andsecondary liquefaction necrosis Black, foul smelling, pus containing

Dry gangrene ---tissue dries out and becomes darkand mummifiedGangrene can occur with diabetics typically whenthere is significant peripheral vascular disease

usually on lower extremity or toes due toperipheral vascular diseaseGas gangrene occurs with some Clostridiuminfections


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Dry gangrene

Toe becomes mummified


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Wet gangrene


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Calcifications

Necrotic or inflamed tissue attracts calcium saltand frequently undergoes calcificationCalcification of necrotic tissue is calleddystrophic calcification (Note: this is in contrastto conditions of hypercalcemia (example:hyperparathyroidism) which gives rise tometastatic calcifications deposition of calcium in

normal tissues )


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APOPTOSIS

Active form of cell death-requires energyand requires activation of a certain set ofgenes (suicide genes) and enzymes

Called programmed cell deathTypically affects single cellsRemnants of cell are taken up by

macrophages or PMNs

Apoptosis Versus Necrosis


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Apoptosis Versus NecrosisApoptosis

Physiologic-single cell Cell shrinkage Intact organelles Requires energy-gene

expression and proteinsynthesis

Cell rounded up@fragmented

Occurs in minutes

NO inflammation Apoptotic bodies

phagocytosed

Necrosis

Passive does not requireenergy or proteinsynthesis-exogenousinjury

Involves many contiguous

cells Membrane ruptures Free radicals Cell swelling

Membrane blebs Organelles breakdown Ghost cell residual Takes hours

Intense inflammation


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End of Chapter 1

cell pathology 11

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