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181 Cards in this Set

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DESCRIPTION

8 ELEMENTS
Location

Distribution

Shape and Contour

Size / Extent

Colour

Consistency / Texture

Margins

Special Features
LOCATION
Indicate name of affected organ(s)
~~ ie lung or bronchioles

Use precise anatomical terms
~~ ie subcutis, cranial lung lobe, pars esophagea

Include any abnormal positions and or relationships to other organs
~~ ie attachment, rotation, displacement
DISTRIBUTION

3 TYPES
Often the single most useful observation

Single Lesion

Multiple Lesions

Diffuse Lesions
SINGLE LESIONS
Focal
~~ single lesion representing small portion of the entire organ

Locally Extensive
~~ a single LARGE lesion involving a considerable amount of the entire organ

Useful Terms
~~ Segmental - for segments of linear organs
~~ Unilateral, bilateral etc
MULTIPLE LESIONS

2 TYPES

2 KEY QUALIFIERS

5 USEFUL TERMS
Multifocal
~~ multiple lesions throughout an organ separated by UNAFFECTED tissue

Multifocal to Coalescing
~~ multiple lesions which merge together to create larger lesions

Random
~~ scattered without any predictable pattern
~~ ie lesions caused by blood born infectious agents

Zonal
~~ distributed throughout the organ according to predictable repetitive pattern
~~ ie bronchioles
~~ ie zones of hepatic lobule

Miliary
~~ numerous small focal lesions

Disseminated
~~ numerous small lesions evenly distributed throughout the whole organ or tissue

Bilateral
~~ lesions in PAIRED organs
~~ lung, kidneys, brain

Billaterlly Symetrical

Generalized Distribution
~~ indicates all structures of an organ (ie glomeruli) or all organs of a system (ie lymph nodes) are affected

Note can also quantify lesions
DIFFUSE LESIONS
Entire organ, tissue or specified subunit is involved
~~ easy to overlook because no contrast with normal

Widespread or Extensive
~~ large portion of specimen , organ, tissue involved

Transmural
~~ affecting the entire thickness of the wall of an organ or cavity
SHAPES

DIRTY DOZEN
Spherical

Rectangular

Rhomboidal

Pyramidal

Circular

Dilated

Wedge-shaped

Reniform
~~ yes as in renal

Striated

Irregular

Linear

Reticular
~~ net like
SURFACE CONTROUR

14 DECORATIVE STYLES
Bulging or Raised

Depressed

Flat or Level

Pitted

Smooth

Rough

Corrugated or Rugose

Crusted

Eroded
~~ NOT through basment membrane
~~ tf no leakage of ISF
~~ tf no exudate or fibrin

Ulcerated
~~ through basement membrane

Umbilicated

Nodular

Papillated
~~ nipple shaped projections

Villar
~~ numerous short hair like projections on membranes
SIZE
Metric Measure

% of organ affected
COLOUR

10 STANDARDS
Black

White

Grey

Green

Red

Brown

Mahogany

Tan

Yellow

Transparent

or combinations

Avoid ISH !!!

Avoid redundancy
~~ ie red in colour
CONSISTENCY AND TEXTURES

13
Must Touch
~~ tip for 4th yr don't describe texture if you can't touch it

Friable
~~ crumbles easily when palpated

Turgid
~~ hard due to internal fluid pressure

Firm
~~ used as a moderate form of hard

Rubbery
~~ slight increase in firmness

Spongy

Flaccid

Hard vs Soft

Strong vs Weak

Fluid, semi liquid, viscuous, gelatenous

pliable

pitting

elastic

Fibrous
~~ strong as in tendon
MARGINS

5
Well Demarcated
~~ lesion has distinc, clearly defined boundary

Poorly Demarcated
~~ boundary between lesion adn adjacent tissue is not sharp

Indistinc

Infiltrative
~~ invasive

Expansile
~~ out of tissue
~~ ie wart
SPECIAL FEATURES

7
Weight

Odor

pH

Protein content

Specific Gravity

Fluorescence

etc
MORPHOLOGICAL DIAGNOSIS

2 BIGGIES
Main Disease PROCESSES
~~ inflammation - decribe exudate
~~ necrosis
~~ hemorrhage
~~ neoplasia
~~ hypertrophy
~~ etc

Anatomical LOCATION
~~ precise

Also

Duration
~~ acute
~~ subacute
~~ chronic

Severity
~~ mild
~~ mutltifocal
~~ diffuse

Distribution
DIFFERENTIAL MORPHOLOGICAL DIAGNOSIS
Alternative diagnosis, since more than one interpretation may be possible based on gross characteristics of the lesion or set of lesions
ETIOLOGICAL DIAGNOSIS
interpretation based on the cause of the lesions
~~ location
~~ etiologcal name of disease
EITIOLOGY
Cause
~~ ie name of bacteria
DEFINITIVE DIAGNOSIS
Name of Disease
PATHOLOGY

DEFINITION
Study of structural and functional consequences of diseases
FOUR ASPECTS OF DISEASE
Eitiology

Pathogenesis

Morphologic Chandges

Clincal Significance
LESION
A pathologic chane in the tissues
~~ avoid using this term at all costs!!!
HYPERPLASIA
Increase in the NUMBER of cells in an organ or tissue

Usually results in an increased volume of the organ or tissue

Only occurs in tissues which have cells capable of MITOTIC division

Often occurs in conjuction with hypertrophy
~~ may be trigged by same external stimulus

Physiologic or Pathologic
HYPERTROPHY
Increase in the size of cells through NORMAL METABOLIC processes
~~ synthesis of structural components
~~ increase in cytoplasm

NOT due to cellular swelling
~~ ie influx of water

Generally restricted to
~~ skeletal muscle
~~ cardiac muscle
~~ smooth muscle
~~ - ~~ often enlargement is due to hyperplasia as in uterus

Mechanisms
~~ Pathologic
~~ Physiologice
~~ via increased funtional demand
~~ via specific hormonal stimulation
ORGAN HYPERTRPOPY
Increase in size of organ due to increase in size but NOT number of cells
CELLULAR ATROPHY
Shrinkage in SIZE of cell by loss of cell substance
ORGAN OR TISSUE ATROPHY
Decrease in size of an organ or tissue AFTER it has reached NORMAL size
`` caused by LOSS of cells or DECREASED cell size

Physiologic
~~ ie early embryonic development
~~ ie female reproductive organs

Pathologic
~~ local
~~ generalized
METAPLASIA
Reversibel change in which on ADULT cell type (Epithelial or Mesenchymal) is replaced by another NORMAL adult cell type that does NOT normally belong in that location

May represent an adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment

Metaplasioa of respiratory columnar sqamnous epi tintrache, bronchi andbronchioles exposed to chronic irritation
~~ ie cigarette smoke
~~ ie lung worms

Vit A deficiency
~~ tf Night Blindness aka Nyctolopia
~~ tf induction of squamous metaplasia in Lacrimal duct
~~ tf Xerophthalmia via decreased tears
~~ in birds squamous metaplasia in esophageal glands and respiratory epi

Estrogen producing Sertoli Cell tumor
~~ tf squamous metaplasia of prostate epi
OSTEOPOROSIS
Reduction in the quantity of bone
CACHEXIA
General weight loss and wasting
AUTOPHAGY
Segregation and disposal of damaged organelles within a cell
CARDIAC HYPERTROPHY
Physiologic
~~ ie increased exercise

Pathologic
~~ ie systemic hypertension
~~ ie semilunar stenosis

Triggers
~~ Mechanical - ie stretch
~~ Trophic - polypeptide growth factors, vasoactive agents (angiotensin, alpha adrenergic agonists)

Significance
~~ eventually linited by blood supply and or nutrient and waste flow
~~ tf increased burden can not be compensated for
~~ tf "heart failure"
~~ degenerative changes
~~ - ~~ lysis
~~ - ~~ loss of myofibrillar contractile elements
~~ - ~~ apoptosis or necrosis
HYPERTROPHY

TUNICA MUSCULARIS GASTRIC PYLORUS

DOGS
Postprandial vomiting
HYPERTROPHY

TUNICA MUSCULARIS ILEUM

HORSES
Functional obstruction

Predisposition to fatal intestinal incidents
HYPERTRPOPHY

TUNICA MUSCUALRIS ESOPHAGUS DUE TO OBSTRUCTON AT CARDIA DUE TO ULCERATION AT PARS ESOPHOGEA

HORSES
Funtional obstruction
PHYSIOLOGIC HYPERPLASIA
Usually driven by hormones

Hormone induced hyperplasia increases the function capacity of tissue when needed
~~ hyperplasia of endrometrium of uterus
~~ accompanied by hypertophy of smooth muscle of uterus

Compensatory Hyperplasia increases tissue mass after damage of partial loss
~~ hepatocellular compensator hyperplasia after loss of hepatic tissue
~~ - ~~ Prometheus
~~ - ~~ rats replace lobes in weeks
~~ unilateral compensatory renal hyperplasia after pephrectomy
~~ bone marrow hyperplasia after loss of blood
HYPERPLASIA

MECHANISMS

3
Generally

Increased local production of Growth Factors

Increased levels of Growth Factor Receptors on responding cells

Activation of specific Intracellular signalling pathways

All of which lead to production of transcription factors leading to gene expression for
~~ growth factors
~~ receptors for groth factors
~~ cell cycle regulators

Resuts in Cellular Proliferation
PATHOLOGIC HYPERPLASIA

2

DISTINGUISH FROM NEOPLASIA
Excessive Hormonal Stimulation

Exessive production of Growth Factors

Hyperplastic tissue responds to normal regulatory control mechanisms
~~ tf when stimulus removed hyperplasia STOPS
~~ in Neoplasia proliferative response continues in absence of stimulus

However, Pathologic hyperplasia provides opportunity for development of neoplasia
CYSTIC ENDOMETRILA HYPERPLASIA

BITCH
Secondayr to an exaggerated response of estrogen primed endometruum to progesterone.

Also associated with administration of long acting progestational compounds to delay onse of estrus in bitches
LASONIA INTRCELLULARIS

PIGS
Bacteria invading enterocytes causes severe hyperplasia of SI mucosa
PROSTATIC HYPERPLASIA

INTACT DOGS
Significant interference with defecation

Moderate interference with micturation
LYMPHOID HYPERPLASIA
Activation of lymph nodes due to inflamatory processes in drainage field

Could also be a neoplasia metastisizing along lyphatic system
DISUSE ATROPHY
Skeletal muscle hypotrophy and Osteoporosis as a result of disuse
~~ ie limb in cast
~~ lack of wieght bearing

Initial rapid decrease in cell size is reversable if activity is resumed in short period of time

Prolonged disuse results in loss of myoctyes
DENERVATION ATROPHY
Normal function of skeletal muscle requires neuronal stimulation
~~ ie trauma to brachial plexus
ATROPHY DUE TO DIMINISHED BLOOD SUPPLY
Pathological process in kidneys may produce diffuse Fibrosis

Contracting fibrotic tissue interferes with blood supply

Partially contributes to decrease in parenchymal mass of kidney
PRESSURE ATROPHY
Tissue compression for any lenght of time can cause atrophy

In part caused by compromise of blood supply

Enlarging benign tumor compresses surrounding tissue

Hydronephrosis
HYDRONEPHROSIS
Loss of medullar tissue as a result of pressure atrophy created by accumulation of urine due to urinary tract blockage
NUTRITION ATROPHY
CACHEXIA (aka Muscle Wasting)
~~ prolonged protein / calrie deficits
~~ - ~~tf use of muscle protein for GNG
~~ chronific inflammatory diseases and cancer
~~ - ~~ tf chronic overproduction of Tumor Necrosis Factor
~~ - ~~ tf appetite suppression and muscle atrophy

SEROUS ATROPHY OF ADIPOSE TISSUE
~~ prolonged severe negative caloric balance
~~ normal fat replaced by water gelatinous fluid
~~ assumed to be ISF seeping into empty space vacated by triglyceride storage vacuoles
~~ starvation
~~ poor dentition
~~ severe enteric disease
~~ increased energy demands
`~ - ~~ pregnancy
~~ - ~~ cold weather
JUST TO MIX THINGS UP

WHAT IS THE DIFFERENCE BETWEEN

NEOPLASIA AND ADENOMA
Neoplasia
~~ any unregulated cellular proliferation (ie any tumor) in any tissue

Adenoma
~~ BENIGN tumor in a GLAND
ENDOCRINE STIMULATION ATROPHY
Loss of or Exagerated Endocrine Stimulation

Loss

~~ atrophy of mammary glands and reproductive organs after pregnancy

Exagerated

~~ long term exogenous adiminstration of corticosteroids
~~ tf decreased ACTH
~~ tf bilateral adrenal cortical atrophy
~~ tf iatrogenic hyperadrenocorticism (aka Cushings Disease)
~~ also dermal adnexal atrophy

~~ Sertoli cell tumor may produce increased estrogen
~~ tf testicular atrophy
SENILE ATROPHY
Aging process is associated with cell loss

tf tissues without mitotic capabilty shrink

Senile Brain Atrophy
~~ loss of brain cells
MECHANISMS OF ATROPHY

3
Atrophic cells have diminshed function due to reduction of structural components but are NOT dead

If blood supply, nutrition and trophic stimulation continue to diminish APOPTOSIS may induced by the same signals that produce atrophy

LYSOSOMES
~~ acid hydrolases ie cathepsins
~~ other proteolytic enzymes
~~ tf degrade emdocytosed proteins from
~~ - ~~ extracellular environment
~~ - ~~ cell surface
~~ - ~~ some cellular components

UBIQUITIN - PROTEASOME PATHWAY
~~ degratdation of cytosolic and nuclear proteins
~~ conjugated to Ubiquitin
~~ degraded in Proteasome
~~ induced by
~~ - ~~ Tumor Necrosis Facor
~~ - ~~ Glucocorticoids
~~ - ~~ Thyroid Hormone

AUTOPHAGY
~~ segregation and disposal of damaged organelles via autophagic vacuoles
~~ large increases in number of autophagic vacuoles are associated with autophagy
~~ lysosomes merge and inject hydrolytic contents
~~ some cell debris resists digestion and remain as membrane bound cytosolic Sarcophagi
~~ - ~~ ie Lipfuscin
~~ - ~~ tf "Brown Atrophy"
POST NECROTIC ATROPHY
Degenerative tissue losses without apparent necrosis

Different mechanisms from Atrophy

Viral destruction of villus enterocytes
~~ ie carona virus

Infectious, chemical or other injury that produce
shrunken, scarred end stage of organs
CONNECTIVE TISSUE METAPLASIA
Formation of Mesenchymal Tissues
~~ cartilage
~~ bone
~~ adipose tissue
in tissues that normally do not contain these elements

Less clearly seen as an adaptive response

Myositis Ossificans
~~ bone formation in muscle

Ossifying Pachymeningitis
~~ bone formation in the pachymeninx (dura mater) of spinal cord

Pulmonry ossification
SIGNIFICANCE OF ADAPTATIONS

WORDS OF WISDOM
Virtually all lesions are significant

Some will cause clincal signs

Others may be significant only as pieces of a comlex puzzle

Each lesion has a story to tell

If we are clever enough to listen
PLASMA MEMBRANE
Most important structure Pathogenically

Barrier between cell and environment
~~ tf semipermeable membrane
~~ tf diffusion, passive, active transport

Plasma membrane proteins important
~~ cellular antigens
~~ receptors for hormones
~~ cell to cell interactions
~~ cell to substrate interactions
~~ recognition by pathogens, neutrophils, macrophages

Morphological Specilizations
~~ microvilli
~~ myelin
~~ intracellular attachements
NUCLEUS
Heterochrmatin
~~ condensed
~~ intensely basophilic

Euchromatin
~~ dispersed ie ACTIVE
~~ lightly staining
~~ prominent in cells actively synthesizing protein and RNA
~~ - ~~ tf rapidly dividing cells
~~ - ~~ tf neoplasia or hyperplasia
~~ specific patterns indicate Apoptosis
NUCLEOLUS
Site of synthesis of most components of Ribosomal RNA
~~ tf significant in neoplasms
CYTOPLASMIC ORGANELLES
High Nucleic Acid Content vs protein produces basophilia
MITOCHONDRIA
Energy Production via oxidative phosphorylation

Cell Death is associated with drastic damage to mitochondria
ROUGH ENDOPLASMIC RETICULUM
Protein Synthesis via Ribosomes
~~ tf basophillia
~~ mainly secretatory proteins
~~ - ~~ free ribos for intracellular proteins
~~ high protein secretion common in proliferative cells
GOLGI APPARATUS
Packaged produced proteins into Secretatory vesicles
SMOOTH ENDOPLASMIC RETICULUM
No ribos

Membranous carrier for metabolic and biosynthetic enzymes

Site of metabolosis of toxins and drugs in hepatocytes
HETEROPHAGY
Lysosomaldigestion of material ingested from extracellualr environment

Common activity in Professional Phagocytes
~~ neutrophils
~~ macrophages
AUTOPHAGY
Lysosomal digestion of cell's own components

Removal of organelles damaged in cell injury

Cellular remodeling during differntiation

Pronounced in cells undergoing atrophy
~~ nutrient deprivation
~~ hormonal involution
FILAMENTS
Composed of Actin, myosin and associated regulatory proteins

Proper functioning critical for Leukocyte movement and phagocytosis
MICROTUBULES
Polymerization of Tubulin protein

Rapid assembly and dissasembly

Essential for leukocyte migration and phagocytosis

Defects can inhibit
~~ sperm motility
~~ immobilize cilia of respiratory epi
~~ tf inabilty to clear inhaled bacteria
~~ tf bronchiectasis
~~ - ~~ aka immotile cilia syndrome
~~ - ~~ aka Kartagener's Syndrome
INTERMEDIATE FILAMENTS

5 NAMES

5 CELL TYPES

DONT YOU LOVE THAT HISTOLOGICAL MINUTIA NOW

BUT WE DO CARE - WHY?
flexible intracellular scaffold

Keratin filaments - epi cells

Neurofilaments - neurons

Desmin Filaments - muscle cells

Vimentin Filaments - connective tissue cells

Glial Fibrillary Acidic Protein (GFAP)

Important in the identification of neoplasms
~~ identifies tissue type
NECROSIS
Death of cells and tissues in the living animal
DEGENERATION
Reversible deteriorating pathologic change in cells or tissues
~~ functions impaired or destroyed
REVERSIBLE CELL INJURY

2 HALLMARKS
Functional and morphological changes
~~ reversible if the damaging stimulus is removed


Reduced Oxidative Phosphorylation
~~ tf reduced ATP level

Cellular Swelling
~~ loss of ion and fluid homeostasis
~~ changes in ion and protein concentration
~~ - ~~ decrease ATPase activity
~~ - ~~ lactate and ATP and creatine phosphate breakdown products etc
~~ water influx

Also Fatty Change
~~ hypoxic injury
~~ - ~~ tf decreas beta oxidation
~~ toxic or metabolic injury
~~ - ~~ tf inability to metabolize fatty acids
REVERSIBLE CELL INJURY

GROSS CHANGES

3
Mild Enlargement

Turgid

Pale
~~ depends on cause of degeneration
REVERSIBLE CELL INJURY

LIGHT MICROSCOPE CHANGES

5
Cell Swelling

Cloudy Swelling
~~ altered staining characteristics

Vacuolar (aka Hydropic)Degeneration
~~ vacuoles in cytoplasm
~~ distended organelles esp ER
~~ lipid droplets

Ballooning Degeneration
~~ big vacuole

Lipidosis (aka Fatty Change)
~~ accumulation of excessive intracellular lipid
~~ esp hepatocytes - high fat metabolism
~~ lipid filled vacuoles in cytoplasm
REVERSIBLE CELL INJURY

6 ULTRASTRUCTURAL CHANGES
Plasma Membrane
~~ blebbing
~~ blunting of microvilli
~~ myelin figures
~~ loosening of intercellular attachements

Mitochondrial Swelling

Dilation of ER (aka Vacuolation
~~ detachment and dsaggregation of ribosomes
HEPATIC LIPIDOSIS
Reversibly injured cells often cannot adequately carry out normal funtions but are able to maintain homeostasis
~~ tf reamain alive

Most common in
~~ hepatocytes
~~ renal tubular epithelium

Liver
~~ if most hepatocytes are affected
~~ - ~~ diffusely yellow, greasy friable grossly
~~ if hepatocytes affected zonally
~~ - ~~ reticular pattern grossly

Mechanisms
~~ lipids enter as Free Fatty Acids
~~ most esterfied to Triglycerides
~~ some utilized for cholesterol esters or phospholipids
~~ some degraded to ketones
~~ for export TGs complexed with Apolipoprotein or liid acceptor protein to form lipoproteins
~~ accumulation of TG via
~~ - ~~ Exessive delivery of FFA via negative caloric balance
~~ - ~~ toxic injury impairs ability to synthesize apolipoprotein
~~ - ~~ Hypoxia interferes with FFA oxidation in ER
HYPOXIC DAMAGE
Damage due to lack of oxygen delivery

Normal Circulation
~~ tf anemia
~~ tf CO, CN toxicity etc
ISCHEMIA DAMAGE
Absence of Circulation

Low O2

Low Nutrients

High Lactic Acid

High Metabolic Waste
STEROID HEPATOPATHY
Massive Glycogen Accumulation

Induced by high levels of Corticosteroids

Enlarged and Bronze coloured grossly

Feathery Vaculation of hepatocytes Histologically
~~ intially microvacuolar
~~ chronically macrovacuolar
HYPERCORTICOSTEROIDISM
Steroid Hepatopathy

Dermal Degeneration

Skeletal Muscle Atrophy

All lead to pot belly
HEPATIC RETICULAR PATTERN
Zonal !!!!!
~~ tf Hypoxia
~~ - ~~ ie right heart failure
~~ tf Ischemia
~~ tf Metabolic Changes
~~ tf Toxic Change

Almost NEVER infection
~~ randam via septic shower from blood
IRREVERSIBLE CELL INJURY

2 MAJOR SIGNS

2 TYPES OF DEATH
Depth of injury from which cell cannot recover

Severe Mitchondrial Damage

Loss of Membrane Functionality

Necrosis
~~ severe membrane damage
~~ - ~~ tf lysosomal enzymes enter cytoplasm
~~ - ~~ acid hydrolases active in high lactic acid low pH environment of injured cell
~~ - ~~ tf leakage of cellular contents

Apoptosis
~~ noxious stimuli esp DNA damaging
~~ nuclear dissolution without complete loss of membrane integrity
CELLULAR NECROTIC CHANGES
Spectrum of morphologic changes that follow cell death in living tissue

Largely result from progressive degraditive action of released enzymes

Tissues Fixed immediately are dead but NOT necrotic

Necrosis is the gross and histologic correlate of cell death occurring in the setting of irrreversible injury.
NECROSIS

CLINICAL IMPORTANCE
Leakage of intracellular prodteins across degraded cell membrane
~~ tf reliable detection of tissue specific cellular injury
~~ - ~~ skeletal muscle CK ~~ - ~~ Hepatocytes ALT
MORPHOLOGY

CELL INJURY AND NECROSIS

TIMING
All stressors and noxious influences produce effects first at molecular or biochemical level

Time lag between stress and morphologic changes

Histochemical and Ultrastructural techniques
~~ show changes minutes to hours after ischemic events

Gross examination or light microscopy
~~ several hours to show ischemic events
~~ 4 - 12 hrs for myocardial infarction
~~ - ~~ yet irrevesible injury occured 20 - 60 min
~~ - ~~ tf cant see infarcts that kill
MORPHOLOGY

CELL INJURY AND NECROSIS

CYTOPLASMIC 8
Cytoplasm Swollen

Increase cytoplasmic eosinophilia
~~ loss of ribos
~~ increased binding to denatured proteins

Hyalinized cytoplasm
~~ glassy appearance

Vacuolated cytoplasm

Calcification
~~ Sarcoplasmic Reticulum
~~ ISF

Overt discontinuities in plasma and organelle membranes

Marked dilation of mitochondria
~~ large amorphous densisties

Intracytplasmic Myelin Figures
MORPHOLOGY

CELL INJURY AND NECROSIS

NUCULEAR 3
Nonspecific Breakdown of DNA results in in typical chronology:

Pycnosis
~~ nuclear shrinkage
~~ increased basophillia
~~ - ~~ condenstation of DNA

Karyolysis
~~ basophilia of chrmatin fades
~~ - ~~ degrading activity of DNase

Karyorrhexis
~~ pyknotic or partially pyknotic nucleus undergoes fragmentation
COAGULATIVE NECROSIS
Preservation of basic outline of cogulated cell
~~ at least some days

Affected tissues
~~ pale
~~ swollen
~~ firm
~~ demarcated hyperemic (reaction) zone
~~ - ~~ more friable than surrounding tissue
~~ - ~~ via proteolytic destruction of cytoskeleton
~~ cellular acidosis becomes severe enough to impair proteolytic enzymes
~~ cogulation of cytoplasmic proteins
~~ reduced blood flow via cell swelling in necrotic area

Renal INfarct
~~ acidophilic coagulated anucleate cells persist for days

Characteristic of Hypoxic death of cells
~~ in all tissues except brain

Impaired circulation preventing leuckocyte invasion may result in
~~ coagulative focus persisting for weeks as sequestrum

Microscopic
`` Eosino;hillic shadow
`` Cellular shape & tissue organization still apparent
`` Nucleus usually lost
~~ - ~~
LIQUEFACTIVE NECROSIS
Characteristic of focal pyogenic bacterial infections
~~ stimulate accumulation of
~~ - ~~ inflammatory cells
~~ - ~~ proteolytic enzymes
~~ tf affected tissue liquefied

Malacia
`` Hypoxic death of CNS cells also evokes lquefactive necrosis

Liquefaction completely digest dead cells
~~ tf liquid viscous mass
~~ if accute inflammation material is creamy yellow
~~ - ~~ via dead leucocytes
~~ - ~~ tf pus
CASEOUS NECROSIS
Distinctive form of Coagulative necrosis

Foci infected with highly toxigenic bacteria
~~ mycobacterium bovis
~~ Corynebaceruim pseudotuberculossis

Cheesy white and dry gross appearance

Microscopically
~~ amorphous granular debris
~~ fragmented coagulated cells
~~ enclosed within distinctive granulomatous inflammatory process

TISSUE ARCHITECTURE IS COMPLETELY OBLITERATED

Not common
GANGRENOUS NECROSIS
Not a distinctive process of cell death

Blood loss to extremity results in coagulation necrosis
`` Dry Gangrene
~~ subsequent bacterial infection modifies coagulative necrosis
~~ - ~~ liquefactive aciton of leukoxytes attracted to bacteria
~~ WET Gangrene
FAT NECROSIS
Not a specific pattern of necrosis

Focal areas of fat destruction
~~ typically result of release of activated pancreatic lipases
~~ within and around inflamed pancreas
~~ activated pancreatic enzyme escape from acinar cells and ducts
~~ liquify fat cell membranes
~~ activated lipases split the triglyceride esters within
~~ released fatty acids combine with calcium
~~ produce gossly visble chalk white areas (aka Saponification)

Histologically
~~ foci of shadowy outlines of necrotic fat cells
~~ basophillic calcium deposits
~~ surrounded by inflammatory reaction

If not cleared in liveing patient
~~ calcium salts and other minerals aggregate
~~ tf calcifiation
~~ aka Dystrophic Calcification
DISQUISES OF NECROSIS

3 BIG ONES

BUT WHAT GIVES US STRENGHT IN THIS PERPLEXITY
Classic Gross Appearance
~~ swollen demarcated area of pallor
~~ short lived
~~ gives way to many sequels
~~ BUT LOSS OF STRENGH PERSISTS THROUGHOUT

Colour
~~ most changes due to influx of red blood cells
~~ - ~~ subsequent breakdown
~~ mineralization
~~ inflammation
~~ loose tissues like lung and subcutis
~~ - ~~ swelling of dying cells does not prevent massive inrush of blood at periphery
~~ - ~~ tf red appearance from start of process
~~ Abundant Dystrophic Calcification
~~ - ~~ white granular gritty appearance

Demarcation by inflammatory reaction of leukocytes and erthrocytes
~~ red and white ring
~~ exists only at initial stages
~~ subsequent blood leakage and inflammatroy infiltration

Texture
~~ initial texture allways weaker or more friable
~~ coagulation necrosis tissue feels firm via turgidity of cell swelling
~~ - ~~ but is friable and ruptures easily if palpated
~~ will liquify after a few days
~~ healing process
~~ - ~~ proliferation
~~ - ~~ angioblasts
~~ - ~~ fibroblasts (granulation tissue)
~~ deposits collagen (fibrosis)
~~ - ~~ tf tissue becomes firm
SIGNIFICANCE OF NECROSIS TO ANIMAL

4 DEPENDS
Depends on
~~ size
~~ site
~~ speed of progression
~~ sequels

Focus of necrosis within brainstem or myocardial conductions system is almost always fatal

Organs with large functional reserve such as liver and kidney can sustain large areas of necrosis

Rapid loss clinically more significant than slow loss

Sequels such as inflammation and scaring may be more important than necrosis
~~ ie esophageal constriction
~~ ie endothelial repair

Focal necrosis on a growth plate causes limb deformity
~~ healthy portion continues osteogenisis
SIGNIFICANCE OF NECROSIS OF DIAGNOSTICIAN
Character and location of necrotic lesion(s)
~~ important clues about the cause and pathogenesis

Group of lesions
~~ create pattern typical of specific disease
~~ footprints of disease
~~ even though lesion themselves have no functional significance
DRY GANGRENE
Ischemic Necrosis of Extremities
`` bacterial infection absent
TYPICAL NECROTIC COLOUR PROGRESSION

3 STEPS
Cellullar swelling excludes blood
`` tf pale firm tissue
`` 1st 24 hrs

Degradation of cells lowers pressure and blood rushes in
`` tf red
`` next 24 hrs

Macrophages remove blood and fibrous tissue forms
`` tf pale and contracted
FROST BITE AND LOOSE TISSUE

HAVE WHAT IN COMMON
Initially Red in Colour when necrotic

Loose Tissue
`` cellular swelling does not compress blood vessels

Frost Bite
`` high water content tissue damaged most
`` ie blood vessels tf extravasated blood
APOPTOSIS
Pathway of cell death that is induced by a tightly regulated intracellular energy dependent program

Cells destined to die activate enzymes that degrade the cell's own nulear DNA and cytoplasmic proteins
APOPTOSIS

SEVEN SCINTTILATING FACTS
Cell Shrinks and fragments

Energy Dependent

Regulated enzymatic degradation of DNA and cytoplasmic proteins

Plasma membrane remains intact
`` tf no leakage

Avid phagocytosis via surface ligands

No or low inflammatory response
`` bc no leakage
`` bc rapid phagocytosis
NECROSIS

AS OPPOSED TO

APOPTOSIS
Cell Swells

Loss of membrane integrity

Enzymatic digestive free for all

Loss of energy production

Often inflammatory reaction
APOPTOSIS AND NECROSIS

DO THEY COEXIST
Sometimes
PHYSIOLOGIC APOPTOSIS

4 EXAMPLES
Programmed destruction of cells during embryogenesis
`` implantation
`` organogenisis
`` developmental involution
`` metamorphosis

Hormone dependent involution in adult
`` reproductive cycle endometrial cell breakdown
`` development and regression of mammary glands

Cell Deletion in proliferating cell populations
`` maintaining constant number of intestinal crypt epithelia

Death of old cells that have done their duty
`` lymphocytes after the storm
`` `` an unemployed lymphocyte is a bad thing..
PATHOLOGIC APOPTOSIS

5 EXAMPLES
DNA Damage via radiation, cytotoxic drugs etc
`` repair mechanisms overwhelmed by injury
`` tf apoptoptic pathways initiated
`` avoids potential damage of mutant cell / proteins

ER stress
`` induced by accumulation of unfolded proteins
`` triggers apoptotic pathways

Pathologic atrophy in parenchymal organs
`` ie via duct obtstruction

Cell death in tumors
`` most frequently during regression
`` can also occur in actively growing tumors

Cell death induced by Cytotoxic T Cells
`` defense mechanism against viruses and tumors
`` eliminates virus infected cells
`` eliminates neoplastic cells
`` responsible for rejection of transplants
APOPTOSIS

5 MORPHOLOGIC CHARACTERISTICS

IDENTIFIY THE MOSTEST
Cell Shrinkage
`` smaller in size
`` dense cytoplasm
`` organelles normal but tightly packed

Chromatin Condensation
`` most characteristic feature of apoptosis
`` peripheral aggregation into dense masses
`` nucleus breaks into two or more fragments

Cytoplasmic Blebs and Apoptotic bodies
`` first shows extensive surface blebbing
`` then fragments into membrane bound apoptotic bodies
`` `` cytoplasm
`` `` tightly packed organelles
`` `` with or without nuclear fragments

Phagocytosis of Apoptotic Cells or cell bodies
`` usually by macrophages
`` apoptotic cells express ligands for macrophages
`` `` tf early recognition
`` `` tf no release of cellular components
`` `` tf no inflammation

Plasma membrane remains intact during apoptosis
APOPTOSIS

HISTOLOGICAL PERSPECTIVES

TAKE 5
Intensely Eosinophilic cytoplasm

Dense nuclear chromatin fragments

Single cells or small clusters of cells

Apoptotic cell
`` round or oval mass

Considerable apoptosis can occur before histologically apparent
`` cell shrinkage
`` rapid formation of apoptotic bodies
`` rapid phagocytosis
`` lack of inflammation
NECROSIS vs APOPTOSIS

EIGHT HANDY FEATURES TO THINK ABOUT
Distribution

Cell Size

Nucleus

Plasma Membrane

Cellular Contents

Adjacent Inflammation

Physiologic vs Pathologic

Energy
NECROSIS vs APOPTOSIS

DISTRIBUION
Distribution

`` often contiguous cells

vs

`` Usually single cells
NECROSIS vs APOPTOSIS

CELL SIZE
Enlarged via swelling

vs

Reduced via shrinkage
NECROSIS vs APOPTOSIS

NUCLEUS
Pyknosis
Karyorrhexis
Karyolysis

vs

Fragmentation into nucleosome size
NECROSIS vs APOPTOSIS

PLASMA MEMBRANE
Disrupted

vs

Intact
`` altered structure
`` esp orientation of lipids
NECROSIS vs APOPTOSIS

CELLULAR CONTENTS
Enzymatic Digestion
`` may leak out of cell

vs

Intact
`` may be released in apoptotic bodies
NECROSIS vs APOPTOSIS

ADJACENT INFLAMMATION
Frequent

vs

Rare to None
NECROSIS vs APOPTOSIS

PHYSIOLOGIC PATHOLOGIC
Invariable Pathologic
`` ie consequence of irreversible cell injury

vs

Often Physiologic
`` eliminating unwanted cells

Can be pathologic
`` `` cell injury esp DNA damage
NECROSIS vs APOPTOSIS

ENERGY
Does not require energy

vs

Requires energy
MECHANISMS OF APOPTOSIS

TWO PHASES

TWO PATHWAYS
Initiation Phase
`` capases become catalytically active

Execution Phase
`` caspase enzymes act to cause cell death

Initiation of apoptosis occurs principally via signals from

Extrinsic Pathway
`` aka Receptor Initiated
`` aka Death Receptor Initiated

Intrinsic Pathway
`` aka Mitochondrial

Both pathways converge to activate caspases
EXTRINSIC AKA DEATH RECEPTOR INITIATED PATHWAY
Initiated by engagement of cell surface death receptors
`` variety of cells

ie Fas (CD95) Protein
`` Fas binds ligant
`` associated death domain initiates activation of caspase-8
`` `` C protein driven
`` `` Cleaves Aspartate
`` `` Degrades
`` subsequently triggers execution of apoptosis
INTRINSIC AKA MITOCHONDRIAL PATHWAY
Result of increased mitochondrial permeability
`` release of pro apoptotic molecules into cytoplasm
`` `` cytochrome C
`` without involvement of death receptors

Reduced production of anti apoptotic members
`` via lack of trophic hormones or cell damage
`` tf anti apoptotic Bcl-2, Bcl-x of Bcl-2 family proteins
`` replaced by pro apoptotic Bak, Bax of Bcl-2 family proteins
`` tf increased mito membrane permeability
`` tf leakage of messangers of death aka Cytochrom C
`` tf activation of caspase-9
`` tf subsequent triggering of apoptosis
APOPTOSIS

EXECUTION PHASE
Final phase of apoptosis

Mediated by proteolytic cascade of caspase enzymes
`` more than 10 members
`` initiators
`` `` ie caspase 8 and 9
`` executioners
`` `` ie caspase 3 and 6

After initiator caspase is activated
`` enzymatic death program set in motion
`` rapid sequential activation of executioner caspases
`` tf cleavage of
`` `` cytoskeleton
`` `` nuclear matrix proteins
`` tf activation of endonucleases
`` `` cellular fragmentation
`` `` formation of apoptotic bodies
APOPTOSIS

REMOVAL OF DEAD CELLS
Dying cells secrest soluble factors that recruit phagocytes

Facilitates prompt clearance of apoptocic cells
`` tf no secondary necrosis
`` tf no release of cellular contents
`` tf no inflammation

Surface receptors on apoptotic cells and fragments bind phagocytes

Efficient process
`` tf dead cells disappear without a trace
`` tf no inflammation
APOPTOSIS

NAME 4 EXAMPLES
Growth Factor Deprivation

DNA Damage Mediated

Cytotoxic T-Lymphocyte Mediated

Dysregulated
APOPTOSIS

GROWTH FACTOR DEPRIVATION
Hormone sensititive cells

Lymphoctes
`` not situmlated by anitgens and cytokines

apoptosis triggered by intrinsic pathway
`` excess of pro apotototic members of Bcl family relative to anti apotototic
APOPTOSIS

DNA DAMAGE
aka Genotoxic Stress
`` radiation
`` chemotherapeutic agents

Initiates mechanism involving tummor suppressor gene P53
`` aka Correct or Die
`` `` best said in heavy Transalvanian accent

P53 accumulates when DNA is damaged
`` arrests cell cycle
`` `` allows time fro repair
`` if DNA repair process fails
`` `` p53 stimulates production of pro apoptotic members of Bcl Family
`` `` tf leakage of mitochondrial membrane
`` `` tf cytochrome c leakage
`` `` tf activation of caspases

Note - when p53 mutated or absent
`` cell incapable of inducing apoptosis
`` survival favored
`` favorite of certain cancers
APOPTOSIS

CYTOTOXIC T LYMPHOCYTE
Bypasses upstream signalling events

Recognizes foreign antigens on infected cells

Secretes Perforin
`` transmembrane pore forming molecule
`` allows entry of Granzyme B

Granzyme B cleaves aspartate residues
`` tf activates cellular caspases
`` tf directly induces Execution Phase of apoptosis

Cytotoxic T Lymphocytes also express FasL
`` tf bind Fas receptors
`` tf induce Extrinsic Pathway
APOPTOSIS

DYSREGULATED
Too Little or Too Much

Inappropriately low rate of apoptosis
`` prolong cell survival
`` reduce turnover of abnormal cells
`` accumlated cells can give rise to
`` `` neoplasia
`` `` autoimmune disorders
`` `` `` non elimination of auto reactive lymphocytes after self antigen encounter

Increase apoptosis
`` excessive cell death
`` diseases characterized by marke loss of normal cells
`` `` ie death of virus infected cells
`` `` `` feline panleukopenia virus
HYPOXIA

4 KEY POINTS
Deficiency of Oxygen

Creates Cell Injury
`` via reducing aerobic oxidative respiration

Important and Common cause of cell injury and death

Glycolytic Energy production continues
`` ie nutrients delivered
`` ie waste products removed
HYPOXIA

CONSEQUENCES
Adapt

Sustain Injury

Die
ISCHEMIA

4 KEY POINTS
Loss of Blood Supply
`` impeded arterial flow
`` reduced venous drainage

Reduced aerobic oxidative respiration

Inhibited Glycolytic Function
`` lack of substrates
`` accumulation of waste metabolites
`` `` ie lactic acid

Injury compared to hypoxia
`` more rapid
`` more severe
HYPOXIA

3 EXAMPLES
Inadequeate oxygentation of Blood
`` cardiorespiratory failure

Loss of Oxygen carrying capacity
`` Anemia
`` CO poisoning
ISCHEMIA

3 EXAMPLES
Embolism

Heart Failure

Shock
CELL INJURY

4 PHYSICAL AGENTS
Mechanical Trauma

Extremes of Temperature

Radiation

Electric Shock
CELL INJURY

INFECTIOUS AGENTS
Viruses, Bacteria, Fungi, Parasites
`` tf diverse range of mechanisms

Viruses
`` alter metabolism of host cells

Bacteria
`` secrete toxins
`` tf direct damage to tissue
`` ie proteolytic enzymes
`` `` Fusobacterium necrophorum
`` ie coagulation necrosis
`` `` Clostridial sp
CELL INJURY

IMMUNOLIGIC REACTIONS
Anaphylatic reactions to foreign proteins

Autoimmune Disease
`` reaction ot endogenous self antigens
CELL INJURY

GENETIC DERANGEMENTS
Genetic Defects can result in cell injury

Enzymatic Defects
`` storage diseases
`` Bovine Familial Convulsion and Ataxia
`` `` swollen axons
CELL INJURY

NUTRITIONAL IMBALANCES
Prolonged and Severe protein-caloric deficiencies can be fatal

Vitamin and Mineral Deficiencies
`` Vit E / Se
`` `` White muscle disease
`` `` reduced scavenging of free oxygen radicals
CELL INJURY

CHEMICAL AGENTS
Many

Trace Amounts can destroy enough cells to cause death within minutes to hours
`` arsenic
`` cyanide
`` mecuric salts

Environmental pollutants

Insecticides

Herbicides

Therapeutic and Recreational Drugs
3 ELEMENTS OF CELL INJURY

THAT DETERMINE CELLS RESPONSE
Type of Injury

Duration of Injury

Severity of Injury
3 CELLULAR CHARACTERISTICS

THAT DETERMINE CONSEQUENCE

OF INJURY
Type of Cell

State of Cell

Adaptability of cell

ie skeletal striated myocytes
`` resistent to intermitant decrease in blood supply

ie cardiac striated myocytes
`` susceptable to intermitant decrease in blood supply
4 SITES OF INJUROUS STIMULUS
ATP
`` loss of energy dependent cellular functions
`` `` swelling of ER
`` `` cell swelling
`` `` loss of microvilli
`` `` blebing
`` `` decreased pH
`` `` decreased proteins
`` `` increased lipids

Membrane Damage
`` mitochondria
`` `` cell death
`` lysosome
`` `` enzymatic digestion of cellular components
`` plasma membrane
`` `` loss of cellular contents

Intracellular Ca
`` protein break down
`` DNA damage

Reactive Oxygen Species
`` protein break down
`` DNA damage
DEPLETION OF ATP

HOW MUCH IS TOO LITTLE

4 WAYS TO CELLULAR PAIN
< 5% - 10% of Normal
`` widespread effects on many critical cellular systems

Reduction in activity of plasma membrane energy dependent Na transporters
`` intracellular Na accummulation
`` loss of intracellular K via diffusion
`` net gain of solute
`` `` osmotic inflow
`` `` `` cellular swelling
`` `` `` dilation of ER

Switch to anaerobic metabolism ie via ischemia
`` glycogen stores rapidly deplete
`` accumulation
`` `` inorganic phosphates
`` `` lactic acid
`` tf decrease cellular pH
`` `` decreased cellular enzymes

Failure of Ca pump
`` influx of Ca
`` damages numerous cellular components
`` activates enzymes that destroy cellular structures

Disruption of protein syntetic apparatus
`` via prolonged ATP depletion
`` detachement of ribosomes from RER
`` decreased protein synthesis
`` irreversible damage to mito and lysosome membranes
`` `` tf cellular necrosis
MITOCHONDRIAL DAMAGE

3 WAYS TO GET IT

2 DEADLY CONSEQUENCES
Decreased ATP results in morphologic changes
`` swelling
`` large amourphous densities

Increased cytosolic Ca

Oxidative Stress

Phospholipid Breakdown
`` phospholipase A2
`` lipid peroxidation products

Formation of high conductance channels (aka pores)on inner membrane
`` prevent maintenance of proton motive force
`` tf no mito oxidative phosphorylation

Leakage of cytochrome C into cytosol
`` triggers apoptotoic death pathways
LOSS OF CALCIUM HOMEOSTASIS

NORMALS

MECHANISM

CONSEQUENCES
Normal Levels
`` Intracellular <0.1 micromol
`` Extracellular 1.3 mmol
`` most intracellular Ca sequestered
`` `` mitos
`` `` ER
`` Gradients modulated by energy dependent Ca Mg ATPases (calcium pumps)

Ischemia and specific Toxins generate early increase in cytosolic [Ca]
`` via net inward flux across plasma membrane
`` via release from ER
`` Subseqent increases via
`` `` nonspecific increases in membrane permeability

Increased Ca activates many enzymes
`` ATPases speed ATP depletion
`` phospholipase damage membranes
`` proteases breakdown
`` `` membrane proteins
`` `` cytoskeletal proteins
`` endomuclease fragment DNA and chromatin

Increase Ca results in mito membrane leakage
`` releas of pro apoptotic messangers
OXIDATIVE STRESS

NAME EM

MECHANISM

SELF ABUSE

3 MAJOR HARMFUL EFFECTS
via Oxygen Derived Free Radicals
`` `` O2-
`` `` H2O2
`` `` OH-
`` `` NO3-
`` single unpaired electron in outer orbit
`` energy released via reactions with adjacent molecules
`` `` membrane proteins
`` `` membrane lipids
`` `` membrane carbohydrates
`` `` nucleic acids
`` tf cellular damage

Initiate Autocatalytic Reactions
`` molecules react with selves
`` tf converted to free radicals
`` tf propagation of damage

Lipid Peroxidation of Membranes

Oxidative Modification of Proteins

DNA Damage
OXIDATIVE STRESS

LIPID PEROXIDATION OF MEMEBRANES

LOCATION

MECHANISM

PROTECTION
Plasma and Oranelle Membranes

Oxygen derived free radicals (esp OH) attack membrane Unsaturated Fatty Acids
`` produce Peroxides
`` induce autocatalytic chain reaction
`` tf extensive organelle and cell damage

Scavenger required to to terminate autocatylitic chain reaction
`` Vit E embeded in membrane on good days
OXIDATIVE STRESS

OXIDATIVE MODIFICATION OF PROTEINS

MECHANISMS 3

PROTECTION
Oxidation of amino acid residue sidechains

Formation of protein-protein cross linkages
`` ie disulphide bonds

Oxidation fo protein backbone
`` tf protein fragmentation

Damaged cellular proteins conjugated with ubiquitin
`` tf degrade by proteasome complex
OXIDATIVE DAMAGE

DNA
Reactions with thymine produce single stranded breaks
`` nuclear
`` mito
implicated in
`` cell aging
`` malignant transformation
FREE RADICAL GENERATION

6 PROCESSES
Mito respirtation
`` generation of energy
`` via sequential reduction of molecular oxygen to water

Activated polymorphonuclear leukocytes
`` during inflammation
`` rapid burst of superoxide production

Transition Metals accept and Donate free electrons
`` Cu, Fe
`` during intracellular reactions
`` Catalyze formation of Free Radicals
`` ie Fenton Reaction
`` `` H2O2 + Fe2+ > Fe3+ + OH + OH-

NO (Nitric Oxide)
`` produced by endothelial cells and macrophages
`` can act as free radical
`` can be converted to highly reactive peroxynitrite anion
`` ONOO-

Radiant Energy
`` uv light, x rays
`` hydrolyzes water into free radicals
`` `` OH and H

Enzymatic metabolism of Exogenous chemicals or drugs
OXIDATIVE STRESS

3 DEFENSES
Antioxidants
`` block initiation of free radical fromation
`` inactivate free radicals
`` `` ie scavenge
`` Vit E,A,C and Glutathione

Metal Binding Proteins
`` bind Cu and Fe
`` tf reduced catalysis of ractive oxygen species
`` transferrin
`` lactoferrin
`` ceruloplasmin

Free Radial Scavenging Enzymes
`` Superoxide Dismutase
`` `` converts superoxide (2O2-) to H2O2
`` Catalase decomposes H2O2 to H2O and O2
`` `` present in peroxisomes
DEFECTS IN MEMBRANE PERMEABILITY

5 BIOCHEMICAL MECHANISMS

NAME EM

EXPLAIN EM
Mitochondrial Dysfunction
`` results in decreased ATP
`` tf decreased phosopholipid synthesis and reacylation
`` tf degradation of all cellular membranes

Loss of Membrane Phospholipids
`` increased intracellur Ca activates endogenous phospholipases
`` initiates degradation of phospholipids
`` increased acuumulation
`` `` free fatty acids
`` `` other lipid metabolites
`` `` `` ie detergents

Cytoskeletal Abnormalities
`` increased intracellular Ca activates proteases
`` tf damage to cytoskeleton
`` tf detachment from cell membrane
`` tf susceptability to stretching and rupture

Reactive Oxygen Species
`` damage to membranes, lipids, proteins, DNA

Breakdown Product Accumlation
`` unesterfied free fatty acids
`` catabolic products resulting from phospholipid degradation
`` detergent effect on cell membranes
`` `` changes in permeability
REVERSIBLE ISCHEMIC CELL INJURY

TELL THE STORY OF ESCALLATION
ATP depletion via loss of oxidative phosphorylation

Failure of Sodium Pump
`` intracellular accumulation of Na
`` loss of K
`` influx of water
`` cellular swelling

Morphologic Deterioration
`` dispersion of cytoskeleton
`` loss of ultrastructure
`` `` microvilli disappear
`` `` formation of blebs
`` Myelin Figures form from membranes
`` mitos swell
`` ER dilated
`` cell markedly swollen
IRREVERSIBLE ISCHEMIC CELL INJURY

TELL THE STORY
Morphology
`` mitos
`` `` severe swelling
`` `` large amorphous densities
`` extensive membrane damage
`` lysosomal swelling

Massive influx of calcium
`` especially during reprofusion
`` activation of catabolic enzyemes and apoptosis

Cell Death
`` cell components progressively degraded
`` widespread leakage of cellular enzymes into extracellular space
`` influx of macromolecules
`` inflammation, disintigration phagocytosis
``
REPROFUSION INJURY

2 OUTCOMES

3 MECHANISMS
Reversible Injury
`` Depending on intensity and duration
`` `` Recovery
`` `` Death via new and damaging processes

Irreversible injury
`` Death
`` `` via necrosis
`` `` via apoptosis

Increased Generation of Oxygen Free Radicals
`` antioxidants decreased during ischemia
`` initiated during reoxygenation
`` from
`` `` affected tissue
`` `` infiltrated neutrophils
`` antioxidnt defense mechanisms compromised
`` `` tf free radical scavanger therapy may benefit

Inflammation
`` hypoxic parenchymal and endothelial cells
`` `` cytokine production
`` `` adhesion molecule expression increased
`` tf reprerfusion results in increased inflammation

Complement Pathway Activation
`` IgM ABs deposited in ischemic tissues
`` `` from residual blood during isxhemia
`` upon reperfusion
`` `` complement binds ABs
`` `` activates complement pathway
`` `` direct cell injury via attack complexes
`` `` inflammation
PATHOLOGIC CALCIFICATION

WHAT IS IT

WHAT ARE THE FORMS
Abnormal Tissue Deposition of calcium salts
`` toegether with smaller amounts of
`` `` Fe, Mg and other mineral salts

Dystrophic Calcification

Metastatic Calcification
DYSTORPHIC CALCIFICATION

WHAT IS IT

PHASES
Occurs locally in necrotic or degenerative tissues
`` without highserum levels
`` without derangements in calcium metabolism

Associated with Necrosis of any type
`` coagulation
`` caseous
`` liquefactive
`` fat

Initiation (aka Nucleation)
`` Intracellular
`` `` mitos of dead or dying cells that accumulate Ca
`` Extracellular
`` `` phospholipids in membrane bound vesicles from degenerating cells
`` `` phosphatases generate phosphate
`` `` Ca binds phosphate and generates a microcrystal

Propagation
`` microcystal propogates and penetrates membrane
`` propagation dependent on
`` `` [Ca], [PO4]
`` `` inhibitors and other proteins in extra cellular space
`` `` `` CT, matrix proteins

Accentuated by hypercalcemia
METASTATIC CALCIFICATION

MECHANISM

4 CAUSES
May occur in normal tissues in presence of hypercalcemia

Principally affects tissues which lose acid creating a alkalotic micro environment
`` gastric mucosa
`` kidneys
`` lungs

Increased secretion of Parathyroid hormone (PTH)
`` subsequent bone resorption
`` parathyroid tumor
`` paraneoplastic syndrome
`` `` secretion of PTH related proteins by other tumors

Destruction of Bone Tissue
`` primary or metastatic tumors

Vitamin D Toxicity

Renal Failure
`` retention of phosphate
`` secondary hyperparathyroidism
`` `` inorder to maintain plasma Ca:P ration
PATHOLOGIC CALCIFICATION

MORPHOLOGY
Similar for dystrophic and metastatic

Gross
`` Fine white granules or clumps
`` `` often with gritty texture

Histologically
`` Basophilic amorphous granular
`` `` sometimes clumped
`` intracellular extracellular or both
PATHOLOGIC CALCIFICATION

SIGNIFICANCE
Usually mineral salts caus no dysfunction to affected tissues

Important indicators of Pathological Processes
CELLULAR AGING

5 PROCESSES
Reduced Mitochondrial Oxidative Phosphorylation

Reduced Synthesis

Reduced Nutrient Uptake

Reduced DNA Repair

Accumulation
CELLULAR AGING

REDUCED SYNTHESIS

5
Nuleic Acids

Structural Proteins

Enzymatic Proteins

Cell Receptors

Transcription Factors
ACCUMULATION

3 JUNK PILES
Lipofuscin Pigment
`` product of lipid peroxidation

Glycation End porducts
`` ie age related glcosylation of lens proteins
`` senile cataracts

Abnormally folded proteins
REPLICATIVE SENESCENCE

WHO

HOW
Somatic cells have limited capacity for replication

Arrest in terminally non dividing state
`` after fixed number of replications
`` aka cellular senescence
`` regulated by telomeres
TELOMERES

WHAT ARE THEY

SIGNIFICANCE
aka Genetic Clock

Short repeated sequences of DNA at linear ends of chromosomes
`` ensure complete replication
`` protect chromasomal ends

DNA replication enzymes in somatic cells stop at end of DNA
`` tf can not repicate final bit of telomere
`` tf telomere gradully lost over multiple replications
`` eventually end of chromosome is exposed and damaged
`` `` signals arrest of cell cycle
`` `` `` tf cell cannot be replaced
IMMORTALITY

WHAT DO YOU NEED TO BE

WHAT DO YOU NEED
Germinal or Stem Cells

Express telomerase RNA-Protein Complex
`` uses own RNA as template for adding nucleotides to end of chromosome
`` tf unlimited life of chromosome
IMMORTAL CANCER CELLS

DO WHAT
Express Telomerase
`` tf telomere elongation important in tumor formation
EVEN IF YOU HAD THE ENERGIZER BUNNIE IN YOUR SOMATIC GENETIC CLOCKS WHAT ELSE WOULD LIMIT CELLULAR LIFE
Accumulation of
`` Metabolic Damage
`` Genetic Damage
CELLULAR LIFE

METABOLIC DAMAGE

WHAT DOES IT

WHAT IS THE EVIDENCE
Free Radical Damage of Oxidative Phosphorylation
`` covalent modifications of
`` `` proteins
`` `` lipids
`` `` nucleic acids

Accumulation of toxic products is implicated in aging because
`` overexpression of Superoxide Dismutase (SOD) and Catalase extends life span
`` increased generation of mitochndrial superoxde anion radical reduces lifespan
`` smaller animals with higher metabolic rates
`` tf more metabolic products
have shorter livespans
CELLULAR LIFE

DNA DAMAGE

WHAT IS THE KEY COMPONENT
DNA repair enzymes fix most DNA damage
`` ie DNA Helicase
`` defects result in rapid accumulation of chromosomal damage
`` similar to cellular aging injuries
PIGMENTS

WHAT ARE THEY

WHERE DO THEY COME FROM
Coloured Substances

Endogenous
`` normal cell constituents
`` `` ie melanin
`` abnormal cell constituents
`` `` accumulate when problems

Exogenous
PIGMENTS

EXOGENOUS
Coal Dust
`` most common
`` ubiquitous urban air pollutant
`` picked up by alveolar macrophages
`` transported to lymphnodes in tracheal bronchal regions
ANTHROCOSIS
Accumulations of coal dust pigment in lungs and lymph nodes
ENDOGENOUS PIGMENTS

NAME 4
Lipofuscin

Melanin

Hemosiderin

Bilirubin
LIPOFUSCIN

WHERE DOES IT COME FROM

WHY DO WE CARE
aka Wear and Tear pigment

Histologically
`` yello brown
`` finely granular
`` intracytoplasmic
`` often perinuclear

Insoluble

Derived via lipid peroxidation of
`` polyunsaturated lipid membranes

Not injurious to cell or functions

Telltale sign of
`` Free Radical injury
`` lipid peroxidation
HEMOSIDERIN
Endogenous Pigment of Intracellar Iron
`` Hemoglobin derived
`` Golden yellow brown
`` granular

Iron
`` normally carried by specific transport proteins
`` `` transferrins
`` stored intracellularly in association with
`` `` apoferritin
`` `` forms ferritin micelles
`` excess iron causes hemodiderin to accumulate in cells
`` `` localized ie hemorrhage
`` `` systemic ie brown lymph nodes
BRUISE
Best example of localized hemossiderosis

Local Hemorrhage
`` are first red - blue
`` erytrocytes lyse
`` macrophages phagocytize red cell debris
`` lysosomal enzymes sequentually converts hemoglobin to
`` `` biliverdin (green)
`` `` blirubin (red)
`` `` hemosiderin (yellow)
HEMOSIDEROSIS
Consequence of systemic iron overload
`` inherited
`` `` ie genetic defect in iron metabolism
`` aquired
`` `` hemolytic anemia
`` `` blood transfusion

Hemosiderin deposited in many organs
`` spleen
`` liver
BILIRUBIN
Normal major pigment of bile

Derived from hemoglobin
`` contains no iron
`` normal formation and excretion vital to health
ICTERUS

WHAT IS IT

4 PLACES TO FIND IT

WHAT ARE THE TYPES AND MECHANISMS
aka Jaundice

Excess of bilirubin within cells and tissues
`` yellow discolouration of white or pale tissues
`` `` aorta
`` `` fat
`` `` sclera
`` `` mucous membranes

Prehepatic
`` hemolytic anemia
`` high amount of bilirubin in circulation
`` hepatic capacity overwhelmed

Hepatic
`` normal level of circulating bilirubin
`` reduced hepatic capacity due to disease

Post Hepatic
`` bilirubin processed machinery in liver normal
`` but bile duct obstruction prevents secretion
`` tf hepatic levels rise
`` tf circulatory levels rise
HEMOGLOBIN
Red erythrocytic pigment
HEMOGLOBINURIA
Presence of hemoglobin in plasma
MYOGLOBIN
Red muscle pigment
MYOGLOBINURIA
Myoglobin in Plasma

Indicates massive damage to muscle
`` capture myopathy
`` exertional rhabdomyolysis
INTRACELLULAR INCLUSIONS

4

NAME EM

DESCRIBE EM
Viral Inclusions
`` important diagnostically
`` Intranuclear
`` `` adenovirus
`` `` herpesvirus
`` `` parvovirus
`` Intracytoplasmic
`` `` rabies virus
`` `` distemper virus
`` `` pox virus

Intracellular Non Viral Pahtogens
`` coccidia
`` Mycobacteria sp

Storage Diseases
`` usually hereditary
`` defects in lysomal enzymes
`` `` tf impaired degradation of macromolecules
`` `` tf accumulation in lysosomes
`` neurons particularly affected
`` manosidosis
`` locoweed toxicity

Prion Diseases
`` Transmisssible Spongiform Encephalopathies TSE
`` characterized by intrneuronal vacuoles
`` BSE
`` Scrapie
`` Chronic Wasting Disease CWD
INTRACELLULAR INCLUSIONS

4

NAME EM

DESCRIBE EM
Viral Inclusions
`` important diagnostically
`` Intranuclear
`` `` adenovirus
`` `` herpesvirus
`` `` parvovirus
`` Intracytoplasmic
`` `` rabies virus
`` `` distemper virus
`` `` pox virus

Intracellular Non Viral Pahtogens
`` coccidia
`` Mycobacteria sp

Storage Diseases
`` usually hereditary
`` defects in lysomal enzymes
`` `` tf impaired degradation of macromolecules
`` `` tf accumulation in lysosomes
`` neurons particularly affected
`` manosidosis
`` locoweed toxicity

Prion Diseases
`` Transmisssible Spongiform Encephalopathies TSE
`` characterized by intrneuronal vacuoles
`` BSE
`` Scrapie
`` Chronic Wasting Disease CWD