VTPA 342 Cell and Tissue Injury
Terms
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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
-
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 - 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 - 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