Cellular Adaptations to disease / cell & Death II

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Cellular Adaptations to disease / cell Death II
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• Reaction of Cells to injury
• - Reversible injury ( Degeneration)
• - Cell functions impaired but cell can
  recover
• - Irreversible injury
• - Cessation of all cell functions with
  cellular death
• - Necrosis
• - Sum of the degradative
  inflammatory
• reactions occuring after tissue
  death.
• - Apoptosis
• - programmed cell death

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• Causes of cell injury ( injurious stimuli)
• 1- Hypoxia
• - lack of oxygen to tissues ( i.e. infarct)
  
• 2- Genetic
• - Enzyme deficiency
• - Abnormality ( e.g. diabetes mellitus)
• 3- Nutritional
• - Effects on cells growth
• 4- Physical
• - Trauma - Cold - Heat
  - Electrical
• 5- Chemical
• - Therapeutic ( e.g. aspirin)
• - Non-therapeutic ( e.g ethanol abuse)
• 6- Biological
• - Infectious agents Bacteria
  viruses , fungi
• 7- Immunological - Hyposensitivity or
  Hypersensitivity
• 8- Aging - Life span of cells -
  Environment

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• Targets of injurious stimuli
• 1- Aerobic respiration
• - Loss of ATP
• - Sodium pump failure water enters
  cell . Cell swells
• 2- Membranes
• - Defect in permeability . Water enters
  cells cell
• swells even death
• 3- Synthetic mechanisms
• - Enzymatic structural proteins are
  not synthesized
• .. Cell swells
• 4-Genetic apparatus
• - DNA RNA changes
• - Inherited or acquired
• - If enzymes deficient . Substrate
  accumulates
• cell swells

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• Changes of injury
• 1 - Congestion
• - increase of blood flow within vessels
  
• - Vessels are dilated packed with
  RBCs
• 2 - Edema
• - Increase in interstitial fluid with
  widened space between
• interstitial components
• - Causes swelling except in bone
• 3 - Hemorrhage
• - Accumulation of blood outside of
  vessels
• - Extravasation of RBCs into the
  tissues or external surfaces.
• 4 - Thrombosis
• - Clot within a blood vessel formed
  during life
• 5 - Embolus
• - Detached intravascular solid ,
  liquid or gaseous mass that is carried in
• the blood to a site distant from it
  is point of origin.
• Ex. Fat , bubble of air or N2 ,
  atherosclerosis plaque , tumour , bone
• marrow , foreign bodies

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• Changes of injury
• - Cellular infiltration - influx of
  cells usually from inflammation
• 
  - Neutrophils , macrophages , lymphocytes ,
• 
  plasma cells , fibroblasts , angioblast.
• - Fibrosis - Presence of
  collagenous tissue
• - Fibroblasts
  , fibrocytes , collagen ground substance.
• - Substance accumulation
• - Deposition of substances in cells or
  interstitium
• - Ex. lipid accumulation within cells
  as in Gaucher,s disease
  
• - Ex. Amyloid
• Fibrillary protein produced
  abnormally due to longstanding
• inflammation or immune
  dysfunction.
• Accumulates in the interstitium
  between cells ultimately kills
• the cells causing major
  damage to organ

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Fibrosis Keloid
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• Hypoxic Cell Injury
• Results from cellular anoxia or hypoxia due to
  
• 1- Ischemic
• Obstruction of arterial blood flow ,
  most
• common cause
• 2- Anemia
• Reduction in number of oxygen
  carrying
• red blood cells.
• 3- Carbon monoxide poisoning
• Diminution in the oxygen carrying
  capacity RBCs by
• chemical alteration of hemoglobin.
• 4- Decreased perfusion of tissues by oxygen
  carrying blood
• Cardiac failure hypertension
  shock
• 5- Poor oxygenation of blood secondary to
  pulmonary disease.

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• Hypoxic Cell Injury
• Early stage
• - Affect mitochondria
  Decreased oxidative phosphorylation ATP
• synthesis
• - Decreased ATP availability
  consequences
• Failure of the cell
  membrane pump
• 1 - Increased
  intercellular Na H2o decreased intracellular
  K
• 
  cellular swelling swelling of organelles
• 2 - Cellular
  swelling ( hydropic change) has large vacuoles in
  the
• cytoplasm
• 3 - Swelling of the
  ER ( early reversible EM change)
• 4 - Swelling of the
  mitochondria
• -
  Progresses from reversible to irreversible with
  marked
• 
  dilatation of the inner mitochondrial space.

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• Hypoxic Cell Injury
• - Early Stage
• Disaggregation of ribosomes failure of
  protein
• synthesis
• - Ribosomal disaggregation is
  also promoted by
• membrane damage
• Stimulation of phospholipids activity
• - Results in increased glycolysis
• - Accumulation of lactate
• - Decreased intracellular PH
• - Acidification causes reversible
  clumping of nuclear
• chromatin

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• Hypoxic Cell Injury
• - Late stage
• - membrane damage to plasma to lysosomal
  other
• organelle membranes , with loss of membrane
  
• phospholipides
• - Reversible ( or irreversible ) morphologic
  signs of damage
• including formation of
• Myelin figures - Whorl like
  structures probably
• 
  originating from damaged membrane
• Cell blebs - Cell surface deformity
  most likely
• caused by
  disorderly function of
• the cellular
  cytoskeleton

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• Cell death caused by severe or prolonged
  injury
• - Point of no return is marked by
  irreversible damage to
• cell membranes .. Massive calcium
  influx , extensive
• calcifications of the mitochondria ,
  cell death.
• - Intracellular enzymes various other
  proteins are
• released from necrotic cells into the
  circulation as a
• consequence of the loss of integrity
  of cell membranes .
• The basis of a number of useful
  laboratory
• determinations as indicators
  of necrosis ..

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• Myocardial enzymes in serum
• - Enzymes useful in the diagnosis of
  myocardial infarction
• - Aspartate aminotransferase ( AST aka
  SGOT)
• - Lactate dehydrogenase ( LDH)
• - Creatinine kinase ( CK aka CPK)
• - Troponins
• - Myoglobin
• Liver enzymes in serum
• - Transaminases
• - AST
• - Alanine aminotransferase ( ALT)
• - Alklaline phosphatase
• - Gamma glutamyltransferase (
  GGT)

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• Vulnerability of cells to hypoxic injury varies
  with the tissue or cell type
• - Irreversibilty occurs after
• - 3-5 minutes for neurons
• - 1-2 hours for myocardial cells
• hepatocytes
• - Many hours for skeletal muscle
  cells

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• Free Radical injury
• Free radicales ( reactive oxygen metabolites)
• - Molecules with a single unpaired electron
  in the outer orbital
• - Exemplified by activated products of oxygen
  reduction which includes
• - superoxide ( O2-)
• - Hydroxyl radicales ( OH- , H2O2 )

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• Generation of free radicals
• - Normal metabolism
• - Oxygen toxicity
• - Ex. alveolar damage in adult
  respiratory distress
• syndrome
• - Ionizing radiation
• - Ultraviolet light
• - Drugs chemicals
• - Many promot proliferation of SER
  induction the p-450
• system of mixed function of
  oxidases of the SER
• - Ex. proliferation
  hypertrophy of the SER of the
• hepatocytes in barbiturate
  intoxication
• - Reperfusion after ischemic injury

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The role of reactive oxygen species in cell
injury. O2 is converted to superoxide (O2-) by
oxidative enzymes in the endoplasmic reticulum
(ER), mitochondria, plasma membrane, peroxisomes,
and cytosol. O2- is converted to H2O2 by
dismutation and thence to OH by the
Cu2/Fe2-catalyzed Fenton reaction. H2O2 is also
derived directly from oxidases in peroxisomes.
Not shown is another potentially injurious
radical, singlet oxygen. Resultant free radical
damage to lipid (peroxidation), proteins, and DNA
leads to various forms of cell injury. Note that
superoxide catalyzes the reduction of Fe3 to
Fe2, thus enhancing OH generation by the Fenton
reaction. The major antioxidant enzymes are
superoxide dismutase (SOD), catalase, and
glutathione peroxidase. GSH, reduced glutathione
GSSG, oxidized glutathione NADPH, reduced form
of nicotinamide adenine dinucleotide phosphate.
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• Chemical cell injury
• - Model liver cell membrane damage induced by
• carbon tetrachloride ( CCl4)
• - CCL4 processed by P-450 system of mixed
  function oxidases within SER .. CCl3 (
  highly reactive free radical) .
  Diffuses throughout the cell .. Lipid
  peroxidation of intracellular membrane.
• -Disaggregation of ribosomes .. Decreased
  protein synthesis
• - Plasma membrane damage .. Cellular
  swelling massive influx of calcium .
  Mitochondrial damage , denaturation of cell
  proteins , cell death.

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• Apoptosis
• Programmed physiological cell death that
  removes unwanted cells
• - Cell deletion without rupture of the cell
  that otherwise would elicit the inflammatory
  process ( aka necrosis
• gt Helps to maintain homestasis growth in
  tissue
• - Distinguished from necrosis
• gt Greek term meaning falling away from
• - Involutional process similar to
  physiologic loss of leaves
• from a tree
• gt Has subtle cellular damage
• - With enzymes causes nuclear
  codensation
• fragmentation

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• gt important mechanism for the removal of cells
  with irreparable
• - Free radicals , viruses , cytotoxic
  immune
• mechanism
• - If falls then can lead tom cancers ,
  viral
• infections autoimmune diseases.
• gt Plays a role in wound healing
• gt Also important mechanism for physiologic cell
  removal during embryogenesis in programmed cell
  cycling ( e.g. endometrial cells during
  menstruation )

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• Morphologic characteristics
• - Tendency to involve single isolated cells or
  small clusters of cell s within a tissue.
• - Progression through a series of changes marked
  by lack of inflammatory response
• gt Blebbing of plasma membrane ,
  cytoplasmic shrinkage increased pink
• staining , chromatin condensation
  fragmentation.
• gt Budding of cell separation of
  membrane bound apoptotic bodies.
• gt Phagocytosis of apoptotic bodies by
  neighboring macrophages
• adjacent normal cells.
• - Involution shrinkage of affected cells
  cell fragments .. Small , round eosinophilic
  masses with chromatin remnants
• gt e.g. Councilman bodies of
  viral hepatitis

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• Biochemical events - active , gene expression
  , protein synthesis , energy consumption
• - Initiated by diverse injurious stimuli (
  free radicals , radiation , toxic substances ,
  withdrawal of growth factors or hormones)
• - Signaling by molecules ( e.g. FAS ligand
  , tumour necrosis
• factor ) associated protein
• - Release of cytochrome c AIF (
  apoptosis inducing factor) from mitochondria .
  Caspase activation ( cytosolic cytotoxic
  proteases major executioners)
• gt Aspartate speciific cysteine
  proteases.
• gt Analogues of interleukin -1beta
  converting enzyme

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• - Degradation of DNA by endonucleases ..
  Nucleosomal chromatin fragments ( 180-200 base
  pairs) laddering appearance of DNA on
  electrophoresis
• - Activation of transglutaminases ( cross-
  link apoptotic cytoplasmic proteins)
• - No inflammatory reaction

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• Apoptosis
• - Regulation
• Mediated by a number of genes their products
• gt bcl-2 , gene product inhibits apoptosis
• gt bax , gene product facilitates
  apoptosis
• gt p53 , gene product facilitates
  apoptosis
• by decreasing transcription of bcl-s
• increasing transcription of bax.
  

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The intrinsic (mitochondrial) pathway of
apoptosis. Death agonists cause changes in the
inner mitochondrial membrane, resulting in the
mitochondrial permeability transition (MPT) and
release of cytochrome c and other pro-apoptotic
proteins into the cytosol, which activate caspases
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• Necrosis
• - One of the two morphologic patterns of cell
  death ( the other is apoptosis) - Gross
  irreversible cellular injury
• - Sum of the degradative inflammatory reactions
  occuring after tissue death caused by injury
• -e.g. hypoxia , exposure to toxic
  chemicals
• - Passive process since does not require gene
  involvement or new protein synthesis
• - Triggers or elicits a marked inflammatory
  response
• - Liberation of lysosomal enzymes ,
  digestion of cell membranes , disruption of cells
  influx of macrophages due to release of
  chemotactic factors.
• - Removal of debris by phagocytic
  macrophages.

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• Necrosis
• general cellular characteristics
• - Change appears after the cells die.
• - Occurs within living organisms many
  contiguous cells , fixed cells of pathologic
  specimens are dead but not necrotic
• - DNA fragmentation is haphazard with smudge
  pattern on electrophoresis
• gt Autolysis
• - Degradative reactions in cells
  caused by intracellular
• enzymes indigenous to the cells.
• - Postmortem autolysis occurs after
  death of the entire
• organism ? necrosis

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• gt Heterolysis Cellular degradation by enzymes
  derived from sources extrinsic to the cell ( e.g.
  , bacteria , leukocytes) increased pink
  cytoplasm.
• - Nuclear changes
• - Morphological recognizable light
  microscope nuclear
• changes . Progressive nuclear
  condensation with
• eventual disappearance of stainble
  nuclei.
• - Pyknosis the shrinkage of the
  nucleus into a small
• deeply basophilic or black
  clumps of chromatin.
• - Karyorrhexis a fragmentation
  of the nucleus into
• multiple small black dots or
  pieces.
• - Karyolysis the fading of the
  nucleus less less
• basophilic until it disappears.

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Shrinkage (pyknosis), increased nuclear
basophilic staining (hyperchromasia), nuclear
fragmentation (karyorrhexis, karryolysis), are
classic features of apoptosis.
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• - Cytoplasmic changes
• - Increased pink cytoplasm eosinophilic
  ,
• glassy , less RNA
• - Generalized swelling of organelles ,
  e.g.
• endoplasmic reticulum mitochondria
• - Disruption of ribosomes
• - Autophagy ( lysis of the cell,s own
• contents)
• - Phagocytosis of deteriorating
  organelles by
• lysosomes.

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• - Seven types of necrosis
• 1- Coagulative
• 2- Liquefactive
• 3- Caseous
• 4- Gangrenous
• 5- Fibrinous
• 6- Gummatous
• 7- Fat

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• 1- Coagulative necrosis
• - Most common type
• - Cause is most often from sudden loss of
• blood supply to an organ ( ischemia)
• - Heart kidney
• gt End arteries with limited
  collateral
• circulation
• - Adrenal glands
• - Results in denaturation of proteins
• - Early stages
• - Preservation of tissues
  architecture

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• - Histology
• - General architecture well preserved
• - Progressive nuclear condensation
• with eventual disappearance of
• stainble nuclei
• - Increased pink cytoplasm
• ( eosinophilic , glassy) with
  ghost
• like structures.

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• Cardiac muscle
• - Hypertrophy
• - Normal
• - Ischemia
• - Infarction / necrosis

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• 2- Liquefactive necrosis
• - Characterized by digestion of tissue
• - Gross liquid
• - Histology softening liquefaction of
  tissue
• - Usually ischemic injury to the CNS ..
  Death of CNS
• cells followed by autolysis
• - Usually bacterial infection origin , Ex.
  Commonly seen in
• brain
• - Also in suppurative infections ( pus
  formation)
• - Liquefied tissue debris intense
  inflammatory
• response of neutrophils abscess
• - Heterolytic mechanisms with
  neutrophilic enzymes
• . Digest leukocytes tissue
  structure

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Oedema due to acute apical periodontitis. An
acute periapical infection of a canine has
perforated the buccal plate of bone causing
oedema of the face this quickly subsided when
the infection was treated.
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Liquifactive Necrosis Periapical Abscess
Acute chronic apical periodontitis. In this
early acute lesion inflammatory cells, mainly
neutrophil polymorphonuclear leukocytes, are seen
clustered around the apex of a non-vital tooth.
The inflammatory cells are spreading around and
into bone and there has not yet been time for
significant bone resorption to develop.
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• 3- Caseous necrosis
• - Gross cheese like ( caseous)
  consistancy
• - Histology
• - Architecture not preserved
• - Amorphous pink , granular appearance
• - Few nuclei but no ghost like
  appearance
• - Combines features of coagulative
  liquefactive necrosis
• - Occurs as part of granulomatous
  inflammation
• - Manifestation of partial
  immunity caused by the
• interction of T lymphocytes (
  CD4 , CD8 ) ,
• macrophages , cytokines
• - Most often seen in tuberculosis

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Caseous means cheese-like this is a GROSS
observation, not a microscopic one. Cheese has
less texture than meat, and is flaky. Many people
from Wisconsin have been called caseous, i.e.,
cheeseheads.
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• 4- Gangrenous necrosis
• - Extensive
• - Most often due to interruption of blood
  supply to lower extremities or bowel ( secondary
  to vascular occlusion)
• - Most often associated with bacterial
  infections
• gt Wet gangrene
• - Complicated by heterolysis
  consequent
• liquefactive necrosis .
• gt Dry gangrene
• - Coagulative necrosis without
  liquefaction

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• 5- Fibrinoid necrosis
• - Often associated with immune-mediated
  vasculitis
• - C.T. muscle replaced by homogenous pink
• material resembling fibrin Ex. Deposition
  of
• fibrin like material in the arterial
  walls
• - Histology
• - Smudgy pink appearance in vascular
  walls
• - Necrosis may or may not be present

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• 6- Gummatous necrosis
• - Seen in granulomatous inflammation
• such as tertiary syphilis
• - Gross , rubbery
• - Histology
• - No architecture
• - Pink with few nuclei

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• 7- Fat necrosis
• gt Traumatic - Following severe injury to
  tissue with high fat content ( e.g. breast)
• gt Enzymatic type
• - Pancreas ( complication of acute
  haemorrhagic
• pancreatitis
• - Proteolytic lipolytic enzymes diffuse
  into the
• inflammed tissue of the pancraetic
  parenchyma .
• - Can attract calcium . Fatty acids
  form calcium salts
• (saponification soap formation)
• -Histology - Necrotic fat cells , acute
  inflammation , hemorrhage , calcium soap
  formation , lipid-laden macrophages ( enzymatic
  type) .

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• - Aging
• gt Associated with degeneration loss of
  function of many cellular systems
• - Cumulative environmental exposure to
  a causative agent .. Many important
  diseases OR process of biological aging itself

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• - Cellular aging
• - Reduced mitochondrial oxygen
  utilization
• - Less synthesis of RNA DNA
• - Less capability for repair
• - Accumulation of lipofuscin
• - Changes to nuclear organelle
• morphology
• - Concept of a cellular lifespan

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• Theories of Aging
• - Programmed aging Limited number of cell
  divisions or
• neuroendocrine stimuli from brain or
  endocrine glands stop
• at certain age.
• - Inefficient DNA repair over time
  proportion of cells carrying abnormal DNA
  increases tissue function impaired nuclear
  mitochondrial DNA
• - Free radical damage Decreased scavening
  systems
• - Failure of protein catabolism
  Inefficiency
• - Summation of cumulative damage sustained
  throughout life to any systems e.g. DNA damage ,
  protein modification , free radical damage , or
  disease