Cell Injury, Adaptation and Death

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Cell Injury, Adaptation and Death
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• WHAT CAUSES CELLULAR INJURY?

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Cellular Injury is caused by exposure to

• Hypoxia
• Mechanical force
• Toxic chemicals
• Infections
• Nutrition Imbalance
• Genetic Defect
• Ionizing Radiation

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HYPOXIA

• A lack of sufficient oxygen
• the most common cause of cell injury and death.

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Hypoxia Causes ATP Depletion orPower Failure

• Aerobic metabolism stops ? less ATP is produced
• Na/K ATPase (enzyme) cannot run fast enough
• Cell swells up with water
• Anaerobic metabolism used ? lactic acid produced
• Acid damages cell membranes, intracellular
  structures, and DNA

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Two Boys Suffered Hypoxia

• One was at a normal body temperature
• The other one was very cold
• Which one will have a lower intracellular pH?
• Which one will have more cell swelling?
• Why?

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CAUSES OF HYPOXIA

• ISCHAEMIA
• HYPOXAEMIA
• FAILURE OF THE CYTOCHROMES
• POOR NUTRITION
• INFECTIOUS AGENT
• IMMUNE INJURY
• CHEMICAL AGENTS
• PHYSICAL AGENTS

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• Ischemia ("ischemic hypoxia" "stagnant
  hypoxia") Loss of arterial blood flow
  (literally, "holding back the blood")
• Local causes
• Occlusion of the arteries that bring in fresh
  blood
• Occlusion of the veins which allow blood to
  leave, so that fresh blood can flow in
• Shunting of arterial blood elsewhere ("steal
  syndromes" "Robin Hood" syndromes)
• Systemic causes
• Failure of the heart to pump enough blood

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Hypoxemia Too little available oxygen in the
blood Oxygen problems ("hypoxic hypoxia") Too
little oxygen in the air Failure to properly
ventilate the lungs Failure of the lungs to
properly oxygenate the blood Failure of the
heart to pump enough blood through the lungs
Tremendously increased dead space (i.e.,
pulmonary thromboembolus)
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Hypoxemia

• Hemoglobin problems ("anemic hypoxia")
• Inadequate circulating red cell mass ("anemia")
• Inability of hemoglobin to carry the oxygen
  (carbon monoxide poisoning, methemoglobinemia)
• Methemoglobin cannot bind oxygen
• "High affinity" hemoglobins that will not give up
  their oxygen to the tissues

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• Failure of the cytochromes ("histotoxic hypoxia")
  
• Cyanide poisoning
• Binds to hemoglobin instead of O2
• Dinitrophenol poisoning
• Shuts down the proton gradient in the
  mitochondria no ATP production
• Other curious poisons

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Ionizing Radiation

• Radiation strong enough to dissociate water into
  H and OH-
• The OH- binds to the DNA and prevents cell
  reproduction
• Affects bond marrow, GI tract, white blood cell
  production
• Can cause DNA mutations

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Intracellular Accumulations
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INTRACELLULAR Accumulations

• The retention of material within the cell
• Fat
• Glycogen
• Cholesterol
• Abnormal Proteins e.g Lewy bodies,
  Neurofibrillary tangles (tan protein), Mallory
  bodies
• Lipofuscin, Melanin, Exogenous pigments like
  Tattoos, Iron and other metals

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Normal Liver
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Fatty Liver
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Atherosclerosis
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Mallory bodies (the red globular material)
composed of cytoskeletal filaments in liver cells
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The brown coarsely granular material in
macrophages in this alveolus is hemosiderin
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These renal tubules contain large amounts of
hemosiderin, as demonstrated by the Prussian blue
iron stain
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Types of Cellular Adaptation
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Cellular Adaptation

• Cells adapt to their environment to
• Protect themselves from injury
• An adapted cells is neither normal nor injured
• Somewhere in between
• The most significant adaptive changes include
• Atrophy
• Hypertrophy
• Hyperplasia
• Metaplasia

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ATROPHY

• A decrease or shrinkage in cellular size

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Atrophy

• Entire organ can shrink if enough cells shrink
• Most common in skeletal muscle, heart, secondary
  sex organs, and brain
• Often due to chronic malnutrition self-eating

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Atrophy

• May be due to Physiologic Changes
• Thymus goes through atrophy during childhood
• May be due to Pathologic Changes
• Decrease in workload, use pressure, blood supply,
  hormonal stimulation
• Disuse atrophy of skeletal muscles
• Aging of the brain cells

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Normal Liver Cells
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Here is the centrilobular portion of liver next
to a central vein. The cells have reduced in size
or been lost from hypoxia. The pale brown-yellow
pigment is lipochrome that has accumulated as the
atrophic and dying cells undergo
autophagocytosis.
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Autophagy

• Degradation of intracellular components by
  lysosomes.
• Cellular degradation pathway for the clearance of
  damaged or superfluous proteins and organelles.
• The recycling of these intracellular constituents
  also serves as an alternative energy source
  during periods of metabolic stress to maintain
  homeostasis and viability.

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Atrophy

• May be caused by
• Decreased protein synthesis
• Increased protein catabolism
• Or Both
• Malnutrition atrophy is accompanied by
  self-eating or autophagy
• Autophagic vacuoles
• Rapid increase in hydrolytic enzymes
• Lipofuscin resists autophagy and accumulates in
  cells shows you the cell is old

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Atrophy

• Muscle cells contain less
• RER
• Mitochondria
• Myofilaments
• Actin and Myosin
• Can be caused by nerve damage,
  decreased Oxygen or amino acid
  consumption

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Normal Cardiac Muscle
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Atrophy Cardiac Muscle
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HYPERTROPHY

• Increase in the size of cells, and hence the size
  of the organ.

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Hypertrophy

• May be due to changes in
• Hormonal (physiological) demand
• Increased functional demand
• May be due to increases in
• RER
• Protein synthesis
• Mitochondria and
• NOT cellular fluid

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Hypertrophy

• During pregnancy hormone induced hypertrophy
• Muscular enlargement heart and skeletal
• Cant increase by mitotic division or production
  of new cells
• Advanced hypertrophy can lead to myocardial
  failure

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Hypertrophy of the muscles of an athlete
                                                  
    
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Cardiac Muscle

• Myocardial hypertrophy
• Caused by dilation of the cardiac chambers
• Is short-lived
• Followed by increased synthesis of cardiac muscle
  proteins
• Advanced hypertrophy can lead to myocardial
  failure

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Cardiac Muscle Cells
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Hypertrophy of cardiac muscles
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Cardiomegaly
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Hypertrophy of the Uterus
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HYPERPLASIA

• An increase in the number of cells in a tissue or
  organ. It occurs in tissues with cells that are
  capable of mitotic division
• As opposed to an increase in the size of each
  cell

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Hyperplasia

• A response to cellular injury that is severe and
  prolonged
• Production of growth factors
• Hypertrophy and hyperplasia often occur together.
• In non-dividing cells (myocardial fibers) only
  hypertrophy occurs

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Compensatory Hyperplasia

• Adaptive mechanism that enables organs to
  regenerate
• Remove 70 of the liver and it will regenerate in
  about 2 weeks.
• Hepatocyte Growth Factor (HGF), Transforming
  growth factor (TGF-a), tumor necrosis factor-a
  (TNF-a)
• A callus is an example of hyperplasia
• Nerve, skeletal muscle, myocardial cells and lens
  cells of the eye do not regenerate and do not go
  through hyperplasia

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Hormonal Hyperplasia

• Occurs chiefly in Estrogen-dependent organs
• Uterus and breast
• Estrogen stimulates endometrial growth

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Pathologic Hyperplasia

• The abnormal proliferation of normal cells
• Can occur as a response to excessive hormonal
  stimulation or effects of growth factors
• Cells have pronounced nuclear enlargement,
  clumping of chromatin and one or more enlarge
  nucleoli
• An example is excessive endometrial growth

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Dysplasia

• A premalignant change of cells
• An expansion of immature cells, with a
  corresponding decrease in the number and location
  of mature cells.
• Abnormal changes in the size, shape and
  organization of mature cells

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Dysplasia

• Frequently encountered in epithelial tissue of
  the cervix and respiratory tract
• Often found adjacent to cancerous cells
• The term dysplasia does NOT indicate cancer and
  may NOT progress to cancer

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Dysplasia

• Classified as
• Mild
• Moderate
• Severe
• Can be a strong predictor of breast cancer
  development

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Squamous Cell Dysplasia
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Dysplasia of the Cervix
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METAPLASIA

• A reversible change in which one cell type is
  replaced by another cell type.
  
• Conversion of a differentiated cell type into
  another.
• An example is replacement of normal columnar
  ciliated cells of the bronchial lining by
  stratified squamous cells that do not secrete
  mucous or have cilia
• Usually induced by cigarette smoking
• Can be reversed????

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Metaplasia
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Definitions

• Hyperplasia - ? Number of cells
• Prostate
• Endometrium
• Breast ducts
• Hypertrophy - ? SIZE of cells
• Myocardium
• Muscle fibres
• Dysplasia Abnormal Development, size, shape,
  arrangement
• Cervical
• Fibrous
• tumour, metastasis, carcinogen
• Metaplasia Change of cell TYPE
• Cervical where glandular ? squamous epithelium
• Bronchioles where glandular ? squamous epithelium

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REVERSIBLE CELL INJURY

• It occurs when environmental changes exceed the
  capacity of the cell to maintain normal
  hemostasis. If the stress is removed in tissue or
  if the cell withstand the assult the injury is
  reversible

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IRREVERSIBLE CELL INJURY

• If the stress remains the severe, the cell injury
  becomes irreversible and lead to cell death

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CELLULAR INJURY

• Reversible injury
• Injured cell may recover
• Irreversible injury
• Cell will die

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Reversible vs irreversible injury(or death)

• Karyolysis- the dissolution of the nucleus - the
  nucleus swells and gradually loses its
  chromatin.
• Pyknosis - Shrunken nucleus with condensed
  chromatin.
• Karyorrhexis - rupture of the cell nucleus in
  which the chromatin disintegrates into formless
  granules that are extruded from the cell.
• Coagulative necrosis
• Liquefactive necrosis
• Caseous necrosis
• Fat Necrosis

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Cellular Death
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Cellular Death

• Pre-programmed cellular death apoptosis or cell
  suicide
• Removes cells that are being replaced or have
  worn out
• Removes unwanted tissue
• Normal process in the body
• Necrotic cell death
• Unregulated death caused by injuries to cells
• Cells swell and rupture
• Inflammation results

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Apoptosis or Pre-programmed Cellular Death

• Damaged or worn-out cells commit suicide
• Turn on their own enzymes inside the cell,
  especially caspases
• Digest their own cell proteins and DNA
• Are then destroyed by white blood cells

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Apoptosis Can Be Caused By

• Signaling factor attached to death domains of
  cell surface receptors
• Mitochondrial damage inside the cell
• Protein p53 activated by DNA damage
• A tumor suppressor protein

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1 2 3
Apoptosis
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Necrosis

• Cell death and degradation
• Cells may undergo
• Liquefaction
• Coagulation
• Infarction
• Caseous necrosis
• Cell contents often released
• Inflammation often results

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NECROSIS

• Refers to cell death in an organ or tissue that
  is still part of a living person

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Necrosis with inflammatory cells
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Many nuclei have become pyknotic (shrunken and
dark) and have then undergone karorrhexis
(fragmentation) and karyolysis (dissolution). The
cytoplasm and cell borders are not recognizable.
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• Autolysis is the dead cell being self-digested by
  its lysosomal enzymes, while Heterolysis is the
  cell being digested by the body's living white
  cells.

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Necrosis
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TYPES OF NECROSIS

• COAGULATION NECROSIS
• LIQUEFACTIVE NECROSIS
• ENZYMATIC FAT NECROSIS
• CASEOUS NECROSIS

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COAGULATION NECROSIS

• Death of groups of cells (most often from loss of
  blood supply), with persistence of their shapes
  for at least a few days.
• Most common type
• Gel-like change in freshly dead cells

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• Grossly, the dead area is likely to be soft and
  pale. After a while, it is likely to shrink
  (catabolism) and turn yellow (its lipids are
  freed up to form little micelles, trapping the
  tryptophan metabolites that impart the yellow
  color to normal body fat).

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• The microscopy is distinctive. After loss of
  their nuclei, the cytoplasm of the cells remains
  intact for days. The "tombstones" reveal the
  structure of the living tissue. If the patient
  lives, the edges of the necrotic area become
  inflamed, and eventually the dead cells will be
  removed by white cells and their noxious
  proteases.
• RULE Unless otherwise specified in this section,
  the death of a group of cells will result in
  coagulation necrosis

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Coagulative Necrosis
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Kidney Coagulative necrosis
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LIQUEFACTIVE NECROSIS

• Cell death in which the dead tissue dissolved
  into fluid
• The result of hydrolysis.
• When the cells die, they are rapidly destroyed by
  lysosomal enzymes, either their own or those from
  neutrophilic leukocytes (i.e., bacterial
  infections), or clostridia or snake poison.
• Acid and lye burns represent the extreme of
  liquefaction.

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The two lung abscesses seen here are examples of
liquefactive necrosis in which there is a liquid
center in an area of tissue injury. One abscess
appears in the upper lobe and one in the lower
lobe. Liquefactive necrosis is typical of organs
in which the tissues have a lot of lipid (such as
brain) or when there is an abscess with lots of
acute inflammatory cells whose release of
proteolytic enzymes destroys the surrounding
tissues.
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Lung Abscess Microscopic appearance
(Liquefactive Necrosis)
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ENZYMATIC FAT NECROSIS

• Specialized necrosis of fatty tissue
• Usually found in retroperitoneal fat around the
  pancrease in cases of pancreatitis

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ENZYMATIC FAT NECROSIS

• When pancreatic enzymes are released into the
  body's tissues, they digest them wholesale.
• Lipase releases free fatty acids (saponification)
  from the local lipids (membranes, depot
  triglyceride).
• This complexes with calcium ions to form salts
  (calcium stearate, etc.)

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ENZYMATIC FAT NECROSIS
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CASEOUS NECROSIS

• A special type of necrosis caused by tuberculosis
  infection
• ("cheese" and "casein") All of the cells in an
  area die, the tissue architecture is obliterated,
  and they turn into a crumbly ("friable"),
  readily-aerosolized powder

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• This is characteristic of a poorly-understood
  subtype of immune injury, and generally it is
  seen in certain granulomatous diseases, notably
  tuberculosis and certain fungal infections
  (coccidioidomycosis, blastomycosis, and
  histoplasmosis)

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Caseous necrosis with granulomatous inflammation
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Caseous necrosis with Giant cells
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Gangrene

• Gangrene is defined as the gradual destruction of
  living tissue
• Due to an obstruction in the supply of blood and
  oxygen to an area of the body

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GANGRENE

• Is not a separate kind of necrosis at all, but a
  term for necrosis that is advanced and visible
  grossly.
• The word gangrene comes from the Latin word
  gangraena, an eating sore.
• Gangrene is death and decay of a body part

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Gangrene

• A large area of necrotic tissue
• Dry gangrene lack of arterial blood supply but
  venous flow can carry fluid out of tissue
• Tissue tends to coagulate
• Wet gangrene lack of venous flow lets fluid
  accumulate in tissue
• Tissue tends to liquefy and infection is likely
• Gas gangrene Clostridium infection produces
  toxins and H2S bubbles

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TYPES OF GANGRENE

• DRY GANGRENE
• WET GANGRENE
• GAS GANGRENE

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DRY GANGRENE

• If there's mostly coagulation necrosis
• The typical blackening, desiccating foot which
  dried up before the bacteria could overgrow

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• Dry gangrene
• This variety is free of infection.
• It is usually brought on by a blood clot,
  frostbite, or poor circulation that causes the
  tissues to become dry and shriveled

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Dry Gangrene
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WET GANGRENE

• If there's mostly liquefactive necrosis
• (i.e., the typical foul-smelling, oozing foot
  infected with several different kinds of
  bacteria) OR
• If it's in a wet body cavity

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"wet gangrene in patient with Diabetes mellitus

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CLOSTRIDIAL GANGRENE

• (including "gas gangrene)
• A dread complication of dirty, blood-deprived
  wounds.
• The clostridia digest tissue enzymatically and
  rapidly, often transforming it into a bubbly
  soup.

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FOURNIER'S GANGRENE

•  Fournier's gangrene
• Bacterial gangrene of the scrotum
• the dreaded "black sack disease

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• THE END

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FREE RADICALS

• A common "final pathway" in a variety of forms of
  cell injury, including injury brought about by
  inflammatory cells, is generation of free
  radicals, i.e., molecular species with a single
  unpaired electron available in an outer orbital.
  Single free radicals initiate chain reactions
  which destroy large numbers of organic molecules

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FREE-RADICAL GENERATION

• 1. Oxidation of unsaturated fatty acids in
  membranes ("lipid peroxidation", etc.)  Basic
  biologists These are the same reactions that
  make unsaturated fats turn rancid.
• 2. Cross-linking of sulfhydryl groups of
  proteins.
• 3. Genetic mutations

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• Free radicals may be generated in the following
  ways
• 1. By absorbing radiant energy (UV, x-rays
  striking water, these generate a hydrogen atom
  and a hydroxyl radical when hydrogen peroxide
  contacts ferrous iron, it is cleaved into two
  hydroxyl radicals ( the Fenton reaction).
• 2. As part of normal metabolism (for example,
  xanthine oxidase and the P450 systems generate
  superoxide our white cells use free radicals to
  attack and kill invaders)
• 3. As part of the metabolism of drugs and poisons
  (the most famous being CCl3.-, from carbon
  tetrachloride even O2 in high concentrations
  generates enough free radicals to gravely injure
  the lungs).

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• The most important free radicals are probably
  those derived from oxygen, i.e., superoxide (O-2)
  and hydroxyl radical (OH.) hydrogen peroxide,
  though not a free radical, is two hydroxyl
  radicals joined.

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The differences between apoptosis and necrosis

1. Apoptosis may be physiological
2. Apoptosis is an active energy dependent process
3. Not associated with inflammation

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PATHOLOGY

• is the scientific study of disease or is the
  study of structural and functional abnormalities
  that are expressed as diseases of organ and system

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PATHOPHYSIOLOGY

• Literally means how physiology is altered by
  disease

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PATHOGENESIS

• of a disease is the sequence of events at the
  organ, cellular, ultrastructural, and molecular
  levels, by which the disease develops

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PERSPECTIVE PATHOLOGY

• is the study of cell injury and the expression of
  a preexisting capacity to adapt to such injury on
  the part of the either injured or intact cell

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Morphology of cell injury

• Swelling (via increased water content)
• Fatty change (steatosis, TG)
• Necrosis (dead cells)
• Intracellular deposits (lipid, CHO, protein)
• Loss of cellular fine structure (microvilli)
• Karyolysis (DNA degradation)
• Pyknosis (nuclear shrinkage)
• Karyorrhexis (nuclear fragmentation)

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GUMMATOUS NECROSIS

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• is, for our purposes, coagulation necrosis seen
  in granulomas in syphilis.

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FIBRINOID NECROSIS

• Is a time-honored term for damage to of the walls
  of arteries which allows plasma proteins to seep
  into, and precipitate in, the media (some
  pathologists call this "insudation").

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NECROBIOSIS

•  Is a curious term for necrosis of fibroblasts
  within still-intact dense fibrous tissue. It's
  characteristic of two lesions -- necrobiosis
  lipoidica and granuloma annulare

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CAVITATION

• Results from removal of necrotic material (i.e.,
  draining a huge abscess, coughing up caseous
  debris in tuberculosis, physiologic removal of
  debris in a cerebral infarct, etc.)

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PATHOLOGICAL CALCIFICATION

• Deposition of mineral salts of calcium in
  tissues other than osteoid or enamel

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• Dystrophic calcification refers to the
  macroscopic deposition of calcium salts in in
  dead or degenerate tissues
• Metastatic calcification reflects deranged
  calcium metabolism in contrast to dystrophic
  calcification and is associated with increase
  serum calcium level

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This is dystrophic calcification in the wall of
the stomach. At the far left is an artery with
calcification in its wall
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Metastatic calcification" in the lung of a
patient with a very high serum calcium level
(hypercalcemia).
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HYALINE

• Is a term that refers to any material that
  exhibits a reddish, homogenous appearance when
  stain with HE. It stand for describing diverse
  and unrelated lesions.