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Cell Injury, Adaptation and Death

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Title: Cell Injury, Adaptation and Death


1
Cell Injury, Adaptation and Death
2
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3
  • WHAT CAUSES CELLULAR INJURY?

4
Cellular Injury is caused by exposure to
  • Hypoxia
  • Mechanical force
  • Toxic chemicals
  • Infections
  • Nutrition Imbalance
  • Genetic Defect
  • Ionizing Radiation

5
HYPOXIA
  • A lack of sufficient oxygen
  • the most common cause of cell injury and death.

6
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

7
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?

8
CAUSES OF HYPOXIA
  • ISCHAEMIA
  • HYPOXAEMIA
  • FAILURE OF THE CYTOCHROMES
  • POOR NUTRITION
  • INFECTIOUS AGENT
  • IMMUNE INJURY
  • CHEMICAL AGENTS
  • PHYSICAL AGENTS

9
  • 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

10
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)
11
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

12
  • 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

13
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

14
Intracellular Accumulations
15
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

16
Normal Liver
17
Fatty Liver
18
Atherosclerosis
19
Mallory bodies (the red globular material)
composed of cytoskeletal filaments in liver cells
20
The brown coarsely granular material in
macrophages in this alveolus is hemosiderin
21
These renal tubules contain large amounts of
hemosiderin, as demonstrated by the Prussian blue
iron stain
22
Types of Cellular Adaptation
23
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

24
ATROPHY
  • A decrease or shrinkage in cellular size

25
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

28
Normal Liver Cells
29
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.
30
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.

31
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

32
Atrophy
  • Muscle cells contain less
  • RER
  • Mitochondria
  • Myofilaments
  • Actin and Myosin
  • Can be caused by nerve damage,
    decreased Oxygen or amino acid
    consumption

33
Normal Cardiac Muscle
34
Atrophy Cardiac Muscle
35
HYPERTROPHY
  • Increase in the size of cells, and hence the size
    of the organ.

36
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

39
Hypertrophy of the muscles of an athlete
                                                  
    
40
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

41
Cardiac Muscle Cells
42
Hypertrophy of cardiac muscles
43
Cardiomegaly
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Hypertrophy of the Uterus
46
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

47
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

48
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

49
Hormonal Hyperplasia
  • Occurs chiefly in Estrogen-dependent organs
  • Uterus and breast
  • Estrogen stimulates endometrial growth

50
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

51
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54
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

55
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

56
Dysplasia
  • Classified as
  • Mild
  • Moderate
  • Severe
  • Can be a strong predictor of breast cancer
    development

57
Squamous Cell Dysplasia
58
Dysplasia of the Cervix
59
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????

60
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61
Metaplasia
62
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

63
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

64
IRREVERSIBLE CELL INJURY
  • If the stress remains the severe, the cell injury
    becomes irreversible and lead to cell death

65
CELLULAR INJURY
  • Reversible injury
  • Injured cell may recover
  • Irreversible injury
  • Cell will die

66
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
69
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

70
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

71
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

72
1 2 3
Apoptosis
73
Necrosis
  • Cell death and degradation
  • Cells may undergo
  • Liquefaction
  • Coagulation
  • Infarction
  • Caseous necrosis
  • Cell contents often released
  • Inflammation often results

74
NECROSIS
  • Refers to cell death in an organ or tissue that
    is still part of a living person

75
Necrosis with inflammatory cells
76
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.
77
  • 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.

78
Necrosis
1 2
79
TYPES OF NECROSIS
  • COAGULATION NECROSIS
  • LIQUEFACTIVE NECROSIS
  • ENZYMATIC FAT NECROSIS
  • CASEOUS NECROSIS

80
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

81
  • 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).

82
  • 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

83
Coagulative Necrosis
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Kidney Coagulative necrosis
86
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.

87
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.
88
Lung Abscess Microscopic appearance
(Liquefactive Necrosis)
89
ENZYMATIC FAT NECROSIS
  • Specialized necrosis of fatty tissue
  • Usually found in retroperitoneal fat around the
    pancrease in cases of pancreatitis

90
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.)

91
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

94
  • 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)

95
Caseous necrosis with granulomatous inflammation
96
Caseous necrosis with Giant cells
97
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

98
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

99
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

100
TYPES OF GANGRENE
  • DRY GANGRENE
  • WET GANGRENE
  • GAS GANGRENE

101
DRY GANGRENE
  • If there's mostly coagulation necrosis
  • The typical blackening, desiccating foot which
    dried up before the bacteria could overgrow

102
  • 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

103
Dry Gangrene
104
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

105
"wet gangrene in patient with Diabetes mellitus

106
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.

107
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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111
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

112
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

113
  • 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).

114
  • 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.

115
The differences between apoptosis and necrosis
  1. Apoptosis may be physiological
  2. Apoptosis is an active energy dependent process
  3. Not associated with inflammation

116
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

117
PATHOPHYSIOLOGY
  • Literally means how physiology is altered by
    disease

118
PATHOGENESIS
  • of a disease is the sequence of events at the
    organ, cellular, ultrastructural, and molecular
    levels, by which the disease develops

119
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

120
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)

121
GUMMATOUS NECROSIS
  •  
  • is, for our purposes, coagulation necrosis seen
    in granulomas in syphilis.

122
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

125
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.)

126
PATHOLOGICAL CALCIFICATION
  • Deposition of mineral salts of calcium in
    tissues other than osteoid or enamel

127
  • 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

128
This is dystrophic calcification in the wall of
the stomach. At the far left is an artery with
calcification in its wall
129
Metastatic calcification" in the lung of a
patient with a very high serum calcium level
(hypercalcemia).
130
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.
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