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Pathology > 2. Cellular response to stress > Flashcards

2. Cellular response to stress Flashcards

1
Q

Cellular response to environmental stimuli

A
  • Stress / increased demand:
    Normal cell (homeostasis) → Adaptation
  • Injurious stimulus:
    Normal cell (homeostasis) → Cell injury → Cell death
  • Inability to adapt:
    Adaptation → Cell injury → Cell death
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2
Q

What is homeostasis?

A

Homeostasis is the ability of cells & tissues to maintain a steady state & handle physiological demands.

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3
Q

What are adaptations?

A

Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment.

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4
Q

What is cellular adaptation?

A

Cellular adaptation occurs in response to a certain stimulus & stops once the need for adaptation has stopped (stimulus removed).

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5
Q

What is physiologic adaptation?

A

Physiologic adaptations represent responses of cells to normal stimulation (physiological stressors, such as hormones or endogenous chemicals mediators.

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6
Q

What are pathological adaptations?

A

Pathologic adaptations are responses to stress that induce cells to change their structure & function to escape injury & preserve viability & function.

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7
Q

Hypertrophy

A
  • Increase in the size of the cell leads to increase in the size of the organ.
  • Caused by:
    1. increased functional demand
    2. growth factors
    3. hormonal stimulation
  • Adaptive response in cells with limited capacity to divide ( skeletal muscle & heart).
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8
Q

Hypertrophy examples

A
  1. Skeletal muscles
  2. Heart
  3. Uterus
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9
Q

Pathological hypertrophy

A
  • Pathological hypertrophy:
  • Cardiac hypertrophy involving the left ventricle of a patient with systemic hypertension.
  • The size of myocardial fibers increase in response to the increased workload leading to the marked thickening of the left ventricle.
  • The left ventricle of a healthy human adult is normally less than his 1.5 cm.
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10
Q

Hyperplasia

A
  • Hyperplasia:
  1. Is the number of cells in a tissue or organ (bone marrow after blood loss).
  2. Is an adaptive response in cells capable of replication.
  3. Example: Hyperplasia in the female breast (glandular epithelium) at puberty & during pregnancy & lactation additional hormones).
  4. (Note: The breast also increase in size by hypertrophy)
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11
Q

Pathological Hyperplasia

A
  • Thyroid goiter:
  • insufficient available dietary iodine
  • cannot make enough thyroid hormone
  • extra demand by pituitary (TSH)
  • thyroid gets huge.
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12
Q

Atrophy

A
  • Reduction in cell size by loss of cell substance caused by decreased protein synthesis & increased protein degradation in cells. It happens due to:
  • Decreased workload (atrophy of disuse). Immobilization causes skeletal muscle atrophy.
  • Loss of innervation (paralysis)
  • Diminished blood supply (ischemia) as a result of arterial occlusive disease or arteriosclerosis.
  • Inadequate nutrition: profound protein-calorie malnutrition results in marked wasting (cachexia).
  • Loss of endocrine stimulation: The loss of estrogen stimulation after menopause results in physiologic atrophy of the endometrium & breast. The uterus decreases in size shortly after parturition.
  • Aging (senile atrophy): particularly the brain & heart.
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13
Q

Metaplasia

A
  • Adaptive substitution of one type of differentiated cell for another type of cell. It usually occurs in response to chronic irritation.
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14
Q

Stages in the cellular response to stress & injurious stimuli

A
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15
Q

When does cell injury happens?

A
  • Cell injury happens when cells are no longer able to adapt in response to damaging agents or intrinsic abnormalities.
  • Injury may progress through a reversible stage or may lead to cell death.
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16
Q

What does the cellular response to injurious stimuli depends on?

A
  • Nature, duration, & severity of the injury
  • Type & adaptability of the injured cell
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17
Q

Define reversible cell injury

A

cellular injury is mild & sublethal

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18
Q

Define irreversible cell injury or cell death

A

Injury is severe & lethal

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19
Q

Internal causes of cell injury

A
  1. Oxygen deprivation: hypoxia is the most common cause of cell injury.
    Causes of hypoxia include:
    • reduced blood flow (ischemia)
    • inadequate oxygenation of blood ( hypoxemia, cardiorespiratory failure, & anemia).
    • ???
  2. Genetics defects: causing deficiencies of functional properties.
  3. Immune-mediated mechanisms: autoimmune diseases
  4. Aging
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20
Q

External causes of cell injury

A
  • Physical or mechanical trauma:
    1. Extreme temperatures
    2. UV lights
    3. Radiation
  • Chemicals & toxins:
    1. Drugs
    2. Alcohol
    3. Environmental & occupational hazards
  • Microbial agents:
    1. Bacteria
    2. Viruses
  • Nutritional:
    1. Deficiency of proteins or vitamins
    2. Excess cholesterol
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21
Q

Mechanisms of cell injury

What are the cell injury damages key cellular functions?​​

A
  1. Mitochondrial damage:
    • ​​↓ ATP → Multiple downstream effects
    • ↑ ROS → Damage of lipids, proteins, & DNA
  2. Entry of Ca2+:
    • ​​↑ Mitochondrial permeability
    • Activation of multiple cellular enzymes
  3. Membrane damage:
    • ​​Plasma membrane → Loss of cellular components
    • Lysosomal membrane → Enzymatic digestion of cellular components
  4. Protein misfolding & DNA damage:
    • ​​Activation of pro-apoptotic proteins
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22
Q

What is the most common injury stimulus?

A

Ischemia

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23
Q

Mitochondrial Damage

What are the functional & morphological consequences of decreased intracellular ATP during cell injury?

A
  1. ↓ Oxidative phosphorylation
  2. ↓ ATP:
    • ​↓ ​Na+ pump
    • Anaerobic glycolysis
    • Detachment of ribosomes
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24
Q

Mitochondrial Damage Consequences

↓ ATP

A
  • ↓ ATP:​​
    1. ↓ ​Na+ pump:
      • ​​Influx of Ca2+, H20, & Na+
      • Efflux of K+
      • → Cellular Swelling
    2. ↑ Anaerobic glycolysis:
      • ​​↓ Glycogen
      • ↑ Lactic acid → ↓ pH → clumping of nuclear chromatin
    3. Detachment of ribosomes → ↓ protein synthesis
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25
Q
  • Mitochondrial Damage Consequences: ↑ ROS
  • Role of reactive oxygen species (ROS) in cell injury
A
  • Damage of lipids, protein, & DNA
  • Production of ROS
    1. → Removal of free radicals
    2. → Pathological Effects:
      • Lipid peroxidation → Membrane damage
      • Protein modifications → Breakdown & Misfolding
      • DNA damage → Mutations
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26
Q

ROS - Induced Injury

A
  • In physiological state, there is a balance between the level of ROS formation & degradation keeping ROS at low level (ROS homeostasis). ROS accumulation is counterbalanced by specialized enzymes ( SOD, Glutathione peroxides, Catalaze) & antioxidants (vitamins E, A, C ).
  • The production of ROS is increased by many injurious stimuli (radiation, reperfusion, toxins). Oxidative stress is a transient or persistent increase of ROS level that disturb cellular function & signaling pathways.
  • Oxidative modification of lipids, proteins, & DNA results in cell injury & may culminate in cell death via necrosis or apoptosis.
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27
Q

What are the 3 mechanisms that ROS damage cells?

A
  1. Lipid peroxidation damages the double bonds in membrane lipids.
  2. DNA fragmentation through reacting with Thymine in nuclear & mitochondrial DNA to produce single strand breaks.
  3. Protein cross-linking: Free radical promote sulfhydryl-mediated protein cross-linking, resulting in increased degradation or loss of protein activity.
28
Q

Cell injury - Increased cytosolic calcium

A
29
Q

What contributes to membrane damage?

A
  1. ROS: Reactive Oxygen Species
  2. Phospholipid reacetylation / synthesis
  3. Phospholipidase activation by Ca2+
  4. Protease activation
30
Q

Mechanisms of membrane damage in cell injury

A
  • Damage of cellular membranes may affect plasma, lysosomal, & mitochondrial membranes, which lead to necrosis.
  • Decreased O2 & increased cytosolic Ca2+ typically are seen in ischemia but may accompany other forms of cell injury.
  • Note: ROS produced on repercussion of ischemic tissues can cause membrane damage & cell death.
31
Q

What is the first manifestation of cell injury?

A

Swelling

32
Q

Morphologic changes in cell injury: Swelling

A
  • Swelling:
    1. is the first manifestation of cell injury
    2. is a reversible alteration that may appear at the level of the whole organ. At the level of the organ it:
      • causes pallor (due to compression of capillaries)
      • increase in weight of the organ
33
Q

Ultra-structural changes of reversible cell injury

A
  1. Plasma membrane alterations with blebbing & loss of microvilli
  2. Mitochondrial swelling
  3. Dilation of ER & detachment of ribosomes
  4. Nuclear alterations with clumping of chromatin
  5. The cytoplasm may contain phospholipid masses, called myelin figures.
34
Q

Hydropic change

A
  • Accumulation of water in the cell.
  • Reversible injury in kidneys.
35
Q

Fatty change

A
  • Fatty change is manifested by the appearance of lipid vacuoles in the cytoplasm.
  • It is principally encountered in cells participating in fat metabolism:
    1. ​​Hepatocytes
    2. Myocardial cells
  • It is caused by defective transport of lipids (defects in synthesis of transport proteins).
  • It is also reversible.
  • Graph description: Fatty change in the liver.
    Imposed lipoprotein transport due to injury (alcoholism) leads to accumulation of lipids in the cytoplasm of hepatocytes, which are active in fat metabolism.
36
Q

Severe cell injury is irreversible - Cell death

A
37
Q

What are two characteristics of reversible cell injury?

A
  1. Hydropic change
  2. Fatty change
38
Q
  • True or False:
  • In cell injury, there is less protein synthesis.
A
  • True.
  • There is less protein synthesis in cell injury.
39
Q

What are very important in determining reversible or irreversible cell injury?

A

Membranes

40
Q

Irreversible cell injury

A
  • Injury beyond cell ability to adapt or maintain survival leads to irreversible cell injury.
  • Persistent or excessive injury causes cells to pass the “point of no return” into irreversible injury / cell death.
41
Q

What are the phenomena’s that characterize irreversibility?

A
  1. The inability to correct mitochondrial dysfunction
  2. Profound disturbances in membrane function
  3. Injury to lysosomal membranes
  4. Necrosis
42
Q

Define Necrosis

A
  • Necrosis:
  1. Cell death due to irreversible cell injury
  2. (Cells die in groups)
43
Q

Morphology of cell death - Necrosis

What is pyknosis?

A
  • Nuclear shrinkage & increased basophilia.
    DNA condenses into a solid shrunken mass.
44
Q

Morphology of cell death - Necrosis

Karyorrhexis

A
  • Karyo: Nucleus
  • Karyorrhexis: Nucleus undergoes fragmentation.
45
Q

Morphology of cell death - Necrosis

Karyolysis

A
  • In 1 to 2 days, the nucleus in a dead cell may completely disappear.
  • Deoxyribonuclease (DNase) activity causes nuclear dissolution.
  • Karyolysis: Empty cell in necrotic tissue.
46
Q

Why do necrotic cells show increased eosinophilia (pink staining from the eosin dye)?

A
  • Increased eosinophilia in (H & E) stains, attributable in part to the loss of cytoplasmic RNA (which binds the blue dye, hematoxylin) and in part to denatured cytoplasmic proteins (which bind the red dye, eosin).
  • Increased eosinophilia?
    1. Loss of cytoplasmic RNA → binds hematotoxylin / blue dye
    2. Denatured cytoplasmic proteins → binds eosin / red dye
47
Q

What happens when enzymes have digested cytoplasmic organelles?

A

The cytoplasm becomes vacuolated.

48
Q

How are necrotic cells characterized?

A
  1. Discontinuities in plasma & organelle membranes
  2. Dilation of mitochondria
  3. Disruption of lysosomes
  4. Intracytoplasmic myelin figures
49
Q

Describe graph A

A
  • Normal kidney tubules with viable epithelial cells
  • Normal nucleus & cytoplasm
50
Q

Describe graph B

A
  • Early (reversible) ischemic injury showing:
    1. surface blebs
    2. increased eosinophilia of cytoplasm
    3. swelling of occasional cells
  • ​More compact
  • More red → eosinophilia → denaturation of protein
51
Q

Describe graph C

A
  • Necrotic (irreversible) injury of epithelial cells, with:
    1. Loss of nuclei
    2. Fragmentation of cells
    3. Leakage of contents
  • No known organization
  • Fragmented
  • Nucleus = compact + blue
  • No nucleus in cells
52
Q

Define Coagulate Necrosis

A
  • Coagulate necrosis is a form of necrosis where the underlying tissue architecture is preserved for at least several days.
  • The injured tissue stays firm since the injury denatures not only structural proteins but also proteolytic enzymes, thereby blocking the proteolysis of the dead cells.
  • Leukocytes are recruited to the site of necrosis, and the dead cells are digested by the action of lysosomal enzymes from the leukocytes. The cellular debris is then removed by phagocytosis.
  • Coagulate necrosis is characteristic of infarction (ischemic necrosis) in all solid organs except the brain.
  • Description of the graph: Coagulate necrosis in the kidney.
    Within the infarcts cells are red (eosinophilic), nuclei are lysed (karyolysis) but tissue architecture is preserved. It is the result of proteins being denatured.
53
Q

Define Liquefactive Necrosis

A
  • Liquefactive necrosis is seen in focal bacteria or fungal infections, bcz microbes stimulate the accumulation of inflammatory cells & the enzymes of leukocytes digest (liquefy) the tissue.
  • Hypoxia death of cells within the CNS (brain) appear as liquefactive necrosis (unknown reason).
  • Dead cells are completely digested, transforming the tissue into a liquid viscous mass.
  • The digested tissue is later removed by phagocytes. If bacterial infection is the cause of cell death, the material is creamy yellow & is called pus.
  • Description of the graph: cerebral infarction demonstrates liquefactive necrosis.
54
Q

Define Caseous Necrosis

A
  • Caseous = cheese-like.
  • Caseous necrosis is found in loci of TB infection.
  • The tissue architecture is completely erased & cellular outlines cannot be seen.
  • The area of caseous necrosis is usually surrounded by an inflammatory border (focus of inflammation called granuloma).
  • On microscopic examination the necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular appearance.
  • Description of the graph:
  • *TB** of the lung with an area of caseous necrosis.
55
Q

Define Fat Necrosis

A
  • Fat necrosis occurs in acute pancreatitis where fat destruction results from release of pancreatic enzymes into the pancreas & the peritoneal cavity.
  • Pancreatic enzymes leak out of the damaged cells & ducts & liquefy the membranes of fat cells in The peritoneum. Lipase split the triglyceride esters contained within fat cells.
  • The released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification).
56
Q

The relationship among normal, adapted, reversible injured, and dead myocardial cells.

A
  • Adaptation → hypertrophy
  • Reversible injury → ischemia
  • Irreversible injury → ischemic coagulate necrosis
57
Q

What is apoptosis?

A
  • Apoptosis = programmed cell death
  • Apoptosis is a regulated mechanism that serves to eliminate unwanted & irreparably damaged cells to maintain homeostasis (single cell death)
58
Q

Physiological conditions of apoptosis

A
  • During development (embroyogenesis) for removal of excess cells.
  • To maintain cell population in tissues with high turnover of cell, such as skin & bowels.
  • Hormone-dependent involution:
    1. Endometrium
    2. Ovaries
    3. Breasts
59
Q

Pathological conditions of apoptosis

A
  • DNA damage from:
    1. ionizing radiation
    2. toxic chemicals
  • Stress conditions ,e.g., starvation.
  • Excessive accumulation of misfolded proteins.
  • To remove cells damaged by viruses.
  • Cell death in autoimmune diseases.
60
Q

Apoptosis

A
61
Q

Mechanisms of apoptosis

A
  • The two pathways of apoptosis differ in their induction but both lead to activation of caspases.
  • In the mitochondrial pathway, proteins of the bcl-2 family & cytochrome C activate caspases.
  • In the death receptor pathway, signals from plasma membrane receptors cause the assembly of adaptor proteins into a “death-inducing signaling complex”, which activates caspases.
  • Caspases activation leads to DNA fragmentation & cytoskeleton breakdown with intact plasma membranes (apoptotic bodies).
  • Apoptotic bodies express new ligands for binding & uptake by phagocytes. They are removed by phagocytosis without inducing inflammatory reactions.
62
Q

Mechanisms of Apoptosis (graph)

A
63
Q

Apoptosis mitochondrial pathway

[IMPORTANT]

A
  • Induction of apoptosis by the mitochondrial pathway is dependent on a balance between pro- & anti-apoptotic proteins of the Bcl family.
  • Injurious stimuli activate cytoplasmic sensors & lead to reduced production anti-apoptotic proteins & increased amounts of pro-apoptotic proteins.
  • The proapoptotic proteins sense DNA & protein damage & activate effectors that insert in the mitochondrial membrane & promote leakage of mitochondrial proteins.
  • In a viable cell, anti-apoptotic members of the Bcl-2 family prevent leakage of mitochondrial proteins.
  • The mitochondrial proteins that leak out activate 9 series of caspases (first the initiators & then the executioners).
  • These enzymes cause fragmentation of the nucleus & the cell.
64
Q

The unfolded protein response

A
  • In heathy cells, newly synthesized proteins are folded with the help of chaperones & are then incorporated into the cell or secreted.
  • Various external stresses or mutations induce a state called ER stress, in which the cell is unable to cope with the load of misfolded proteins.
  • Accumulation of these proteins in the ER triggers the unfolded protein response, which:
    1. tries to restore protein homeostasis
    2. activates signaling pathways that increase production of chaperones
    3. reduce protein translation, thus reducing the level of misfolded proteins.
  • If this response is inadequate, the cell dies by apoptosis.
65
Q

The unfolded protein response

A
66
Q

Apoptosis / Necrosis

A
67
Q

Features of necrosis & apoptosis

A

Pathology (2 decks)

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