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Colin MOD > Ch. 2 - Cellular Response to Stress and Toxic Insults: Adaption, Injury, and Death > Flashcards

Ch. 2 - Cellular Response to Stress and Toxic Insults: Adaption, Injury, and Death Flashcards

1
Q

What is the cellular response to increased demand?

A

Hyperplasia and Hypertrophy

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2
Q

What is the cellular response to decreased nutrients?

A

Atrophy

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3
Q

What is the cellular response to chronic irritation (physical or chemical)?

A

Metaplasia

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4
Q

What is the cellular response to reduced oxygen supply?

A

Cell injury

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5
Q

What is the cellular response to increased stimulation (e.g., by growth factors, hormones,etc)?

A

Hypertrophy and Hyperplasia

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6
Q

What is the cellular response to decreased stimulation (e.g., by growth factors, hormones, etc)?

A

Atrophy

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7
Q

What is the cellular response to chemical injury?

A

Cell injury

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8
Q

What is the cellular response to microbial infection?

A

Cell injury

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9
Q

What is the cellular response to acute and transient stress?

A

Acute reversible injury

Cellular swelling fatty change

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10
Q

What is the cellular response to progressive and severe stress (including DNA damage)?

A

Irreversible injury –> cell death

Necrosis
Apoptosis

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11
Q

What is the cellular response to Metabolic alterations, genetic or acquired?

A

Intracellular accumulations

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12
Q

What is the cellular response to chronic injury?

A

Calcification

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13
Q

What is the cellular response to cumulative sub-lethal injury over long life span?

A

Cellular Aging

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14
Q

What is the stain that colors Myocardium magenta?

A

Triphenyltetrazolium

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15
Q

What is the most common stimulus for skeletal muscle hypertrophy?

A

Increased Work load

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16
Q

What is the most common stimulus for cardiac muscle hypertrophy?

A

Increased hemodynamic load

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17
Q

What is the key characteristic of hypertrophy?

A

Increased protein synthesis

(increase in cytoskeleton

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18
Q

What are the three general signals responsible for cardiac hypertrophy?

A

Mechanoreceptors detecting an increased workload

Growth Factors

Vasoactive Agents

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19
Q

What are the Growth Factors involved in signaling cardiac hypertrophy?

A

TGF-beta

IGF-1 (insulin-like growth factor-1)

FGF (fibroblast growth factor)

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20
Q

What are the Vasoactive Agents invovled in signaling cardiac hypertrophy?

A

Angiotensin II

Endothelin 1

Alpha Adrenergic Agonists

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21
Q

What are the two major biochemical signal transduction pathways of cardiac hypertrophy?

A

GPCR Pathway

PI3K/AKT Pathway

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22
Q

Which signal transduction pathway is more important for Physiologic Cardiac Hypertrophy?

A

PI3K/AKT Pathway

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23
Q

Which signal transduction pathway is more important for Pathologic Cardiac Hypertrophy?

A

GPCR Pathway

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24
Q

What are the transcription factors activated by the signal transduction pathways and what are they responsible for?

A

GATA4
NFAT
MEF2

These TFs are responsible for increasing synthesis of muscle proteins

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25
Q

What switch occurs with hypertrophy in cardiac muscle?

A

During hypertrophy, contractile proteins will switch from their adult form to their fetal/neonatal forms

Reversible

Adult Myosin Heavy Chain = alpha

Fetal Myosin Heavy Chain = beta

In hypertrophy, Alpha form switches to Beta form

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26
Q

What is different between the Adult and Fetal Contractile Proteins in cardiac muscle?

A

Adult (Alpha) Myosin Heavy Chain is FASTER, but LESS energetically economical contraction

Fetal (Beta) Myosin Heavy Chain is SLOWER, but MORE energetically economical contraction

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27
Q

What signal is expressed in cardiac muscle in response to hypertrophy and what does it do?

A

ANP is released from the atria of the heart

It signals secretion of Na+ from blood into renal tubules. Water follows, resulting in decreased blood volume

Increases hematocrit

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28
Q

What happens when the hypertrophy of the cardiac muscle reaches its limit?

A

Occurs when adaptive change (hypertrophy) can’t keep up with the stress

Heart begins to give up

Lysis/loss of contractile elements

In extreme cases, can cause myocyte death

NET RESULT: Heart Failure

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29
Q

Cell injury occurs when hypertrophy of the cardiac muscle reaches its limit, what is used to treat it?

A

Inhibitors of the Transcription Factors responsible for the muscle hypertrophy:

NFAT Inhibition
GATA4 Inhibitor
MEF2 Inhibitor

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30
Q

What signals Physiologic Hyperplasia?

A

Growth factors and hormones

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31
Q

What is an example of compensatory hyperplasia?

A

Regeneration of the liver

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32
Q

What signals Pathologic Hyperplasia?

A

Excessive/innapropriate amounts of hormones or growth factors

OR

Inapropriate actions of hormones or growth factors

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33
Q

A 68 year old obese, post-menopausal woman experiences abdominal pain. A biopsy of her uterus is obtained and shows increased proliferation of endometrial tissue and presence of glands. What is the underlying mechanism of this hyperplasia?

A

Increased levels of estrogen

Estrogen is coming from peripheral conversion in adipocytes

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34
Q

What adaptation constitutes a “fertal soil” in which cancerous proliferations may eventually arise?

A

Pathologic Hyperplasia

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35
Q

What is the characteristic sign of Atrophy?

A

Autophagy and decreased protein synthesis

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36
Q

What are the 6 forms of atrophy?

A
  1. Decreased Workload (disuse)
  2. Diminished blood supply
  3. Inadequate nutrition
  4. Loss of innervation
  5. Reduced Endocrine Stimulation
  6. Pressure
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37
Q

What is Senile Atrophy?

A

A form of atrophy due to Diminished Blood Supply

Seen in old age

Occurs in response to atherosclerosis of blood vessels leading to the heart or brain

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38
Q

What is Marasmus?

A

Profound protein-calorie malnutrition

Leads to body eating skeletal muscle for energy when other energy source reserves have been used up (body fat)

Leads to cachexia

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39
Q

What is cachexia?

A

Marked muscle wasting

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40
Q

What is the role of TNF in cancer?

A

TNF suppresses appetite and depletes lipid stores

Leads to wasting of the muscle tissue (cachexia)

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41
Q

What does atrophy result from?

A

Decreased protein synthesis and increased protein degradation

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42
Q

What is the pathway responsible for atrophy due to inadequate definition and disuse?

A

Ubiquitin-Proteosome Pathway

Inadequate nutrition/disuse signals the activation of Ubiquitin Ligases

Ubiuitin Ligases attach ubiquitin to small proteins, which makes the protein a target for degradation via proteasome

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43
Q

What process is commonly associated with atrophy?

A

The hallmark of atrophy is autophagy

Autophagy - starved cells eat their own components in an attempt to meet nutrient demands

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44
Q

What happens to structures that are indigestible during autophagy?

A

The indigestible materials remain in membrane-bound structures called Residual Bodies

Ex: Lipofuscin granules, gives the tissue a yellow-brown appearance
- Brown Atrophy

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45
Q

What is Lipofuscin?

A

Wear-and-tear pigment
- So-called because it inevitably accumulates with age

Also accumulates in Residual Bodies
- Membrane-bound structures containing indigestible material in cells conducting autophagy

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46
Q

What is the adaptation observed in the respiratory tract in response to Vitamin A (retinoic acid) deficiency?

A

Squamous Metaplasia

Ciliated Columnar cells of the respiratory tract are replaced with stratified squamous epithelium

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47
Q

What is the adaptation observed in cases of Barrets Esophagus?

A

Columnar Cell Metaplasia

Squamous cells of the lower esophagus are replaced with Intestinal-like Columnar Cells

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48
Q

Which cells undergo metaplasia?

A

Stem Cells

OR

Undifferentiated mesenchymal cells present in connective tissue

These cells undergo reprogramming resulting in a change in phentoype

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49
Q

What signals tell cells t undergo metaplasia?

A

Cytokines

Growth Factors

Extracellular Matrix Signals

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50
Q

What occurs to a cell undergoing reversible cell injury?

A

Reduced Oxidative Phosphorylation leads to decreased ATP synthesis

Decreased ATP synthesis leads to disruption of Na-K-ATPase and Ca2+ pump

Na+ and Ca2+ accumulate in the cytosol and water follows, causing cellular swelling

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51
Q

What are the two causes of cell death?

A

Necrosis and Apoptosis

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52
Q

What is necrosis?

A

Damage to membranes is severe (including membrane of lysosomes)

Lysosomal enzymes enter the cytosol and digest the cell

Cell contents leak out and lead to inflammation

Always a result of pathology

NOT PHYSIOLOGIC

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53
Q

What is the hallmark of necrosis?

A

When cellular contents leak out of the cell, INFLAMMATION occurs

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54
Q

What is apoptosis?

A

Programmed cell death

Characterized by nuclear dissolution, fragmentation of the cell WITHOUT COMPLETE LOSS OF MEMBRANE INTEGRITY

Rapid removal of cellular debris

NO INFLAMMATION

Highly regulated, programmed cell death

Can be physiological and pathological

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55
Q

What are the 7 causes of cellular injury?

A
  • Oxygen Deprivation
  • Physical Agents (mechanical trauma, temperature extremes, radiation, electric shock)
  • Chemical Agents (drugs)
  • Infectious agents
  • Immunological Reactions
  • Genetic Derangements
  • Nutritional Imbalances
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56
Q

What happens to a cell during oxygen deprivation

A

Cell becomes hypoxic

- Reduced ability to conduct aerobic respiration and oxidative phosphorylation

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57
Q

What are the three causes of Oxygen Deprivation?

A

Ischemia - reduced blood flow (infarction)

Hypoxemia - reduced O2 content of blood (high altitude, pulmonary fibrosis)

Anemia - decreased O2 carrying capacity (CO poisoning)

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58
Q

How does cellular response to Oxygen Deprivation differ if it is immediate onset or gradual?

A

Immediate onset (such as a thrombus) cells can die

If the injury occurs gradually over time, the cell can adapt and atrophy

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59
Q

What are the morphological changes seen in REVERSIBLE cell injury?

A
  • Generalized swelling of the cell and its organelles (ATP depletion leads to Na+ accumulation, which causes water retention)
  • Blebbing of the cell membrane (outcroppings/pouches of membrane formed)
  • Detachment of ribosomes from Rough ER (reducing Protein syntehsis)
  • Clumping of Neuclear Chromatin

ALL are caused by decreased ATP synthesis, loss of membrane integrity, defects in protein synthesis, cytoskeletal damage, and DNA damage

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60
Q

What are the reversible changes to a cell that can be seen under a light microscope?

A

Cellular Swelling

Fatty Change

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61
Q

What causes cellular swelling in reversible cell injury?

A

Cell swelling is the first manifestation of almost all forms of cell injury.

Occurs when cell loses ability to maintain proper ion gradients (which requires ATP)

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62
Q

What is pallor?

A

Unhealthy pale appearance

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63
Q

What is hydropic change or Vacuolar Degeneration?

A

During reversible cell injury, the endoplasmic reticulum degrades by pinching off small clear vacuoles, giving the cytoplasm the appearance of containing many small bubbles

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64
Q

Why do cells that have undergone reversible cell injury show increased eosinophilia with H/E stains?

A

H/E staining refers to Hematoxylin/Eosin staining

  • Loss of cytoplasmic RNA (which binds blue dye: hematoxylin)
  • Denatured cytoplasmic proteins bind to red dye: eosin
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65
Q

What causes the fatty change observed in reversible cell injury?

A

Fatty Change ONLY OCCURS FOR SPECIFIC REVERSIBLE CELL INJURIES:

  • Hypoxic Injury
  • Toxic Injury
  • Metabolic Injury

Manifested by the appearance of lipid vacuoles in the cytosol of cells

These lipid vacuoles are involved and dependent on Fat Metabolism (i.e., hepaocytes and myocardial cells)

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66
Q

What are Ultrastructural Changes of reversible cell injury?

A

Plasma Membrane Alterations

  • Blebbing
  • Bunting (loss of microvilli due to swelling; think inflating a rubber glove)

Mitochondrial Changes

  • Swelling of mitochondria
  • Appearance of small, shapeless densities

Dilation of ER
- Detachment of ribosomes

Nuclear Alterations
- Disaggregation of granular and fibrillar elements

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67
Q

What physical presentation defines Necrosis/irreversible cell injury?

A

Cell membrane can’t be maintained and contents of the cell leak out

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68
Q

What is the source of the digestive enzymes responsible for necrosis/irreversible cell injury?

A

Lysosomal enzymes of the necrotic cell as well as lysosomal enzymes of the leukocytes recruited as part of the inflammatory reaction

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69
Q

How long does it take for histological evidence of an MI to become apparent?

A

Its takes 4-12 hours for MI biomarkers to become present

These markers (troponin) are normally found only within the cell, but necrosis involves the loss of plasma membrane integrity, thus these markers leak out of the necrotic cells

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70
Q

Aside from loss of plasma membrane integrity, what other indicators of necrosis/irreversible cell injury become apparent?

A

Glossy/Glassy appearance
- Due to loss of glycogen

Cytoplasm is vacuolated and moth-eaten
- Due to digestion of organelles

Cells replaced by Myelin Figures

Nuclear changes:

  • Pyknosis
  • Karyorrhexis
  • Karyolysis
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71
Q

What are myelin figures?

A

Large twisted phospholipid masses that are formed from pieces of damaged cell membranes

These myelin figures are then eaten up by other cells and broken down into fatty acids

OR

Are calcified into calcium soaps through saponification

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72
Q

What are the 3 patterns of nuclear changes seen in necrosis/irreversible cell injury?

A

Pyknosis

  • Nuclear shrinkage
  • Increased basophilia from chromatin condensing into a solid basophilic mass

Karyorrhexis
- Pyknotic (condensed) nucleus is fragmented

Karyolysis

  • Basophilia of chromatin fade due to loss of DNA via Endonucleases
  • DNA fragments after karyorrhexis are further broken down
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73
Q

What are the 6 patterns of necrosis?

A

Coagulative Necrosis

Liquefactive Necrosis

Gangrenous Necrosis

Caseous Necrosis

Fat Necrosis

Fibrinoid Necrosis

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74
Q

What is coagulative necrosis?

A

Architecture of the dead tissue is preserved, leaving tissue firm and structurally intact

Structural proteins and ENZYMATIC proteins are affected, thus breakdown of cell structure is inhibited.

Cells appear eosinophilic and Anucleate (no nucleus present)

Occurs in tissues affected by obstruction of blood vessel

Affected area is called an infarct

Occurs in every organ EXCEPT THE BRAIN

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75
Q

What is liquefactive necrosis?

A

Characterized by digestion of the dead cells, turning dead tissue into a liquid, viscous mass

Observed in focal BACTERIAL and FUNGAL infections

  • Recruits leukocytes which digest everything
  • Can result in abcess due to puss acumulation (dead leukocytes)

Also observed in Hypoxic/Ischemic death of CNS cells
- Microglia digest dead tissue

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76
Q

What is gangrenous necrosis?

A

Not a specific pattern, but a common term used in clinical practice

Describes Coagulative Necrosis of an extremity

Can be called “wet gangrene” when there is bacterial infection superimposed on it and there is some liquefactive necrosis present because of actions of degradative enzymes.

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77
Q

What is Caseous Necrosis?

A

“Cottage Cheese Like”
- Friable white appearance

  • Often occurs with TB infection
  • On microscopic examination, area appears as a collection of fragmented and lysed cells and amorphous granular debris within a distinctive inflammatory border known as GRANULOMA
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78
Q

What is Fibrinoid Necrosis?

A

Special form of necrosis seen in immune reactions involving BLOOD VESSELS

Complexes of antigens and antibodies are deposited in the walls of arteries
- Type III Hypersensitivity (arthritis, farmers lung)

These deposits, along with fibrin, results in a bright pink and shape-less appearance in H/E staining
- Called fibrinoid because it is “fibrin-like”

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79
Q

What is Fat Necrosis?

A

Not a specific pattern of necrosis, common term in clinical practice

Local areas of fat destruction resulting from release of pancreatic lipases into substance of pancreas and the peritoneal cavity (affecting peripancreatic fat)
- acute pancreatitis

Lipases split TAG esters within fat cells, which then combine with Ca2+ to produce a chalky-white appearance (fat saponification)

Histological examination shows necrosis taking the form of foci of shadowy outlines of necrotic fat cells with basophilic Ca2+ deposits surrounded by an inflammatory reaction

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80
Q

What happens if necrotic cells are not destroyed and phagocytosed by leukocytes?

A

The necrotic cells act as a nest for calcification

This process is called Dystrophic Calcification

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81
Q

What are the major causes of ATP depletion?

A

Reduced O2 Supply

Mitochondrial Damage

Actions of some toxins, such as cyanide

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82
Q

What changes occur when ATP is depleted in the cell?

A

Even a 5-10% decrease in ATP, effects occur:

Na-K-ATPase Pump stops functioning

AMP levels increase

Ca2+ pump stops functioning

Misfolding of proteins

At GREATER than 5-10% decrease in ATP:

Ribosomes detach from Rough ER, thus decreasing protein synthesis

Damage to mitochondria and lysosomal membrane that will cause the cell to go into necrosis

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83
Q

What happens when the Na-K-ATPase stops functioning?

A

Na+ leaks into the cell and accumulates

K+ Leaks out of the cell

Water follows the Na+, causing cellular swelling and dilation of ER

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84
Q

What happens when AMP accumulates in the cell?

A

Increased AMP levels causes cell to start utilizing Anaerobic Metabolism

Leads to lactic acid production, thus decreasing cellular pH levels.

Decreased pH leads to denaturation of enzymes

Additionally, inorganic phosphate concentrations increase

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85
Q

What happens when Ca2+ Pump stops functioning?

A

Ca2+ is normally very low in cytosol (stored in SER and Mitohondria)

Three things:

  1. Ca2+ opens Mitochondria Permeability Transition Pores
  2. Ca2+ activates many enzymes that can damage the cell:
    - Phospholipases - membrane damage
    - Proteases - membrane and cytoskeletal proteins
    - Endonucleases - DNA and chromatin fragmentation
    - ATPases - increased depletion of ATP
  3. Direct activation of Apoptosis via caspases (INTRINSIC PATHWAY)
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86
Q

What causes the increase in misfolded proteins and what is the result of this?

A

Misfolded proteins are produced as a result of damage to the ER and loss of ribosomes

The accumulation of misfolded proteins induces UNFOLDED STRESS RESPONSE

aka

ER STRESS RESPONSE

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87
Q

What are the three major consequences of mitochondrial damage?

A

Formation of mitochondrial permeability transition pore

Abnormal Oxidative Phosphorylation, which leads to production of ROS

Cytochrome C

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88
Q

What are the concequences that follow the formation of a mitochondrial permeability transition pore?

A

Formation of Mitochondrial Permeability Transition Pore causes:

Loss of electric potential needed for Oxidative Phosphorylation to produce ATP
- Loss of ATP –> necrosis

Cyclophili D is a component of the pore and it is targeted by the immunosuppressive drug known as Cyclosporine
- Reduces injury by preventing opening of the pore

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89
Q

Why Cyctochrome C release from mitochondria bad?

A

Cytochrome C activates Caspases in the cytosol

Caspases are apoptosis inducing enzymes
INTRINSIC PATHWAY

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90
Q

What are Reactive Oxygen Species (ROS), a type of free radical?

A

They are reactive/damaging molecules produced by various means

They are:

  • Superoxide (O2-)
  • Hydrogen Peroxide (H2O2)
  • Hydroxyl Ion (OH-)
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91
Q

How are ROS produced?

A

During normal mitochondrial respiration/energy generation:

  • Molecular O2 is reduced by transfer of 4 electrons to H2 to make two molecules of H2O
  • Produces ROS Byproducts (O2-, H2O2, OH-)

Absorption of Radiation:

  • UV Light, X-rays
  • Produce OH-

Transition Metals:

  • Iron and Copper donate or accept free electrons
  • Thus can produce ROS
  • Wilsons Disease - copper buildup - leads to ROS buildup
  • Hemochromatsosis - iron buildup - liver damage due to ROS buildup

Leukocyte Intracellular Oxidases:

  • Leukocytes use NADPH Oxidase
  • NADPH Oxidase is necessary for the “oxidative burst” needed to convert O2 to O2-
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92
Q

What is Chronic Granulomatous Disease (CGD)?

A

CGD is a deficiency in NADPH Oxidase

Causes an increase in susceptibility to catalase positive pathogens

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93
Q

What processes also produces free radicals, but not ROS?

A

Enzymatic metabolism of exogenous chemicals or drugs

  • Generates free radicals that are not ROS, but have similar effects
  • Such as Carbon Tetrachloride (CCl4)

NO

  • Generated by many cells like macrophages, neurons, and endothelial cells
  • Can turn into free radicals such as:
    • ONOO
    • NO2
    • NO3
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94
Q

What is the Fenton Reaction?

A

H2O2 + Fe2+ -> Fe3+ + OH* + OH-

Reduces Fe2+ (Ferrous) to into Fe3+ (ferric)

Reaction is enhanced by Superoxide (O2-)

Produces Hydroxyl ions

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95
Q

How can ROS production be prevented?

A

Antioxidants

  • Block free radical formation or inactivate free radicals
  • Examples: Vit. A, Vit. E, Ascrobic Acid, and Glutathione

Preventing Iron and Copper from participating in reactions, thus preventing ROS prodution

  • Have iron and copper bind to storage or transport proteins
  • Transferin (transport)
  • Ferritin (storage)
  • Lactoferrin
  • Ceruloplasmin
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96
Q

How can ROS be removed?

A

They decay on their own pretty quickly

Some enzymes scavenge and breakdown ROS

  • Catalase
  • Superoxide Dismutase
  • Glutathione Peroxidase
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97
Q

What is Catalase?

A

An enzyme found in Peroxisomes that is responsible for breaking down ROS

Specifically, it takes H2O2 (hydrogen peroxide) and makes O2 and 2 molecules of H2O

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98
Q

What is superoxide dismutase (SOD)?

A

Converts O2- (superoxide) to H2O2 (hydrogen peroxide) and O2

There are two types of SOD:

  • Manganese-SOD, which is found in mitochondria
  • Copper-Zinc-SOD localized in the cytosol
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99
Q

What is Glutathione Peroxidase?

A

Found in the Mitochondria and Cytosol

Breaks down OH- (hydroxyl ion) into H20

Breaks down H2O2 (hydrogen peroxide) into O2 and H2O

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100
Q

What does the Intracellular ratio of Oxidized and Reduced Glutathione tell you?

A

Oxidized Glutathione (GSSG) - Reduced Glutathione (GSH) ratio is a reflexion of the oxidative state of the cell

It is an important indicator of the cell’s ability to detoxify ROS

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101
Q

How is Superoxide inactivated?

A

O2- is inactivated by Superoxide Dismutase

Converts O2- into H2O2 (hydrogen Peroxide) and O2

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102
Q

How is Hydrogen peroxide inactivated?

A

H2O2 is inactivated by Catalase and Glutathione Peroxidase

Catalase (in peroxisomes) converts H2O2 into O2 and H2O

Gutathione Peroxidase (in the cytosol and mtochondria) convert H2O2 into O2 and H2O

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103
Q

How is Hydroxyl ion inactivated?

A

OH- is inactivated by Glutathione Peroxidase

Glutathione Peroxidase (in the cytosol and mitochondria) convert OH- to H2O

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104
Q

What are the pathological effects of Free Radicals?

A

Lipid Peroxidation

Oxidative Modification of Proteins

Lesions of DNA

105
Q

What is Lipid Peroxidation and how are free radicals involved?

A

Free radicals attack double bonds found in lipid membranes of cells

Auto-catalytic chain reaction ensues (propagation)

Causes extensive membrane damage

106
Q

What is Oxidative Modification of Proteins and how are free radicals involved?

A

Free radicals promote oxidation of amino acid side chains

Causes alteration of protein conformation (protein shape determines its function, thus function is disrupted)

Can lead to cell death from proteasomes

107
Q

How are free radicals responsible for Lesions of DNA?

A

Free radicals can cause single and double strand breaks in DNA

Can lead to cell aging and cancer

108
Q

Which ROS is the most reactive, and most responsible for cell damage?

A

OH- (hydroxyl ion)

109
Q

Do ROS provide any use to a cell?

A

Yes

The dose determines the poison

ROS have a role in signaling cell receptors and activating biochemical intermediates

But in high quantities, ROS can cause necrosis and induce apoptosis

110
Q

The major Actions of O2- (superoxide) stem from what?

A

Stem from superoxide’s ability to stimulate the production of degradative enzymes rather than direct damage of macromoleucles

111
Q

What are the mechanisms of membrane damage?

A

ROS and lipid Peroxidation

Decreased phsopholipid synthesis

Increased phospholipid breakdown

Cytoskeletal abnormalities

112
Q

How do ROS and lipid peroxidation lead to membrane damage?

A

ROS attack double bonds in phospholipids and cause a chain reaction that leads to membrane damage

113
Q

What is the mechanism of Decreased Phospholipid synthesis?

A

Phospholipid synthesis deacrease occurs as a result of Hypoxia or Mitochondrial dysfunction

Affects all membranes, including those of organelles

114
Q

What is the meachanism responsible for increased phospholipid breakdown?

A

Phospholipid breakdown occurs as a result of Ca2+-dependent phospholipases
- Increased Ca2+ leads to increased activity of these degradative enzymes

Leads to an increase in lipid breakdown products (fatty acids, acyl carnitine, lysophospholipids) which cause a detergent effect

Detergent effect causes further destruction of the cell membrane

Can alter the permeability and electrophysiology

115
Q

What is the mechanism for cytoskeleton abnormalities that lead to membrane damage?

A

Increased Ca2+ cause proteases to attack cytoskeleton

Cytoskeleton detaches from membrane

Allows the possibility of membrane expansion and rupture

116
Q

What are the consequences of Mitochondrial Membrane Damage?

A

Opening of the transition pore

Causes decrease in ATP synthesis and release of Cytochrome C, which activates caspases (initiating apoptosis)

117
Q

What are the consequences of plasma membrane damage

A

Loss of osmotic balance and cellular contents, including compounds needed for making ATP

Leaky plasma membrane is bad

118
Q

What are the consequences of Lysosomal Membrane Damage?

A

Leakage of lysosomal enzymes into cytoplasm

As well as activation of acid hydrolases in the acidic intracellular pH of the injured cell

  • RNAses
  • DNAses
  • Proteases
  • Phosphatases
  • Glucosidases

Leads to necrosis

119
Q

What 2 morphological changes consistently represent irreversible changes in cell injury?

A
  1. Inability to reverse mitochondrial dysfunction and profound problems to membrane function
  2. Leakage of Intracellular Proteins through damaged cell membrane
120
Q

What are the biomarkers that are released from cardiac muscle when there is membrane damage?

A

Cardiac Specific isoform of Creatine Kinase

Troponin

121
Q

What are the biomarkers that are released from liver and bile duct epithelium when there is membrane damage?

A

Alkaline Phosphatase

122
Q

What are the biomarkers that are released from hepatocytes when there is membrane damage?

A

Transaminases

123
Q

What are the two potential causes of Ischemia?

A

Mechanical arterial obstruction

OR

Reduced Venous Drainage

124
Q

What is ischemia?

A

Most common type of cell injury in clinical med

Hypoxia induced by reduced blood flow

  • Mechanical arterial obstruction
  • Reduced venous drainage

Ischemia prevents the blood from bringing more substrates and taking away degredation products

125
Q

How is glycolysis affected in Hypoxia vs Ischemia?

A

Hypoxia - Glycolysis (anaerobic) can continue

Ischemia - compromises delivery of substrates for glycolysis, therefore glycolysis cannot continue
- Aerobic AND Anaerobic metabolism is compromised

126
Q

Which is worse? Ischemia or Hypoxia without ischemia?

A

Ischemia is worse

Causes a more rapid and severe cell and tissue injury than hypoxia without ischemia

127
Q

What are irreversible changes that happen to a cell if ischemia persists?

A

Severe swelling of mitochondria

Extensive damage to cell membrane - leading to formation of myeline figures

Large, shape-less densities develop in mitochondrial matrix

128
Q

What is Hypoxia-Inducible Factor 1?

A

Hypoxia-Inducible Factor 1 is a transcription factor

It promotes formation of new blood vessels (angiogenesis))

It also stimulates cell survival pathways and enhances anaerobic glycolysis

129
Q

What is angiogenesis?

A

It is the formation of new blood vessels from from existing blood vessels

Occurs via “sprouting” of endothelial cells thus expanding the vascular tree

130
Q

How ischemia treated?

A

The best strategy for treating ischemia (and traumatic) brain and spinal cord injury is inducing hypothermia

Dropping Core Body Temperature to less than 92 degrees

  • Reduces metabolic demand of stressed cells
  • Decreases cell swelling
  • suppresses formation of free radicals
  • Inhibits host inflammatory response
131
Q

What is Ischemia-reperfusion Injury?

A

Restoration of blood flow can promote recovery in cells that have been reversibly damaged

However, restoring blood flow will exacerbate cells that have been irreversibly injured

Particularly important in myocardial and cerebral infarctions

132
Q

What are the mechanisms of Ischemia-Reperfusion injury mechanisms?

A

Oxidative Stress

Intracellular Ca2+

Inflammation

Complement System Activation

133
Q

How does reperfusion cause oxidative stress?

A

Reperfusion leads to increased ROS and reactive nitrogen species production

Additionally, there is a decrease in anti-oxidants, which favors production ROS

134
Q

How does reperfusion lead to intracelluar Ca2+ overload?

A

Ca2+ influx beings during ischemia since Ca2+ pumps are inactive without ATP

Reperfusion brings lots more Ca2+ to cell. With membrane damaged, more leaks into the cell

Additionally, ROS damage causes SER to leak more Ca2+ into cytosol

Ca2+ causes Mitochondria Transition pores to open, further inhibiting ATP generation

135
Q

How does reperfusion lead to Inflammation?

A

Surrounding cells that are dying from necrosis release factors that attract immune cells to come to the area

Immune cells release more damaging molecules, exacerbates insult

136
Q

How does reperfusion lead to complement system activation?

A

Some IgM antibodies preferentially deposit in ischemic tissues

When blood flow is restored, complement proteins bind to IgM antibodies, become activated, and cause more damage and inflammation

137
Q

What toxic effects does mercury cause to cells?

A

Follows Direct Toxic Injury Mechanism

Mercury, specifically mercuric chloride does the following:

Binds to sulfhydryl groups of cell membrane proteins, which causes:

  • Increased membrane permeability
  • Inhibition of ion transport

The greatest damage occurs to cells that concentrate or excrete chemicals

  • GI
  • Kidney
138
Q

What toxic effects does cyanide cause to cells?

A

Follows Direct Toxic Injury Mechanism

Cyanide binds to Cytochrome Oxidase

This binding inhibits Oxidative Phosphorylation in mitochdondria

Occurs in ALL CELLS

139
Q

What are the two mechanisms of toxic injury?

A

Direct Toxic Injury

Indirect Toxic Injury
- conversion to toxic metabolites

140
Q

What mechanism of toxic injury do antineoplastic chemotherapeutic drugs follow?

A

Direct Toxic Injury Mechanism

141
Q

What is indirect toxicity?

A

Conversion of a toxin to something that is able to attack the cell - reactive toxic metabolites

Toxin is usually present in inactive form, but is activated (usually by Cytochrome p450 mixed function oxidases in smooth ER of the liver) into a reactive toxic metabolite

142
Q

What do reactive toxic metabolites do to a cell?

A

Through mainly formation of free radicals and then lipid peroxidation, causes:

  • Cell membrane damage and general cell injury
143
Q

What toxins are examples of Indirect Toxicity?

A

CCl4 is converted to a free radical

  • Can wreck havoc in the cell, including lipid peroxidation
  • Was used in dry cleaning

Acetaminophen

  • Made toxic in the liver
  • Dont take tylenol when youre hungover
144
Q

What is physiologic apoptosis?

A

Programmed cell death that does not occur in response to some pathology, but as a normal part of homeostasis. Examples:

Embryogenesis

Involution of hormone sensitive dependent organs with hormone withdrawal

Cell Population retraction

Death of cells that have served their purpose

145
Q

Apoptosis in embryogenesis

A

Digitation of hands and feet to form fingers and toes

146
Q

Examples of Apoptosis for involution of hormone sensitive dependent organs with hormone withdrawal

A

Endometrial cell breakdown during the menstrual cycle

Ovarian follicular atresia in menopause

Regression of lactating breast after weaning

Prostatic Atrophy after castration

147
Q

Examples apoptosis for cell population retraction

A

Regression of lymphocytes (WBCs) that fail to express useful antigen receptors

Elimination of self-reactive Lymphocytes (WBCs)

Epithelial cells in intestinal crypts so as to maintain homeostasis

148
Q

Examples of apoptosis for cells that have served their purpose

A

Neutrophils in an acute inflammatory response

Lymphocytes at the end of an immune response

149
Q

What is pathological apoptosis?

A

When a cell induces apoptosis (on its own or from outside signals) in response to a pathology

DNA Damage

Acumulation of misfolded proteins

Virus Induced

Pathological atrophy

150
Q

How does DNA damage trigger apoptosis?

A

If a cell has extensive DNA damage to the point where it irreversible, the cell triggers Intrinsic apoptotic pathway

151
Q

How does accumulation of misfolded proteins trigger apoptosis?

A

Misfolded proteins accumulate in the ER

Causes ER stress

Cell induces apoptosis

152
Q

How does virus induced apoptosis occur?

A

The virus itself can trigger a cascade of signals resulting in apoptosis

OR

T-cells signal cell infected with virus to undergo apoptosis

153
Q

What is the morphology observed in apoptotic cells?

A

Cell Shrinkage

Chromatin condensation

Formation of cytoplasmic blebs and apoptotic bodies

Macrophage phagocytosis of Apoptotic cells or cell bodies

154
Q

What happens during cell shrinkage?

A

Apoptotic cell shrinks, forming a more concentrated cytoplasm and more tightly packed organelles

Opposite of cell injury (swelling)

155
Q

What is the most characteristic feature of apoptosis?

A

chromatin condensation

156
Q

What happens with chromatin condensation?

A

Chromatin condense peripherally into oddly shaped masses

Then even the nucleus may fragment into pieces

157
Q

What are apoptotic bodies and how are they formed?

A

Apoptotic bodies are small vacuoles that break off from the cell body, fragmenting it

They contain tightly packed organelles
- May or may not have nuclear fragments

Formation of apoptotic bodies begins with cytoplasmic blebbing
- Blebbings then pinch off from cell body forming the apoptotic body

158
Q

What happens to apoptotic bodies?

A

Apoptotic bodies, which are very eosinophilic, are consumed by phagocytes

Apoptotic bodies, cell components contained in small bubbles of membrane, do not expose any cellular components to the extracellular space

This prevents the inflammatory process from occuring

159
Q

What are the two phases of apoptosis?

A

Initiation Phase

Execution Phase

160
Q

What is the initiation phase of apoptosis?

A

Some caspases (cystein proteases that cleave proteins after aspartic residues) become enzymatically activated

Intrinsic/Mitochondrial Pathway: Caspase-9

Extrinsic/Death Receptor Pathway: Caspase-8 and Caspase-10

161
Q

What is the execution phase of apoptosis?

A

After some caspases become activated, other caspases trigger degredation of cellular components

Common executioner caspases:

  • Caspase-3
  • Caspase-6
162
Q

What are the two apoptotic pathways?

A

Intrinsic pathway

Extrinsic Pathway

163
Q

What is the intrinsic pathway?

A

Increased permeability of the mitochondrial outer membrane and pro-apoptotic molecules trigger the intrinsic pathway; such as Cytochrome C

164
Q

What controls the release of apoptotic signals from the mitochondria?

A

BCL Family proteins.

3 Categories:

  • Pro-apoptotic
  • Anti-apoptotic
  • Apoptotic Sensors
165
Q

What are Anti-Apoptotic BCL family proteins?

A

Found in the outer-mitochondrial membrane, cytosol and ER membrane

Keep outer membrane impermeable, preventing leakage of Cytochrome C

BCL2, BCL-XL, and MCL1

These proteins contain 4 BH (BCL homology) domains

Growth factors and survival signals induce production of BCL2

166
Q

What are Pro-Apoptotic BCL family proteins?

A

When activated these proteins olgomerize within the outer mitochondrial membrane and increase its permeability, permitting leakage of cytochrome c

BAX and BAK

These proteins contain 4 BH (BCL homology) domains

167
Q

What are the BCL Family Apoptotic sensors?

A

Balance the activity of Pro- and Anti-apoptotic BCL proteins

Sense damage, such as ER stress, then in response:

  • activate pro-apoptotic proteins
  • inhibit anti-apoptotic proteins

BAD, BIM, BID, Puma, and Noxa

These proteins only contain 1 BH (BCL homology) domain

168
Q

What is the mechanism of the Intrinsic Apoptotic Pathway?

A

Cytochrome C is released from mitochondria

Cyt-C binds to APAF-1 to form a wheel-like hexamer called “apoptosome”

Apoptosome binds to Caspase-9 (initiator caspase of intrinsic pathway)

Caspase 9 cleaves other caspas-9 molecuels creating an auto-amplification process which activates the executioner caspases (Caspase-3/6)

Lastly, other mitochondrial proteins, Smac/Diablo, neutralize cytosolic enzymes that inhibit activation of caspases
- These enzymes are known as IAPs

169
Q

What initiates the extrinsic pathway?

A

Activation of the death domain receptors of the TNF (tissue necrosis factor) family

  • TNFR1
  • Fas (CD95)

The ligand for Fas is Fas ligand (FasL)

FasL is expressed on T-cells
Fas is expressed on all cells
- However, Fas expression is only induced by cells undergoing apoptosis

170
Q

What mechanism occurs as T-cell interacts with target cell?

A

FasL on T-cell binds to 3 or more Fas proteins on the surface of the target cell

Fas has cytoplasmic death domains that when clumped together upon binding with FasL form a binding domain for FADD (Fas-Associated Death Domain)

Bound FADD binds with inactive pro-Caspase-8 and pro-Caspase-10

  • Recruits other pro-Caspase-8 and pro-caspase-10 molecules
  • They cleave one another, resulting in active-form Caspase-8 and Caspase-10

These active caspases activate Caspase-3, which is an executioner caspase
- This is where the extrinsic pathway merges with the Intrinsic pathway

171
Q

What is FLIP?

A

FLIP is a protein that blocks the extrinsic apoptotic pathway

It does this by binding to Pro-caspase-8, preventing it from being cleaved

Some viruses and normal cells use FLIP to protect themselves from Fas-Mediated apoptosis

172
Q

What happens in the Execution phase of Apoptosis?

A

The execution phase is the common part, where both the Intrinsic and Extrinsic pathways converge.

Initiator caspases (9 intrinsic; 8 and 10 extrinsic) activate executioner caspases 3 and 6 which have the following actions:

Cleave inhibitor of cytosolic DNAse enzyme
- Activates DNA cleavage

Degrade the structural components of the nuclear matrix
- Promotes fragmentation og the nucleus

173
Q

What signal is responsible for macrophage recognition of apoptotic bodies?

A

Phosphatidylserine (PS) is present only on the inner surface of the plasma membrane in normal healthy cells

When it is inverted in the event of apoptotic body formation, it serves as a ligand for macrophage receptors

Allows macrophages to recognize apoptotic bodies and dispose of them accordingly

174
Q

What do apoptotic bodies do in order to be recognized by phagocytes?

A

Thromnospondin is an adhesive glycoprotein molecule that coat apoptotic bodies, attracting phagocytes to them.

Apoptotic bodies may also become coated with natural antibodies and proteins of the complement system
- Notably C1q - which is recognized by phagocytes

175
Q

What is the TP53 gene?

A

Tumor Supressor Gene
- Responsible for producing p53 protein

p53 protein is translated when there is DNA damage. It arrests the cell cycle at G1 phase, allowing time for repair

If damage is too extensive and cannot be repaired, p53 triggers apoptosis

176
Q

How does p53 protein trigger apoptosis?

A

p53 stimulates expression of pro-apoptotic BCL family proteins (BAX and BAK)

177
Q

What happens if the TP53 gene is mutated or absent?

A

Cell cannot signal p53 cell cycle arrest and cannot signal p53-mediated apoptosis in the event of extensive DNA damage

Leads to aberrant cell survival/proliferation
- Cancer

178
Q

What are the causes of apoptosis?

A

Growth factor deprivation

DNA damage

Protein Misfolding

179
Q

What causes protein misfolding?

A

Metabolic alterations that deplete energy stores

genetic mutations in proteins/chaperones

Viral infections

Chemical insults

180
Q

What is the Unfolded Protein Response?

A

Unfolded Protein Response (UPR) is a cytoprotectiv eresponse that is triggered when unfolded/misfolded proteins accumulate in the ER

UPR activates signaling pathways that:

  • Increase production of chaperone proteins
  • Enhance proteasomal degradation of abnormal proteins
  • Slow protein translation (reducing load of misfolded proteins)
181
Q

What happens if the Unfolded Protein Response is unable to cope with accumulation of misfolded proteins?

A

Too much accumulation of misfolded proteins leads to ER stress

ER stress signals the activation of caspases, initiating apoptosis

182
Q

What diseases involve the accumulation of misfolded proteins?

A

Alzheimer’s, Parkinsons, Huntingtons, and maybe Type II Diabetes

183
Q

How do Cytotoxic T Lymphocytes (CTLs) kill cells?

A

Uses the TNF family proteins: FasL on T cells and Fas on target cell

CTLs secrete Perforin

Perforin forms a transmembrane pore in the target cell’s membrane

Pore allows CTLs to inject granzymes into the taret cell

Granzymes cleave proeins at aspartate residues and thus activate a variety of cellular caspases

Ultimately, CTLs kill target cells by directly inducing the effector phase of apoptosis

184
Q

What is the most common mutation in human cancers?

A

TP53 gene mutations are the most common

p53 arrests the cell cycle at G1 when DNA damage occurs, and causes apoptosis if damage is irreversible

Mutation of this gene prevents cell cycle block and apoptosis, thus promoting cell survival/proliferation

185
Q

What disorders are associated with increased apoptosis and excessive cells death?

A

Neurodegenertive diseases

Ischemic Injury

Death of virus infected cells

186
Q

What is necroptosis?

A

Morphologically similar to necrosis:

  • Loss of ATP
  • Cell Swelling
  • ROS generation
  • Lysosomal enzyme release
  • Membrane Rupture

BUT AT THE SAME TIME

Mechanistically similar to apoptosis:
- Triggered by genetically programmed signal transduction events culminating in cell death

187
Q

Does necroptosis utilize caspases?

A

NO

Caspase independent programmed cell death

188
Q

What cell death processes are TNF family proteins involved in?

A

Apoptosis
- FasL/Fas

Necroptosis
- TNFR1/RIP1/RIP3

189
Q

What is the signal transduction cascade of necroptosis?

A

Ligationg of TNFR1 causes recruitment of RIP1 and RIP3 into a mutliprotein complex
- This complex also contains Caspase-8

HOWEVER

Caspases are not activated

The RIP1/RIP3/Caspase-8 complex causes various downstream events to occur including:

  • Permeability of lysosomal membranes
  • Generation of ROS
  • Damage to mitochondria
  • Reduction of ATP

Necrosis morphology

190
Q

What are the physiological functions of necroptosis?

A

Occurs in the formation of the bone growth plate

Associated with cell death in steatohepatitis (Fatty Liver), acute pancreatitis, reperfusion injury, and neurodegenerative diseases (ie., Parkinsons)

Works as a backup in the event where viruses encode caspase inhibitors (i.e., Cytomegalovirus)

191
Q

What is pyropoptosis?

A

Another mechanism of programmed cell death

Accompanied by release of fever inducing Cytokine IL-1 (hence the name pyro)

192
Q

What is the mechanism of pyropoptosis?

A

Microbial products that enter the cytoplasm of infected cells are detected by innate cytoplasmic immune receptors

Activated cytoplasmic immune receptors activate protein complex called Inflammasome

Inflammasome activates Caspase-1

Caspase-1 cleaves precursor form of IL-1, activating IL-1

IL-1 recruits leukocytes and induces Fever

Caspase-1 and Caspase-11 then work together to induce cell death

193
Q

What is the Morphology of Pyropoptosis?

A

Characterized by:

  • Cell Swelling
  • Loss of membrane integrity
  • Release of inflammatory mediators

NO APOPTOSIS

194
Q

What is pyropoptosis good for?

A

Good for killing some microbes that gain entry into the cytoplasm

195
Q

What is autophagy?

A

Process in which the cell eats itself

Prominent in atrophic cells exposed to sever nutrient deprivation

196
Q

What are the functions of autophagy?

A

Used to save cell from starvation

Clean up cellular debris

Turnover cellular oganelles

Recycle critical nutrients

Main integrity of cells by recycling essential metabolites and clearing cell debris

Trigger cell death if autophagy is unable to cope with the stress
(NOT NECROSIS, NOT APOPTOSIS)

197
Q

What are the three ways autophagy can occur?

A

Chaperone Mediated Autophagy

Microautophagy

Macroautophagy

198
Q

What is Chaperone Mediated Autophagy?

A

Direct translocation of material into the lysosomes via chaperone proteins

199
Q

What is Mircoautophagy?

A

Inward invagination of the lysosomal membrane, consuming cytosolic materials

200
Q

What is Macroautophagy?

A

Portions of the cytosol are encapsulated in a double-membrane bound autophagic vacuole known as an Autophagosome

Autophagosomes carry their cytoplasmic contents and fuse with lysosomes

201
Q

What is the first step in the mechanism of autophagy?

A

Formation of an isolation membrane (aka Phagophore)

Phagophore is formed from the ER

Formation of the phagophore is promoted by starvation and lack of growth factors

Starvation also activates the formation of a 4-protein Initiation Complex

The initiation complex Stimulates the assembly of another 4-protein complex, the Nucleation Complex

202
Q

What is the second step of the autophagy mechanism?

A

Elongation of the Autophagosomal membrane

This process uses Ubiquitin-like conjugation systems, including Microtubule Associated Protein Light Chain 3 (LC3)

LC3 is a useful marker for finding cells undergoing autophagy

Loading of cargo into the autophagosome is selective
- LC3 targets protein aggregates and dysfunctional organelles

LC3 helps select contents fromt he cytosol that should be eaten in times of low food

203
Q

What is the third step of the autophagy mechanism?

A

Maturation into the autophagosome and fusion with Endosome/Lysosome

Fusion of the autophagosome with an endosome and then lysosome makes an Autophagolysosome
- Contents in this stage are degraded

Fusion with the lysosome is the last step, where the inner membrane and enclosed cytosolic cargoes are degrded by the lysosoal enzymes

204
Q

In which cases is autophagy involved in human disease?

A

Cancer
- Can promote or inhibit growth depending on the cell/cancer

Neurodegenerative Disorders

  • Alzheimers: autophagy is accelerated
  • Huntingtons: mutant huntingtin (gene product) impairs autophagy

Infectious:Pathogens degraded by autophagy

  • Antigen presentation
  • Deletion of Atg5 in macrophages increases teh susceptibility to TB

Inflammatory Bowel Disease:

  • Crohn’s Disease
  • Ulcerative Colitis
  • Both are linked to single nucleotide polymorphism in autophagy related genes
205
Q

What are intracellular accumulations?

A

Manifestations of metabolic derangements in cells

Intracellular accumulation of abnormal amounts of various substances that may be harmless or associated with varying degrees of injury

206
Q

What are the 4 main pathways of intracellular accumulation?

A
  1. Inadequate removal of a normal substance due to defects in packaging and transport
    - Fatty Change (steatosis) in the liver
  2. Accumulation of an abnormal endogenous sustance as a result of genetic or acquired defects in folding, packaging, transport, or secretion
    - Mutated forms of alpha1-antitrypsin
  3. Failure to degrade a metabolite due to inherited enzyme defeciencies
    - Called storage diseases
    - Progressive and fatal to tissues and patients
  4. Deposition and accumulation of abnormal exogenous substance when the cell is not able to digest or move it
    - Accumulation of carbon or silica particles
207
Q

What are the presentations of lipid accumulation?

A

Steatosis (fatty change)

Atherosclerosis

Xanthomas

Cholesterolosis

Niemann-Pick Disease, type C

208
Q

What is Steatosis?

A

Abnormal accumulation of triglycerides (TAGs) within the parenchymal cells.

Often seen in liver since it does a lot with fat metabolism

Also occurs in the heart, kidney, and muscle tissue

Caused by toxins, protein malnutrition, DM, obesity, and anoxia

Most common causes in developed nations is:

  • Alcohol
  • Obesity
  • Nonalcoholic Fatty Liver Disease (comorbid with diabetes and obesity)
209
Q

What is atherosclerosis?

A

Formation of atherosclerotic plaques that can occlude vessels

Smooth muscle cells and macrophages within the intimal layer of the aorta and large arteries are filled with lipid vacuoles that are mostly composed of cholesterol and cholesterol esters
- These cells are called foam cells, appear yellow and foamy

Come fat laden cells may rupture and release lipids into the extracellular space

Extracellular cholesterol esters may CRYSTALLIZE in the shape of long needles

210
Q

What is Xanthomas?

A

Intracellular accumulations of cholesterol within MACROPHAGES

Characteristic of Hereditary hyperlipidemic states

Xanthoma: tumorous masses formed by clusters of foam cells that accumulate in the subepithelial conncetive tissue of the SKIN and in TENDONS

211
Q

What is cholesterolosis?

A

Focal accumulation of cholesterol-laden macrophages in the lamina propria of the Gall Bladder

212
Q

What is Neimann-Pick disease, Type C?

A

Lysosomal storage disease that affects an enzyme involved in cholesterol trafficking.

Results in cholesterol accumulation in multiple organs

NFL
Neimann-picks Fatty Lysosomes

213
Q

What is the morphology of protein accumulation?

A

Intracellular accumulations of proteins appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm

214
Q

What are the causes of protein accumulation?

A
  • Reabsorption droplets in proximal renal tubules
  • Russell Bodies
  • Defective intracellular transport and secretion of critical proteins
  • Accumulation of cytoskeletal proteins
  • Aggregation of abnormal proteins
  • Hyaline change
  • Extracellular Hyaline
215
Q

How does reabsorption droplets lead to protein accumulation in the proximal renal tubules?

A

Seen in renal diseases with proteinuria (protein loss in urine)

Normally: small amounts of protein are filtered through the glomerulus and are reabsorbed in the proximal tubule

When protein filtered at the glomerulus is too much, the proximal tubule cannot keep up and the protein is reabsorbed into vesicles

These vesicles appear as pink hyaline droplets within the cytoplasm of the proximal tubule cells

This is reversible if the proteinuria diminishes and the droplets are allowed to be metabolized

216
Q

What are Russell Bodies?

A

Proteins that accumulate may be normal secreted proteins produced in excess (e.g., plasma cells actively synthesizing immunoglobulins)

In cells that are producing lots of proteins very quickly, like in synthesis of Igs in plasma cells, then the ER becomes very distended and produces large homogenous eosinophilic inclusions called Russell Bodies

217
Q

How does defective intracellular trnasport and secretion of critical proteins lead to accumulation?

A

In alpha1-antitrypsin deficiency, mutations in the protein significantly slow folding and causes there to be a buildup of partially folded intermediates that accumulate in the ER of the Liver

Partially folded proteins are unable to be secreted (never make it to the golgi)

This manifests itself as emphysema
- Decrease in circulating alpha1-anitrypsin

Pathology comes from both the loss of protein function and from cell death due to ER stress

218
Q

How does accumulation of cytoskeletal proteins occur?

A

Keratin intermediate filaments: characteristic of epithelial cells

  • Alcoholic hyaline is an eosinophilic cytoplasmic inclusion in liver cells that is characteristic of alcoholic liver disease
  • Composed of predominantly keratin intermediate filaments

Neurofilaments: characteristic of neurons

  • Accumulation of keratin filaments and neurofilaments are associated with certain types of cell injury
  • Neurofibrillary tangle found in brain of Alzheimer disease contains neurofilaments and other proteins
219
Q

How does aggregation of abnormal proteins occur?

A

Abnormal or misfolded proteins may deposit intracellulary, extracellulary, or both

Amyloidosis

Sometimes called proteinopathies or protein-aggregation diseases

220
Q

What is Hyaline change?

A

A change that occurs within or outside of cells that makes it look homogenous, glassy, and pink when stained with H/E

Descriptive histologic term rather than a specific marker for cell injury
- Produced by a variety of alternations and does not represent a specific pattern of accumulation

Examples: Russell Bodies, alcoholic hyaline, reabsorption droplets

221
Q

How does extracellular hyaline occur?

A

Happens in Diabetes Mellitus and chronic hypertension

Walls of arterioles, especially kidney, become hyalinized because of extravasated plasma protein and deposition of basement membrane material

222
Q

What is glycogen accumulation?

A

Excessive intracellular deposits of glycogen are seen in patients with glucose or glycogen metabolism defects

These conditions are called glycogen storage diseases or glycogenoses

Can result in massive accumulation and cause cell injury/death

223
Q

How does glycogen accumulation occur in Diabetes Mellitus?

A

Diabetes is the prime example of a disorder of glucose metabolism

Glycogen is found in:

  • Renal Tubular Epithelial cells
  • Liver
  • Beta Cells of Islets of Langerhans
  • Heart Muscle Cells
224
Q

What are pigments?

A

Colored substances

Some are normal and syntehsized in the body (melanin)

Some are abnormal and accumulate in cells only under special circumstances

Can be exogenous (from outside the body)

Can be endogenous (synthesized in the body itself)

225
Q

What are some endogenous pigments?

A

Lipofuscin

Melanin

Hemosiderin granules

226
Q

What are some examples of exogenous pigments?

A

Carbon

Tatooing

227
Q

How is carbon handled as an exogeneous pigment?

A

Carbon (coal dust) from pollution in urban areas

Is breathed in and picked up by macrophages within the alveoli

Macrophages take it to regional lymph nodes in the tracheobronchial region

Accumulation of carbon blackens the lungs (Anthracosis) and invovled lymph nodes

228
Q

How are tattoo pigments handled?

A

Pigments enter the skin and are phagocytosed by dermal macrophages where they live for the rest of the individual’s life

These pigments do no usually invoke any inflammatory response

229
Q

What is Lipofuscin?

A

Endogenous Pigment

  • AKA Lipochrome
  • AKA Wear-and-Tear Pigment

Insoluble yellow-brown pigment

Composed of polymers of lipids and phospholipids complexed with protein
- Derived from Lipid Peroxidation of polyunsaturated lipids of subcellular membranes

Not dangerous to cells

Lipofuscin is a telltale sign of ROS damage and lipid peroxidation

Often perinuclear

Seen in cells undergoing slow/regressive changes and is particularly prominent in the liver and heart of aging patients with severe malnutrition, and cancer cachexia (muscle wasting)

230
Q

What is melanin?

A

Brown-black pigment formed by tyrosinase during the oxidation of tyrosine to dihydroxyphenylalanine in melanocytes

The only endogenous brown-black pigment (all others are exogenous)

231
Q

What is Homogentisic Acid?

A

Black pigment that occurs in patients with alkaptonuria (black urine)
- Rare metabolic disease

Ochronosis = homogentisic acid deposition in the skin, connective tissue, and cartilage of patients with alkaptonuria

232
Q

What are Hemosiderin Granules?

A

Hemoglobin-derived golden yellow-to-brown pigment (can be granular or crystalline)

Hemosiderin is one of the major storage forms of iron

Iron transported by transferrin

  • Iron stored in cells associated with apoferritin
  • This forms ferritin micelles

Hemosiderin represents aggregates of ferritin micelles when there is a local or systemic excess of iron

Small amount of Hemosiderin granules can be seen in mononuclear phagocytes in the bone marrow, spleen, and liver (where RBC breakdown occurs)

233
Q

What is Hemosiderosis?

A

Systemic Overload of Iron

Hemosiderin is deposited in many organs and tissues

Causes:

  • Increased absorption of dietary iron due to an inborn error of metabolism (hemochromatosis)
  • Hemolytic anemia (premature lysis of RBCs causes increased iron)
  • Repeated blood transfusions (tranfused RBCs constitute an exogenous load of iron)
234
Q

How do you explain the cahnging colors of bruising?

A

Bruising is due to local overload of blood and iron due to injury

Extravasated RBCs are phagocytosed over several days

  • Breakdown hemoglobin
  • Recover iron

Heme moiety is converted to biliverdin (green bile), then bilirubin (red bile)

At the same time, iron is incorporated into ferritin, then eventually hemosiderin (golden yellow-brown)

Explains why bruising colors change from:

  • Red-blue
  • Green-Blue
  • Golden Yellow-Brown
235
Q

What is pathologic calcification?

A

Abnormal tissue deposition of Calcium and Salts (mostly), plus a little Iron and Magnesium

236
Q

What are the two types of pathologic calcification?

A

Dystrophic Calcification

Metastatic Calcification

237
Q

What are psammoma bodies?

A

When single necrotic cells become seed crystals that become encrusted with mineral deposits, and more and more layers are deposited, it forms a lamellated configurations called Psammoma bodies

They look like grains of sand

Some types of papillary cancer (i.e., thyroid) are likely to develop psammoma bodies

238
Q

What is asbestosis?

A

Calcium and iron salts gather about long, slender asbestos shards in the lung and create exotic, beaded dumbbell forms

239
Q

What is the morphology of calcification?

A

Same for both dystrophic and metastatic calcification

  • Appear macroscopically as fine, white granules or clumps
  • Felt as gritty deposits
  • Sometimes a tuberculous lymph node is converted to stone
  • Calcium salts have basophilic, shape-less granular, sometimes clumped appearance with H/E staining
  • Can be intracellular, extracellular, or both – ANYWHERE
240
Q

What is dystrophic calcification?

A

Deposition occurs locally in dying tissues despite normal serum levels of calcium and in the absence of derangements in calcium metabolism

Found in areas of necrosis (coagualtive, caseous, or liquefactive)
- Also found in Foci of enzymatic necrosis of fat - fat saponification

Almost always found in the atheromas of advanced atherosclerosis

Commonly happens in aging or damaged heart valves
- compounds the problem

May be a sign of previous cell injury

Problematic because dystrophic calcification can often cause organ dysfunction

SERUM CALCIUM IS NORMAL IN DYSTROPHIC CALCIFICATION
- Hypercalcemia may accentuate dystrophic calcification but does not cause it

241
Q

What is Metastatic Calcification?

A

Deposition of calcium salts in otherwise normal tissues

Almost always the result of hypercalcemia secondary to some disturbance in calcium

242
Q

What causes hyperaclemia due to increased bone resorption?

A
  • Hyperparathyroidism
  • Primary tumors of bone marrow (multiple myeloma, leukemia)
  • Diffuse skeletal metastasis from another cancer (e.g., breast cancer)
  • Paget’s disease in which there is increased bone turnover
  • Immobilization
  • Vitamin D related disorders (Vit D intoxication, sarcoidosis, idiopathic hypercalcemia of infancy [williams syndrome]
  • Renal Failure (leads to retention of phosphate and secondary hyperparathyroidism
243
Q

What other ways does Hypercalcemia occur?

A

Aluminum intoxication
- complication in patients on chronic renal dialysis

Milk-Alkali Syndrome
- Excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate

244
Q

Where does metastatic calcification occur?

A

Metastatic calcification may occur widely through the body

Principally affects the interstitial tissues of the gastric mucosa, kidneys, lungs, systemic arteries, and pulmonary veins

  • Commonality: these areas excrete acid and have an internal alkaline compartment that predisposes to metastatic calcification
245
Q

What regulates cell aging?

A

Aging is regulated by genes that are evolutionarily conserved from yeast to worms to mammals

Aging is influenced by genes

Genetic anomalies underly syndromes resembling premature aging in humans (e.g., Progeria)

246
Q

What is aging?

A

Aging is the result of progressive decline in cellular function and viability caused by genetic abnormalities and teh accumulation of cellular and molecular damage due to the effects of exposure of exogenous influences

247
Q

What leads to cellular aging?

A

DNA damage

ROS (mutations)

Telomere shortening (decreased cellular replication)

Defective protein homeostasis (decreased cellular functions)

248
Q

What counteracts aging?

A

Decreased insulin/IGF signaling and decreased TOR leads to:

Altered transcription

Increased DNA repair

Increased Protein synthesis

249
Q

What is Werner Syndrome?

A

Patients show premature aging due to a defect with DNA Helicase

Defect in this enzyme causes rapid accumulation of chromosomal damage that may mimic the injury that normally accumulates during cellular aging

Think of Rick Werner who has had grey hair since you first met him

250
Q

What two diseases are associated with defective double-stranded breaks repair?

A

Bloom Syndrome

Ataxia Telangiectasia

251
Q

What is Replicative Senescence?

A

Normal cells have a limited capacity for replication and become arrested in a terminally non-dividing state (senescence) following a fixed number of divisions

252
Q

What is Quiescence?

A

Non-dividing state but can enter cell cycle if the envrionment calls for it

253
Q

What is Telomere Attrition

A

Progressive shortening of telomeres with each round of cell division ultimately results in cell cycle arrest

254
Q

What is telomerase?

A

Specialized RNA-protein complex that uses its own RNA as a template for adding nucleotides to the ends of chromosomes

Absent in most somatic tissues

Telomerase is re-activated in cancer cells and telomere length is stabilized

255
Q

How does activation of Tumor Suppressor Genes work?

A

CDK2A locus encodes a protein called p16 or INK4a

These proteins are correlated with chronological aging

They are responsible for cell cycle progression from G1 phase to S phase

This control mechanism protects the cells from uncontrolled mitogenic signals and pushes cells along the senescence pathway

256
Q

What happens to protein folding with aging?

A

Normal folding and degradation of abnormally folded proteins decreases with age

The expression of chaperone proteins are positively correlated with longevity.

257
Q

What happens to nutrient sensing with aging?

A

Caloric restriction == fountain of youth

  • Decreases insulin and IGF-1 signaling
  • Increases Sirtuin activity

Insulin and IGF-1 signaling pathway –> short life; inhibited by rapamycin and caloric restriction

  • Produced in many cells due to the release of growth hormone
  • Informs the cell about the availability of glucose and promotes cell growth and replication – stimulates an anabolic state
  • Activates two kinases: AKT and AKT’s downstream target mTOR
  • Longevity is increased when caloric restriction inhibits this pathway, which can also be mimicked by rapamycin

Sirtuins == fountain of youth; promote longevity

  • Family of NAD-dependent protein deacetylases
  • At least seven types distributed to adapt body to stress
  • Promote expression of genes that promote longevity by inhibiting metabolic activity, reduce apoptosis, stimulate protein folding, and inhibit effects of ROS
  • Also increase insulin sensitivity and glucose metabolism
  • Longevity can be increased by stimulating sirtuins (especially sirtuin 6) by contributing to metabolic adaptations of caloric restriction and promoting genomic integrity via acetylating DNA
258
Q

What is rapamycin?

A

Rapamycin inhibits the mTOR pathway and increases the life span of middle aged mice

Colin MOD (5 decks)

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