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Mechanisms of Disease I > Robbins - Chapter 2 > Flashcards

Robbins - Chapter 2 Flashcards

1
Q

List the four fundamental aspects that are the core of Pathology.

A
  1. Etiology (the cause)
  2. Pathogenesis
  3. Morphological Changes
  4. Functional Derangements and Clinical Manifestations
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2
Q

Which enzyme are you going to use to stain the Myocardium Magenta?

A

Triphenyltetrazolium Chloride

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3
Q

List the two principle pathways of cell death.

A
  1. Apoptosis

2. Necrosis

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4
Q

Describe Hypertrophy.

What is the most common stimulus for hypertrophy?

A

Increase in the size of cells that results in an increase of size in an organ!

No NEW CELLS (just larger existing cells)

Can happen in NON-DIVIDING cells (whereas hyperplasia cannot)

** Most common stimulus for hypertrophy is INCREASED WORKLOAD

Can be Physiologic (pregnancy or working out) or Pathologica

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5
Q

Describe the mechanisms of Cardiac Hypertrophy.

A
  1. Mechanical Sensors (sense an increased work load); Growth Factors (TGF-Beta, IGF-1); Vasoactive agents (angiotensin, alpha-adrenergic hormones)
    2a. Physiological: PI3K/AKT Pathway is activated and will eventually turn on Transcription Factors (GATA4, NFAT and MEF2)
    2b. Pathological: G-Protein Coupled Receptors

*** Hypertrophy is also associated with a switch of proteins from Adult to Fetal (alpha isoform to beta isoform in myosin because it has a slower and more energetically favorable contraction)

*** ANP –> Expressed in BOTH the atrium and ventricle in the embryonic heart, but it is down-regulated after birth. You will see HIGH LEVELS of ANP in Cardiac Hypertrophy because it is trying to DECREASE the hemodynamic load

*** Currently in Clinical trials to INHIBIT Transcription Factors (GATA4, NFAT, and MEF2) because that will larger effect than just knocking out mechanical stretch or agonist etc.

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6
Q

Describe Hyperplasia.

Which cells can partake in hyperplasia?

A

Increase in the NUMBER of cells in an organ or tissue in response to a stimulus

*** Can only take place if the cell is ABLE to DIVIDE

*** Liver can regenerate through the use of Growth Factors or from INTRAHEPATIC stem cells

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7
Q

Differentiate between Physiological and Pathological Hyperplasia.

A
  1. Physiologic Hyperplasia –> Due to the action of Hormones or Growth Factors when there is a reason to increase the number of cells (i.e. Breast Development during puberty, regeneration of a donated liver, etc.)
  2. Pathologic Hyperplasia –> Most forms are caused by EXCESSIVE or INAPPROPRIATE actions of hormones or growth factors acting on target cells (i.e. Abnormal menstrual bleeding, Benign Prostatic Hyperplasia) *** Hyperplasia will be repressed if hormonal stimulation is eliminated!
    - - HPV will interfere will the cells ability to regulate the division of cells
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8
Q

Differentiate between:

  1. Physiologic Atrophy
  2. Pathologic Atrophy
A
  1. Physiologic Atrophy –> Most common during normal embryonic development (some structures have to undergo apoptosis)
  2. Pathologic Atrophy –> Has several common causes
    - DECREASED WORKLOAD (atrophy of disuse) - when a fractured bone is immobilized in a cast or a patient is in bed rest
    - DIMINISHED BLOOD SUPPLY - Ischemia can cause atrophy of the tissue, Senile Atrophy is when you have a decrease in tissue size due to ischemia from Atherosclerosis (occurs in Brain and Heart)(When you have atherosclerosis in the brain, you will have NARROW gyri and WIDENED Sulci)
    - LOSS OF INNERVATION
    - INADEQUATE NUTRITION - Marasmus (protein malnutrition); Can result in Cachexia (muscle wasting)
    - LOSS OF ENDOCRINE STIMULATION
    - PRESSURE
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9
Q

Describe the mechanism of Atrophy.

A

*** Results from decreased protein SYNTHESIS and increased protein DEGRADATION (usually by the Ubiquitin-Proteasome pathway) in cells

    • AUTOPHAGY
    • Lipofuscin Granules –> Debris within the vacuoles that will resist digestion (aka residual bodies) and will persist in the cytoplasm as granules, resulting in “BROWN Atrophy”
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10
Q

Describe Metaplasia.

A

Reversible change in which one differentiated cell type is replaced by another cell type

*** In smoking, normal CILIATED COLUMNAR epithelial cells of the trachea and bronchi are often replaced by STRATIFIED Squamous epithelial cells

*** More “rugged” stratified squamous epithelial cells are going to be able to BETTER SURVIVE under the harsh conditions than the more fragile epithelial cells

*** BARRETT’s ESOPHAGUS

*** Connective Tissue Metaplasia –> Bone formation in muscle known as Myositis Ossificans which will occur after Hemorrhage within the muscle which is a result after cell/tissue injury

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11
Q

Describe the mechanism of Metaplasia.

A

Result of REPROGRAMMING of stem cells that are known to exist in normal tissues, or of undifferentiated mesenchymal cells present in connective tissue!

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12
Q

List some causes of Cell Injury.

A
  1. Oxygen Deprivation
  2. Physical Agents
  3. Chemical Agents and Drugs
  4. Infectious Agents
  5. Immunologic Reactions
  6. Genetic Derangments
  7. Nutritional Imbalances
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13
Q

List the different phases that a cell will go through during irreversible cell injury.

A
  1. Biochemical Alterations (Cell Death)
  2. Ultrastructure Changes
  3. Light Microscopic Changes
  4. Gross Morphological Changes

(Figure 2-7; Pg. 40)

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14
Q

Describe the morphology in Reversible Injuries.

A
  1. Cellular Swelling –> Appears whenever cells are incapable of maintaining ionic and fluid homeostasis due to failure of ATP-dependent pumps in the plasma membrane
  2. Fatty Changes –> Occurs in hypoxia injury and various forms of toxic or metabolic injury (seen mainly in cells that are dependent on fat metabolisms i.e. Hepatocytes and Myocardial Cells), Small White VACUOLES may be seen within the cytoplasm

ULTRASTRUCTURAL changes of Reversible Cell Injury

  • Plasma Membrane Alterations (“Blebbing”, blunting and loss of microvilli)
  • Mitochondrial Changes (Swelling)
  • Dilation of the ER
  • Nuclear Alterations
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15
Q

Describe the process of Necrosis.

A

Plasma membrane is disrupted and Cellular Contents are going to Leak out into the Extracellular Space! This may cause INFLAMMATION in the surrounding tissue.

*** Earliest Histological evidence of Myocardial Necrosis is going to show up 4-12 hours after the first cell dies; however, due to the loss of the plasma membrane integrity, Cardiac-Specific enzymes are rapidly released from necrotic tissues and can be detected 2 hours after Myocardial Cell necrosis

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16
Q

Describe the Morphology of Necrotic Cells.

A

Show increased EOSINOPHILIA in hematoxylin and eosin (H&E) stains due to LOSS of: 1. Cytoplasmic RNA (binds blue dye); 2. Denatured Cytoplasmic Proteins (binds red dye)

*** Dead cells may be replaced by by MYELIN FIGURES (phospholipid masses that are derived from damaged cell membranes); Phospholipids are broken down further to fatty acids and will combine with Calcium to form Calcium Soaps

  • ** NUCLEAR CHANGES
    1. Pyknosis –> Chromatin condenses in a solid, shrunken mass.
    2. Karyorrhexis –> Pyknotic nucleus is going to undergo fragmentation and will totally disappear in a couple of days
    3. Karyolysis –> Change that reflects the loss of DNA
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17
Q

Discuss the various patterns of tissue necrosis:

  1. Coagulation Necrosis
  2. Liquefactive Necrosis
  3. Gangrenous Necrosis
  4. Caseous Necrosis
  5. Fat Necrosis
  6. Fibrinoid Necrosis
A
  1. Coagulation Necrosis –> Dead tissue is preserved in a certain form for a span of a least some days; Localized area of Coagulative Necrosis is called an INFARCT; In all organs EXCEPT for the BRAIN (Figure 2-11; Pg. 43)
  2. Liquefactive Necrosis –> Digestion of dead cells and turning it into a liquid mass; Normally “creamy-yellow” space because of the dead leukocytes; Necrosis in the CNS is going to manifest in this fashion! (Figure 2-12; Pg. 43)
  3. Gangrenous Necrosis –> Usually applied to a limb that has a lost its blood supply and has undergone necrosis involving multiple tissue planes; WET Gangrene (Bacterial Infection (LIQUEFACTIVE Necrosis) is superimposed on Gangrenous Necrosis)
  4. Caseous Necrosis –> Friable white appearance of the area of necrosis (“Cheese-Like”); Aka GRANULOMA (i.e. Tuberculosis) (Figure 2-13; Pg. 44)
  5. Fat Necrosis –> Refers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases; Areas of white chalky deposits represent places of fat necrosis with calcium soap formation (Saponification) (Figure 2-14; Pg. 44)
  6. Fibrinoid Necrosis –> Special form of necrosis usually seen in immune reactions involving blood vessels (Figure 2-15; Pg. 44)
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18
Q

What are some of the principles that are important to consider when thinking about different forms of cell injury?

A
  1. The cellular response to injurious stimuli depends on the nature of the injury, its duration, and its severity
  2. The consequences of cell injury depend on the type, state, and adaptability of the injured cell
  3. Cell injury results from different biochemical mechanisms acting on several essential cellular components (i.e. Mitochondrial damage, entry of Ca2+, Membrane Damage and Protein Misfolding/DNA Damage) (Figure 2-16; Pg. 45)
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19
Q

Describe how and why ATP is depleted during cell injury.

Which components of the cell are going to be affected by a decrease in ATP levels?

A

Major causes of ATP depletion:

  1. Reduced supply of O2 and Nutrients
  2. Mitochondrial Damage
  3. Actions of some toxins (i.e. Cyanide)

Components Effected:
1. Plasma Membrane Na+/K+ ATPase –> Net result is Na+ coming into the cell (water will follow), causing cell swelling and dilation of the ER

  1. Cellular Energy Metabolism Altered –> If you don’t have O2, you cannot do Oxidative Phosphorylation; Anaerobic Glycolysis will take place and your GLYCOGEN stores will be depleted, also you will have an accumulation of LACTIC ACID (this reduces the pH in the cell and will decrease the activity of many cellular enzymes)
  2. Failing Ca2+ Pump –> Leads to an influx of Ca2+
  3. Reduction in Protein Synthesis due to detachment of Ribosomes from the Rough ER
  4. In the absence of O2 or Glucose, proteins may become misfolded and activate the UNFOLDED PROTEIN RESPONSE in the ER
  5. Irreversible damage to mitochondrial and lysosomal membranes and the cell undergoes NECROSIS

(Figure 2-17; Pg. 45)

20
Q

Describe what will happen if you have mitochondrial damage in a cell injury.

A

There are THREE major consequences if you have damage to the mitochondria:
1. Formation of a Mitochondrial Permeability Transition Pore –> Leads to a loss of the mitochondrial membrane potential (no more Ox. Phos.) which will lead to NECROSIS of the cell; CYCLOPHILIN D is a structural component of the MPTP (Targeted by CYCLOSPORIN and is used in GRAFT REJECTION)

  1. Formation of Reactive Oxygen Species
  2. Leakage of Cytochrome C and Caspases from the mitochondria can result in APOPTOSIS

(Figure 2-18; Pg. 46)

21
Q

Describe what happens when you have Influx of Ca2+ in a cell injury.

A

Ca2+ is normally in LOW concentrations intracellularly and that is because most of the intracellular Ca2+ is sequestered in the Mitochondria and ER

*** ISCHEMIA and Certain TOXINS can cause a release of Sequestered Stores of Ca2+ (INITIAL) AND (LATER) damage to the plasma membrane can allow Ca2+ to cross into the cell

Different mechanisms of damage once Ca2+ enters the cell:
1. Mitochondria –> Increase Ca2+ in the mitochondria will cause the Mitochondrial Permeability Transition Pores to open (failure of ATP generation)

  1. Cytosol –> Activates Phospholipases (cell membrane damage), Proteases (breaks down proteins), Endonucleases (DNA and Chromatin Fragmentation), ATPases (ATP depletion)
  2. Induction of Apoptosis –> Increased Ca2+ causes DIRECT activation of Caspases and by increasing the mitochondrial permeability

(Figure 2-19; Pg. 47)

22
Q

Describe what happens when you have Accumulation of Oxygen-Derived Free Radicals in cell injury.

A

Reactive O2 Species are NORMALLY produced in the mitochondria during respiration and energy generation, but they are degraded and removed by the cellular defense system

*** Oxidative Stress –> Occurs when there is an INCREASE in ROS

Generation of Free Radicals
1. Reduction-Oxidation Reactions
2. Absorption of Radiant energy
3. Activated Leukocytes during Inflammation
4. Enzymatic metabolism of exogenous chemicals or drugs
5. Transition metals
6. Nitric Oxide 
(Table 2-3, Figure 2-20; Pg. 48)

Removal of Free Radicals

  1. Antioxidants (block free radical formation by inactive-scavenger free radicals)
  2. Iron and Copper binding to their STORAGE and TRANSPORT proteins (Transferrin)
  3. Catalase (2 H2O2 –> O2 + 2 H2O) Within the PEROXISOMES
  4. Superoxidase Dismutases (2 O2’ + 2H –> H2O2 + O2)
    - - Manganese-SOD: Mitochondiral
    - - Copper-Zinc-SOD: Cytosol
  5. Glutathione Peroxidase –> Good reflection on the cell’s ability to detoxify ROS (Within the MITOCHONDRIA)(-OH to H2O)
    - - Ratio of GSSG (Oxidized Glutathione):GSH (Reduced Glutathione)
    - - MORE GSH is with HEALTHY people

Pathologic Effects of Free Radicals

  1. Lipid peroxidation in membranes (Double bonds in unsaturated fatty acids of the membrane are attacked)
  2. Oxidative Modification of Proteins
  3. Lesions in DNA
23
Q

Describe what happens when you have a defect in Membrane Permeability during cell injury.

A

Membrane is NOT disrupted in APOPTOSIS!!!

Biochemical Processes that contribute to Membrane Damage:
1. Reactive Oxygen Species
2. Decreased Phospholipid Synthesis
3. Increased Phospholipid Breakdown
4. Cytoskeletal Abnormalities
(Figure 2-21; Pg. 49)

Consequences of Membrane Damage

  1. Mitochondrial Membrane Damage (Decreased ATP production)
  2. Plasma Membrane Damage (Loss of osmotic balance and influx of fluids and ions
  3. Injury to Lysosomal Membranes (leakage into the cytoplasm and activation of acid hydrolases which will lead to death by necrosis)
24
Q

Describe what happens when you have damage to DNA and Proteins during cell injury.

A

If damage to the DNA is too great, APOPTOSIS will be triggered

25
Q

What are the TWO phenomena that are associated with IRREVERSIBLE Cell Damage?

What are the biomarkers that are used for injury in the Heart and Liver?

A
  1. Inability to reverse Mitochondrial Dysfunction
  2. Profound Disturbances in Membrane Function

HEART –> Troponin and Creatine Kinase

LIVER –> Alkaline Phosphatase and Transaminase

26
Q

Discuss the mechanisms of Ischemic Cell Injury.

A

*** Ischemia is the MOST common type of cell injury in clinical medicine and it results from hypoxia induced by REDUCED blood flow. With Ischemia, you are not going to be able to perform Aerobic OR Anaerobic Metabolism because the substrates cannot get out to the blood stream.

*** Ischemia tends to be more RAPID and SEVERE than hypoxia without Ischemia

Mechanisms of Ischemic Cell Injury:

  1. Loss of Oxidative Phosphorylation (Decrease in ATP) –> Influx of Na+ and WATER (Cell Swelling)
    * ** Heart muscles cease to contract within 60 seconds of coronary artery occlusion
  2. Ca2+ Influx
  3. Myelin Figures (derived from degenerating cellular membranes may be seen within the cytoplasm)
  4. Mitochondria are usually swollen
    * ** If O2 is restored, these disturbances are reversible!!!!

Irreversible Injury due to Ischemia:

  1. Death is mainly by Necrosis
  2. Massive Influx of Ca2+ (Occurs if the ischemic zone is reprofused)
  3. Apoptotic pathway is activated by the pro-apoptotic factors that are leaking from the mitochondria

Protective Responses to deal with Hypoxic Stress:
1. Hypoxia-Inducible Factor-1 –> Promotes new blood vessel formation, stimulates cell survival pathways and enhances ANAEROBIC glycolysis

27
Q

Describe the Ischemia-Reperfusion Injury.

A

Restoration of blood flow to ischemic tissues can promote recovery of cells if they are reversibly injured, but can also exacerbate the injury and cause cell death!

Mechanisms of Ischemia-Reperfusion:
1. Oxidative Stress –> Can increase ROS and NOS because of incomplete reduction of oxygen by damaged mitochondria; Cellular Antioxidants are going to be compromised by ischemia which will cause accumulation of free radicals

  1. Intracellular Calcium Overload
  2. Inflammation
  3. Activation of the Complement System –> IgM can circulate to tissues when blood flow is resumed
28
Q

Describe a Chemical (Toxic) Injury.

A
  1. Direct Toxicity –> Some chemicals can injure cells directly by combining with critical molecular components (i.e. Cyanide Poisoning which inhibits Ox. Phos.)
  2. Conversion to Toxic Metabolites –> Most toxic chemicals are not biologically active in their native form but must be converted to reactive toxic metabolites which will then attack the target cells (usually accomplished by Cytochrome P450 in the Smooth ER of Hepatocytes)
    - - Dry Cleaners used to use CCl4 and Cytochrome P450 will convert it to the ROS-CCl3 which causes Liquid Peroxidation
29
Q

Discuss the various causes of Apoptosis (Physiologic vs. Pathologic Conditions).

A

Physiologic Conditions

  1. Destruction of Cells during Embryogenesis
  2. Involution of hormone-dependent tissues upon hormone withdrawal (endometrial cell breakdown during the menstrual cycle)
  3. Cell loss in proliferating cell populations (immature lymphocytes in the bone marrow and thymus)
  4. Elimination of Potentially Harmful Self-Reactive Lymphocytes (Either before or after they have completed their maturation)
  5. Death of host cell that have served a useful purpose (i.e. Neutrophil)

Pathologic Conditions

  1. DNA damage –> When the damage is TOO severe and the repair mechanisms cannot fix it
  2. Accumulation of Misfolded Proteins –> Leads to ER stress
  3. Cell Death in Certain Infections
  4. Pathologic Atrophy in parenchymal organs after duct obstruction (pancreas, parotid gland and kidney)
30
Q

List the Morphological Features of Apoptosis.

A
  1. Cell Shrinkage
  2. Chromatin Condensation
  3. Formation of Cytoplasmic Blebs and Apoptotic Bodies
  4. Phagocytosis of apoptotic Ellis or cell bodies, usually by macrophages

(Figure 2-22; Pg. 54)

31
Q

Differentiate between the Intrinsic and Extrinsic Pathways for Apoptosis.

Capsases are going to cleave proteins after which residue?

A

Caspases are Cysteine Proteases that are going to cleave proteins after ASPARTIC residues

  1. Intrinsic Pathway (“Mitochondrial”) –> Major mechanism in mammalian cells; Results in an increase in permeability of the outer mitochondrial membrane with an increase in release of PRO-APOPTOTIC (cytochrome C) factors (Intermembrane Space –> Cytoplasm)
    - BCL2 Family of proteins will tightly regulate Apoptosis
    – Anti-Apoptotic Factors (BCL2, BCL-XL, and MCL1)
    – Pro-Apoptotic Factors (BAX and BAK) form a channel in the outer membrane and allow the leakage of cytochrome C
    – Sensors (BAD, BIM, BID, PUMA and NOXA) –> “BH3 Only” Domains
    (Figure 2-24; Pg. 55)
    • Growth Factors and Other survival signals are going to stimulate the production of Anti-Apoptotic Proteins
    • When BH3 domains detect damage, they are going to activate PRO-Apoptotic effectors (BAX and BAK) and they can bind to and BLOCK Pro-Apoptotic effectors
    • Once Cytochrome C is released into the cytosol, it binds to APAF-1 forming the APOPTOSOME
    • This will then activate Caspase-9
    • Smac/Diablo will NEUTRALIZE Inhibitors of Apoptosis (IAPs which normally block the activation of Caspases-3 to keep cells alive!)
  1. Extrinsic Pathway –> When FasL (ON T-CELL) binds to Fas, the DEATH Domain is going to bind to FADD which will ACTIVATE Caspase-8 (autocatalytic caspase activation) and that will trickle down to the Executioner Caspases
    – Some viruses will produce FLIP (Inhibits pro-caspase 8) and use this inhibitor to protect themselves from Fas-mediated Apoptosis
    (Figure 2-25; Pg. 56)

*** In hepatocytes and Pancreatic Beta Cells, Caspase-8 produced by Fas signaling cleaves and activates the BH3-only protein BID, which then feeds into the mitochondrial pathway

32
Q

Describe the Execution Phase of Apoptosis.

A

Mitochondrial Pathway –> Caspase 9
Death Receptor Pathway –> Caspase 8 & 10

Both lead to Activation of the Executioner Caspases (-3 and -6)

33
Q

Describe the removal of Dead Cells after Apoptosis.

A

Formation of Apoptotic bodies breaks cells up into “bite-sized” fragments that are edible for phagocytes.

    • Phosphatidylserine is FLIPPED to the OUTER membrane where it will signal to Phagocytes to eat it
    • Thrombospondin is a glycoprotein that is recognized by phagocytes and macrophages
    • Apoptotic Bodies become coated with C1q (COMPLEMENT cascade)
34
Q

Give some examples of Apoptosis in Health and Disease.

A
  1. Growth Factor Deprivation –> If you have decreased synthesis of the Anti-Apoptotic effectors (BCL2 and BCL-XL) the cell will die
  2. DNA Damage –> p53 will accumulate in cells that have DNA damage and it will arrest the cell cycle; If p53 has a mutation, cells with DNA damage fail to undergo p53-mediated Apoptosis
  3. Protein Misfoldings –> Accumulation of proteins in the ER will trigger the UNFOLDED PROTEIN RESPONSE (UPR); UPR will DECREASE protein synthesis and INCREASE the production of Chaperones in order to attempt to fixed the misfolded proteins. If the protein folding demand GREATLY exceeds the Protein folding capacity, Apoptosis will occur.
    (Figure 2-26; Pg. 57)
  4. Apoptosis Induced by TNF Receptor Family –> FasL on T cells binds to Fas on the same or neighboring lymphocyte
  5. Cytotoxic T Lymphocyte-Mediated Apoptosis –> Secrete PERFORIN which is going to insert a channel into the target
35
Q

Tell me which protein is affected in the following diseases:

  1. Cystic Fibrosis
  2. Familial Hypercholesterolemia
  3. Tay-Sachs Disease
  4. Alpha-1-antitrypsin deficiency
  5. Creutzfeld-Jacob Disease
  6. Alzheimer’s Disease
A
  1. Cystic Fibrosis –> Cystic Fibrosis Transmembrane Conductance Regulator
  2. Familial Hypercholesterolemia –> LDL Receptor
  3. Tay-Sachs Disease –> Hexosaminidase Beta Subunit
  4. Alpha-1-antitrypsin deficiency –> alpha1 - antitrypsin
  5. Creutzfeld-Jacob Disease –> Prions
  6. Alzheimer’s Disease –> Alpa-Beta Peptide

(Table 2-4; Pg. 58)

36
Q

Talk about disorders associated with dysregulation of Apoptosis:

  1. Not enough Apoptosis
  2. Too Much Apoptosis
A
  1. Not Enough –> p53 and autoimmune disorders

2. Too Much –> Neurodegenerative Diseases, Ischemic Injury, Death of virus-infected cells

37
Q

Describe the process of Necroptosis.

A
  1. Morphologically –> Resembles Necrosis
  2. Mechanistically (Signal Transduction Events) –> Resembles Apoptosis

Often referred to as “Programmed Necrosis” or “Caspase-Independent Programmed Cell Death”

Steps:
1. Signal (TNF) is going to bind to its receptor
2. Binding causes recruitment of RIP1 and RIP3 along with Caspase 8
3. Sometimes Caspase 8 is inhibited allowing RIP1 Kinase and RIP3 Kinase to initiate signals that affect Mitochondrial generation of ATP (decrease) and ROS (increase)
4. This leads to the typical events of Necrosis
(Figure 2-27; Pg. 59)

Physiologic –> Formation of the mammalian bone growth plate

Pathologic –> Steatohepatitis, Acute Pancreatitis, Reperfusion injury, and neurodegenerative diseases (i.e. Parkinson’s disease)

38
Q

Describe the process of Pyroptosis.

A

Programmed cell death by release of fever inducing CYTOKINE IL-1 and because it bears some biochemical similarities with Apoptosis.

Steps:

  1. Microbial products enter the cytoplasm of infected cells are recognized and activate the INFLAMMASOME
  2. Inflammasome is going to activate CASPASE-1
  3. Caspase-1 is going to cleave the precursor form of IL-1 and release it in its biologically active form
    * ** Caspase-11 is going to be the one responsible for inducing cell death
39
Q

What are the three different categories of Autophagy?

Describe the process of Autophagy.

A

Three Categories:
1. Chaperone-Mediated –> Direct translocation across the lysosomal membrane by chaperone proteins

  1. Microautophagy –> Inward invagination of lysosomal membrane for delivery
  2. Macroautophagy –> Sequestering and transportation of portion of cytosol in a double-membrane bound autophagic vacuole (autophagosome)

Physiologic Uses for Autophagy

  1. Formation of Phagopore
  2. Elongation of a vesicle
  3. Maturation of an autophagosome, fusion with a lysosome and degradation of the contents

Formation of the Autophagosome:
1. Cellular stress will activate the Initiation complex which will stimulate the Nucleation Complex
2. Nucleation complex will promote the nucleation of the Autophagosomal membrane
3. Elongation of the Membrane is dependent on LC3 (Ubiquitin-like Conjugation System) which is a good marker to see which cells are undergoing Autophagy!
4. Autphagosome fuses with a lysosome to form an Autophagolysosome
5. Inner membrane and cargo are degraded by the lysosomal enzymes
(Figure 2-28; Pg. 60)

*** LC3 system is used to TARGET protein aggregates and the effected organelles

Autophagy can trigger cell death if it is INADEQUATE to cope with the stress imposed on the cell (this Pathway is distinct from Necrosis and Apoptosis)

DISEASES involved in Autophagy

  1. Cancer
  2. Neurodegenerative Disorders (Formation of Phagosomes is ACCELERATED in Alzheimer’s disease)
  3. Infections Diseases
  4. Inflammatory Bowl Diseases
40
Q

Describe the four mechanisms of intracellular accumulations.

A
  1. Fatty Liver –> Inadequate removal of normal substance secondary to defects in mechanisms of packaging and transport
  2. Defect in Protein Folding –> Causes an accumulation of Misfolded Proteins
  3. Storage Disease –> Failure to degrade a metabolite due to inherited enzyme deficiencies
  4. Ingestion of Indigestible Materials –> Accumulation of carbon or silica particles

(Figure 2-29; Pg. 61)

41
Q

Differentiate between the Intracellular Accumulation of:

  1. Triglycerides
  2. Cholesterol
A
  1. Triglycerides –> In developed nations, most common causes are Alcohol Abuse and NAFLD which is associated with diabetes and obesity
    (Figure 2-30; Pg. 62)
  2. Cholesterol –> Seen in Atherosclerosis, Xanthomas (Clusters of foam cells found in the skin and tendons), Cholesterolosis (Gallbladder), Niemann-Pick Disease, Type C (Mutations in affecting enzymes that cause an accumulation of Cholesterol in multiple organs)
    (Figure 2-31; Pg. 62)
42
Q

Describe the Intracellular Accumulation of Proteins.

A

Have diverse causes:
1. Reabsorption droplets in proximal renal tubules –> Seen in Renal Diseases associated with protein loss in the urine; INCREASED reabsorption of the protein into vesicles and the protein appears as pink hyaline droplets within the cytoplasm (Figure 2-32; Pg 63)

  1. ER of Plasma cells can become distended and produces large inclusions called RUSSELL BODIES
  2. Defective Intracellular Transport and secretion of Critical Proteins –> Can result in Emphysema
  3. Accumulation of Cytoskeletal Proteins –> Accumulation of Keratin intermediate Filaments is present in Alcoholic Liver Disease
  4. Aggregation of Abnormal Proteins –> Misfolded proteins can deposit into tissue and interfere with normal functions; These are called AMYLOIDS
43
Q

Describe intracellular accumulation of Hyaline Change.

A

Intracellular Hyaline Deposits –> Reabsorption droplets, Russell Bodies, Alcoholic Hyaline

Extracellular Hyaline –> Walls of arterioles will become hyalinized in Long-Standing Hypertension and Diabetes Mellitus

44
Q

Describe Intracellular Accumulation of Glycogen.

A

Glycogen Masses –> Appear as CLEAR vacuoles within the cytoplasm

In Diabetes Mellitus you will have the accumulation of Glycogen in the Liver, Renal Tubular Cells, Islets of Landerhans and the Heart muscle groups

45
Q

Differentiate between Exogenous and Endogenous Pigment Accumulation.

A
  1. Exogenous Pigments –> MOST COMMON exogenous pigment is Carbon; Coal Worker’s Pneumoconiosis is when carbon from “Coal Dust” is going to cause fibroblastic reaction or emphysema in the lungs; Tattooing is another form of exogenous pigmentation of the skin!
  2. Endogenous Pigments –> Lipofuscin (contains Polymers of Lipids and Phospholipids (Probably due to Lipid Peroxidation); Its presence is a TELL-TALE sign of FREE RADICALS; In tissue sections it appears as a yellow-brown pigment; MELANIN is a brown-black pigment;; HEMOSIDERIN is one of the major storage forms of iron (Golden yellow-to-brown), When there is a local or systemic EXCESS of iron, ferritin forms hemosiderin granules, which are easily seen with a light microscope
    - - LOCAL excess of Hemosiderin –> Bruise
    - - Systemic excess of Hemosiderin –> Hemosiderosis (hemosiderin may be deposited in many organs and tissues) can occur; Main causes are: 1. Increased absorption of dietary iron due to an inborn error of metabolism (HEMOCHROMATOSIS); 2. Hemolytic Anemias; 3. Repeated blood transfusions, because transfused red cells constitute an exogenous load of iron

(Figure 2-33; Pg. 64)

46
Q

Differentiate between:

  1. Dystrophic Calcification
  2. Metastatic Calcification
A
  1. Dystrophic Calcification –> Deposition occurs LOCALLY with NORMAL serum levels of Calcium; Commonly develops in aging or damage heart valves; Appear as microscopical fine, white granules or clumps, often felt as gritty deposits; Often cause of Organ Dysfunction
  2. Metastatic Calcification –> May occur in NORMAL tissue whenever there is HYPERCALCEMIA; Four Types of Hypercalcemia: 1. Increased Parathyroid Hormone; 2. Resorption of Bone Tissue; 3. Vitamin D-related Disorders; 4. Renal Failure
47
Q

Describe the different components of cellular aging.

A

Cellular Aging is a result of a progressive decline in cellular function and viability caused by Genetic Abnormalities and the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences.

  1. DNA damage –> Accumulates as we age; Werner Syndrome (damaged DNA helicase) will accumulate more errors and you will age faster; Blood Syndrome and Ataxiotelangiectasia (mutated genes fixing double stranded breaks)
  2. Cellular Senescence –> Cells only have a finite amount of time to replicate until it will be in the senescence stage; 1. Telomere shortening (Telomerase will maintain the telomeres and it is almost absent in Somatic Cells - In cancer cells, TELOMERASE is Reactivated so they will not exit the cell cycle!); 2. Activation of Tumor Suppressor Genes (CDKN2A locus mutation –> p16 and INK4a (They control the G1 to S phase of the cell cycle))
  3. Defective Protein Homeostasis –> Decrease in proteins will result in a decrease in cellular functions
  4. Deregulated Nutrient Sensing –> Eating LESS can increase Longevity! Decrease Insulin/IGF signaling, Decrease mTOR (rapamycin will inhibit mTOR), and Sirtuins (promote expression of genes that prolong life!)

(Figure 2-35; Pg. 66)

Mechanisms of Disease I (4 decks)

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