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
2
Q
What is the cellular response to decreased nutrients?
A
Atrophy
3
Q
What is the cellular response to chronic irritation (physical or chemical)?
A
Metaplasia
4
Q
What is the cellular response to reduced oxygen supply?
A
Cell injury
5
Q
What is the cellular response to increased stimulation (e.g., by growth factors, hormones,etc)?
A
Hypertrophy and Hyperplasia
6
Q
What is the cellular response to decreased stimulation (e.g., by growth factors, hormones, etc)?
A
Atrophy
7
Q
What is the cellular response to chemical injury?
A
Cell injury
8
Q
What is the cellular response to microbial infection?
A
Cell injury
9
Q
What is the cellular response to acute and transient stress?
A
Acute reversible injury
Cellular swelling fatty change
10
Q
What is the cellular response to progressive and severe stress (including DNA damage)?
A
Irreversible injury –> cell death
Necrosis
Apoptosis
11
Q
What is the cellular response to Metabolic alterations, genetic or acquired?
A
Intracellular accumulations
12
Q
What is the cellular response to chronic injury?
A
Calcification
13
Q
What is the cellular response to cumulative sub-lethal injury over long life span?
A
Cellular Aging
14
Q
What is the stain that colors Myocardium magenta?
A
Triphenyltetrazolium
15
Q
What is the most common stimulus for skeletal muscle hypertrophy?
A
Increased Work load
16
Q
What is the most common stimulus for cardiac muscle hypertrophy?
A
Increased hemodynamic load
17
Q
What is the key characteristic of hypertrophy?
A
Increased protein synthesis
(increase in cytoskeleton
18
Q
What are the three general signals responsible for cardiac hypertrophy?
A
Mechanoreceptors detecting an increased workload
Growth Factors
Vasoactive Agents
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)
20
Q
What are the Vasoactive Agents invovled in signaling cardiac hypertrophy?
A
Angiotensin II
Endothelin 1
Alpha Adrenergic Agonists
21
Q
What are the two major biochemical signal transduction pathways of cardiac hypertrophy?
A
GPCR Pathway
PI3K/AKT Pathway
22
Q
Which signal transduction pathway is more important for Physiologic Cardiac Hypertrophy?
A
PI3K/AKT Pathway
23
Q
Which signal transduction pathway is more important for Pathologic Cardiac Hypertrophy?
A
GPCR Pathway
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
25
What switch occurs with hypertrophy in cardiac muscle?
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
26
What is different between the Adult and Fetal Contractile Proteins in cardiac muscle?
Adult (Alpha) Myosin Heavy Chain is FASTER, but LESS energetically economical contraction
Fetal (Beta) Myosin Heavy Chain is SLOWER, but MORE energetically economical contraction
27
What signal is expressed in cardiac muscle in response to hypertrophy and what does it do?
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
28
What happens when the hypertrophy of the cardiac muscle reaches its limit?
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
29
Cell injury occurs when hypertrophy of the cardiac muscle reaches its limit, what is used to treat it?
Inhibitors of the Transcription Factors responsible for the muscle hypertrophy:
NFAT Inhibition
GATA4 Inhibitor
MEF2 Inhibitor
30
What signals Physiologic Hyperplasia?
Growth factors and hormones
31
What is an example of compensatory hyperplasia?
Regeneration of the liver
32
What signals Pathologic Hyperplasia?
Excessive/innapropriate amounts of hormones or growth factors
OR
Inapropriate actions of hormones or growth factors
33
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?
Increased levels of estrogen
Estrogen is coming from peripheral conversion in adipocytes
34
What adaptation constitutes a "fertal soil" in which cancerous proliferations may eventually arise?
Pathologic Hyperplasia
35
What is the characteristic sign of Atrophy?
Autophagy and decreased protein synthesis
36
What are the 6 forms of atrophy?
1. Decreased Workload (disuse)
2. Diminished blood supply
3. Inadequate nutrition
4. Loss of innervation
5. Reduced Endocrine Stimulation
6. Pressure
37
What is Senile Atrophy?
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
38
What is Marasmus?
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
39
What is cachexia?
Marked muscle wasting
40
What is the role of TNF in cancer?
TNF suppresses appetite and depletes lipid stores
Leads to wasting of the muscle tissue (cachexia)
41
What does atrophy result from?
Decreased protein synthesis and increased protein degradation
42
What is the pathway responsible for atrophy due to inadequate definition and disuse?
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
43
What process is commonly associated with atrophy?
The hallmark of atrophy is autophagy
Autophagy - starved cells eat their own components in an attempt to meet nutrient demands
44
What happens to structures that are indigestible during autophagy?
The indigestible materials remain in membrane-bound structures called Residual Bodies
Ex: Lipofuscin granules, gives the tissue a yellow-brown appearance
- Brown Atrophy
45
What is Lipofuscin?
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
46
What is the adaptation observed in the respiratory tract in response to Vitamin A (retinoic acid) deficiency?
Squamous Metaplasia
Ciliated Columnar cells of the respiratory tract are replaced with stratified squamous epithelium
47
What is the adaptation observed in cases of Barrets Esophagus?
Columnar Cell Metaplasia
Squamous cells of the lower esophagus are replaced with Intestinal-like Columnar Cells
48
Which cells undergo metaplasia?
Stem Cells
OR
Undifferentiated mesenchymal cells present in connective tissue
These cells undergo reprogramming resulting in a change in phentoype
49
What signals tell cells t undergo metaplasia?
Cytokines
Growth Factors
Extracellular Matrix Signals
50
What occurs to a cell undergoing reversible cell injury?
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
51
What are the two causes of cell death?
Necrosis and Apoptosis
52
What is necrosis?
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
53
What is the hallmark of necrosis?
When cellular contents leak out of the cell, INFLAMMATION occurs
54
What is apoptosis?
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
55
What are the 7 causes of cellular injury?
- Oxygen Deprivation
- Physical Agents (mechanical trauma, temperature extremes, radiation, electric shock)
- Chemical Agents (drugs)
- Infectious agents
- Immunological Reactions
- Genetic Derangements
- Nutritional Imbalances
56
What happens to a cell during oxygen deprivation
Cell becomes hypoxic
| - Reduced ability to conduct aerobic respiration and oxidative phosphorylation
57
What are the three causes of Oxygen Deprivation?
Ischemia - reduced blood flow (infarction)
Hypoxemia - reduced O2 content of blood (high altitude, pulmonary fibrosis)
Anemia - decreased O2 carrying capacity (CO poisoning)
58
How does cellular response to Oxygen Deprivation differ if it is immediate onset or gradual?
Immediate onset (such as a thrombus) cells can die
If the injury occurs gradually over time, the cell can adapt and atrophy
59
What are the morphological changes seen in REVERSIBLE cell injury?
- 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
60
What are the reversible changes to a cell that can be seen under a light microscope?
Cellular Swelling
Fatty Change
61
What causes cellular swelling in reversible cell injury?
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)
62
What is pallor?
Unhealthy pale appearance
63
What is hydropic change or Vacuolar Degeneration?
During reversible cell injury, the endoplasmic reticulum degrades by pinching off small clear vacuoles, giving the cytoplasm the appearance of containing many small bubbles
64
Why do cells that have undergone reversible cell injury show increased eosinophilia with H/E stains?
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
65
What causes the fatty change observed in reversible cell injury?
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)
66
What are Ultrastructural Changes of reversible cell injury?
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
67
What physical presentation defines Necrosis/irreversible cell injury?
Cell membrane can't be maintained and contents of the cell leak out
68
What is the source of the digestive enzymes responsible for necrosis/irreversible cell injury?
Lysosomal enzymes of the necrotic cell as well as lysosomal enzymes of the leukocytes recruited as part of the inflammatory reaction
69
How long does it take for histological evidence of an MI to become apparent?
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
70
Aside from loss of plasma membrane integrity, what other indicators of necrosis/irreversible cell injury become apparent?
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
71
What are myelin figures?
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
72
What are the 3 patterns of nuclear changes seen in necrosis/irreversible cell injury?
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
73
What are the 6 patterns of necrosis?
Coagulative Necrosis
Liquefactive Necrosis
Gangrenous Necrosis
Caseous Necrosis
Fat Necrosis
Fibrinoid Necrosis
74
What is coagulative necrosis?
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
75
What is liquefactive necrosis?
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
76
What is gangrenous necrosis?
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.
77
What is Caseous Necrosis?
"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
78
What is Fibrinoid Necrosis?
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"
79
What is Fat Necrosis?
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
80
What happens if necrotic cells are not destroyed and phagocytosed by leukocytes?
The necrotic cells act as a nest for calcification
This process is called Dystrophic Calcification
81
What are the major causes of ATP depletion?
Reduced O2 Supply
Mitochondrial Damage
Actions of some toxins, such as cyanide
82
What changes occur when ATP is depleted in the cell?
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
83
What happens when the Na-K-ATPase stops functioning?
Na+ leaks into the cell and accumulates
K+ Leaks out of the cell
Water follows the Na+, causing cellular swelling and dilation of ER
84
What happens when AMP accumulates in the cell?
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
85
What happens when Ca2+ Pump stops functioning?
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)
86
What causes the increase in misfolded proteins and what is the result of this?
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
87
What are the three major consequences of mitochondrial damage?
Formation of mitochondrial permeability transition pore
Abnormal Oxidative Phosphorylation, which leads to production of ROS
Cytochrome C
88
What are the concequences that follow the formation of a mitochondrial permeability transition pore?
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
89
Why Cyctochrome C release from mitochondria bad?
Cytochrome C activates Caspases in the cytosol
| Caspases are apoptosis inducing enzymes
INTRINSIC PATHWAY
90
What are Reactive Oxygen Species (ROS), a type of free radical?
They are reactive/damaging molecules produced by various means
They are:
- Superoxide (O2-)
- Hydrogen Peroxide (H2O2)
- Hydroxyl Ion (OH-)
91
How are ROS produced?
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-
92
What is Chronic Granulomatous Disease (CGD)?
CGD is a deficiency in NADPH Oxidase
Causes an increase in susceptibility to catalase positive pathogens
93
What processes also produces free radicals, but not ROS?
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
94
What is the Fenton Reaction?
H2O2 + Fe2+ -> Fe3+ + OH* + OH-
Reduces Fe2+ (Ferrous) to into Fe3+ (ferric)
Reaction is enhanced by Superoxide (O2-)
Produces Hydroxyl ions
95
How can ROS production be prevented?
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
96
How can ROS be removed?
They decay on their own pretty quickly
Some enzymes scavenge and breakdown ROS
- Catalase
- Superoxide Dismutase
- Glutathione Peroxidase
97
What is Catalase?
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
98
What is superoxide dismutase (SOD)?
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
99
What is Glutathione Peroxidase?
Found in the Mitochondria and Cytosol
Breaks down OH- (hydroxyl ion) into H20
Breaks down H2O2 (hydrogen peroxide) into O2 and H2O
100
What does the Intracellular ratio of Oxidized and Reduced Glutathione tell you?
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
101
How is Superoxide inactivated?
O2- is inactivated by Superoxide Dismutase
Converts O2- into H2O2 (hydrogen Peroxide) and O2
102
How is Hydrogen peroxide inactivated?
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
103
How is Hydroxyl ion inactivated?
OH- is inactivated by Glutathione Peroxidase
Glutathione Peroxidase (in the cytosol and mitochondria) convert OH- to H2O
104
What are the pathological effects of Free Radicals?
Lipid Peroxidation
Oxidative Modification of Proteins
Lesions of DNA
105
What is Lipid Peroxidation and how are free radicals involved?
Free radicals attack double bonds found in lipid membranes of cells
Auto-catalytic chain reaction ensues (propagation)
Causes extensive membrane damage
106
What is Oxidative Modification of Proteins and how are free radicals involved?
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
How are free radicals responsible for Lesions of DNA?
Free radicals can cause single and double strand breaks in DNA
Can lead to cell aging and cancer
108
Which ROS is the most reactive, and most responsible for cell damage?
OH- (hydroxyl ion)
109
Do ROS provide any use to a cell?
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
The major Actions of O2- (superoxide) stem from what?
Stem from superoxide's ability to stimulate the production of degradative enzymes rather than direct damage of macromoleucles
111
What are the mechanisms of membrane damage?
ROS and lipid Peroxidation
Decreased phsopholipid synthesis
Increased phospholipid breakdown
Cytoskeletal abnormalities
112
How do ROS and lipid peroxidation lead to membrane damage?
ROS attack double bonds in phospholipids and cause a chain reaction that leads to membrane damage
113
What is the mechanism of Decreased Phospholipid synthesis?
Phospholipid synthesis deacrease occurs as a result of Hypoxia or Mitochondrial dysfunction
Affects all membranes, including those of organelles
114
What is the meachanism responsible for increased phospholipid breakdown?
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
What is the mechanism for cytoskeleton abnormalities that lead to membrane damage?
Increased Ca2+ cause proteases to attack cytoskeleton
Cytoskeleton detaches from membrane
Allows the possibility of membrane expansion and rupture
116
What are the consequences of Mitochondrial Membrane Damage?
Opening of the transition pore
Causes decrease in ATP synthesis and release of Cytochrome C, which activates caspases (initiating apoptosis)
117
What are the consequences of plasma membrane damage
Loss of osmotic balance and cellular contents, including compounds needed for making ATP
Leaky plasma membrane is bad
118
What are the consequences of Lysosomal Membrane Damage?
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
What 2 morphological changes consistently represent irreversible changes in cell injury?
1. Inability to reverse mitochondrial dysfunction and profound problems to membrane function
2. Leakage of Intracellular Proteins through damaged cell membrane
120
What are the biomarkers that are released from cardiac muscle when there is membrane damage?
Cardiac Specific isoform of Creatine Kinase
Troponin
121
What are the biomarkers that are released from liver and bile duct epithelium when there is membrane damage?
Alkaline Phosphatase
122
What are the biomarkers that are released from hepatocytes when there is membrane damage?
Transaminases
123
What are the two potential causes of Ischemia?
Mechanical arterial obstruction
OR
Reduced Venous Drainage
124
What is ischemia?
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
How is glycolysis affected in Hypoxia vs Ischemia?
Hypoxia - Glycolysis (anaerobic) can continue
Ischemia - compromises delivery of substrates for glycolysis, therefore glycolysis cannot continue
- Aerobic AND Anaerobic metabolism is compromised
126
Which is worse? Ischemia or Hypoxia without ischemia?
Ischemia is worse
Causes a more rapid and severe cell and tissue injury than hypoxia without ischemia
127
What are irreversible changes that happen to a cell if ischemia persists?
Severe swelling of mitochondria
Extensive damage to cell membrane - leading to formation of myeline figures
Large, shape-less densities develop in mitochondrial matrix
128
What is Hypoxia-Inducible Factor 1?
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
What is angiogenesis?
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
How ischemia treated?
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
What is Ischemia-reperfusion Injury?
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
What are the mechanisms of Ischemia-Reperfusion injury mechanisms?
Oxidative Stress
Intracellular Ca2+
Inflammation
Complement System Activation
133
How does reperfusion cause oxidative stress?
Reperfusion leads to increased ROS and reactive nitrogen species production
Additionally, there is a decrease in anti-oxidants, which favors production ROS
134
How does reperfusion lead to intracelluar Ca2+ overload?
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
How does reperfusion lead to Inflammation?
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
How does reperfusion lead to complement system activation?
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
What toxic effects does mercury cause to cells?
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
What toxic effects does cyanide cause to cells?
Follows Direct Toxic Injury Mechanism
Cyanide binds to Cytochrome Oxidase
This binding inhibits Oxidative Phosphorylation in mitochdondria
Occurs in ALL CELLS
139
What are the two mechanisms of toxic injury?
Direct Toxic Injury
Indirect Toxic Injury
- conversion to toxic metabolites
140
What mechanism of toxic injury do antineoplastic chemotherapeutic drugs follow?
Direct Toxic Injury Mechanism
141
What is indirect toxicity?
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
What do reactive toxic metabolites do to a cell?
Through mainly formation of free radicals and then lipid peroxidation, causes:
- Cell membrane damage and general cell injury
143
What toxins are examples of Indirect Toxicity?
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
What is physiologic apoptosis?
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
Apoptosis in embryogenesis
Digitation of hands and feet to form fingers and toes
146
Examples of Apoptosis for involution of hormone sensitive dependent organs with hormone withdrawal
Endometrial cell breakdown during the menstrual cycle
Ovarian follicular atresia in menopause
Regression of lactating breast after weaning
Prostatic Atrophy after castration
147
Examples apoptosis for cell population retraction
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
Examples of apoptosis for cells that have served their purpose
Neutrophils in an acute inflammatory response
Lymphocytes at the end of an immune response
149
What is pathological apoptosis?
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
How does DNA damage trigger apoptosis?
If a cell has extensive DNA damage to the point where it irreversible, the cell triggers Intrinsic apoptotic pathway
151
How does accumulation of misfolded proteins trigger apoptosis?
Misfolded proteins accumulate in the ER
Causes ER stress
Cell induces apoptosis
152
How does virus induced apoptosis occur?
The virus itself can trigger a cascade of signals resulting in apoptosis
OR
T-cells signal cell infected with virus to undergo apoptosis
153
What is the morphology observed in apoptotic cells?
Cell Shrinkage
Chromatin condensation
Formation of cytoplasmic blebs and apoptotic bodies
Macrophage phagocytosis of Apoptotic cells or cell bodies
154
What happens during cell shrinkage?
Apoptotic cell shrinks, forming a more concentrated cytoplasm and more tightly packed organelles
Opposite of cell injury (swelling)
155
What is the most characteristic feature of apoptosis?
chromatin condensation
156
What happens with chromatin condensation?
Chromatin condense peripherally into oddly shaped masses
Then even the nucleus may fragment into pieces
157
What are apoptotic bodies and how are they formed?
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
What happens to apoptotic bodies?
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
What are the two phases of apoptosis?
Initiation Phase
Execution Phase
160
What is the initiation phase of apoptosis?
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
What is the execution phase of apoptosis?
After some caspases become activated, other caspases trigger degredation of cellular components
Common executioner caspases:
- Caspase-3
- Caspase-6
162
What are the two apoptotic pathways?
Intrinsic pathway
Extrinsic Pathway
163
What is the intrinsic pathway?
Increased permeability of the mitochondrial outer membrane and pro-apoptotic molecules trigger the intrinsic pathway; such as Cytochrome C
164
What controls the release of apoptotic signals from the mitochondria?
BCL Family proteins.
3 Categories:
- Pro-apoptotic
- Anti-apoptotic
- Apoptotic Sensors
165
What are Anti-Apoptotic BCL family proteins?
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
What are Pro-Apoptotic BCL family proteins?
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
What are the BCL Family Apoptotic sensors?
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
What is the mechanism of the Intrinsic Apoptotic Pathway?
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
What initiates the extrinsic pathway?
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
What mechanism occurs as T-cell interacts with target cell?
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
What is FLIP?
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
What happens in the Execution phase of Apoptosis?
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
What signal is responsible for macrophage recognition of apoptotic bodies?
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
What do apoptotic bodies do in order to be recognized by phagocytes?
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
What is the TP53 gene?
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
How does p53 protein trigger apoptosis?
p53 stimulates expression of pro-apoptotic BCL family proteins (BAX and BAK)
177
What happens if the TP53 gene is mutated or absent?
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
What are the causes of apoptosis?
Growth factor deprivation
DNA damage
Protein Misfolding
179
What causes protein misfolding?
Metabolic alterations that deplete energy stores
genetic mutations in proteins/chaperones
Viral infections
Chemical insults
180
What is the Unfolded Protein Response?
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
What happens if the Unfolded Protein Response is unable to cope with accumulation of misfolded proteins?
Too much accumulation of misfolded proteins leads to ER stress
ER stress signals the activation of caspases, initiating apoptosis
182
What diseases involve the accumulation of misfolded proteins?
Alzheimer's, Parkinsons, Huntingtons, and maybe Type II Diabetes
183
How do Cytotoxic T Lymphocytes (CTLs) kill cells?
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
What is the most common mutation in human cancers?
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
What disorders are associated with increased apoptosis and excessive cells death?
Neurodegenertive diseases
Ischemic Injury
Death of virus infected cells
186
What is necroptosis?
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
Does necroptosis utilize caspases?
NO
Caspase independent programmed cell death
188
What cell death processes are TNF family proteins involved in?
Apoptosis
- FasL/Fas
Necroptosis
- TNFR1/RIP1/RIP3
189
What is the signal transduction cascade of necroptosis?
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
What are the physiological functions of necroptosis?
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
What is pyropoptosis?
Another mechanism of programmed cell death
Accompanied by release of fever inducing Cytokine IL-1 (hence the name pyro)
192
What is the mechanism of pyropoptosis?
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
What is the Morphology of Pyropoptosis?
Characterized by:
- Cell Swelling
- Loss of membrane integrity
- Release of inflammatory mediators
NO APOPTOSIS
194
What is pyropoptosis good for?
Good for killing some microbes that gain entry into the cytoplasm
195
What is autophagy?
Process in which the cell eats itself
Prominent in atrophic cells exposed to sever nutrient deprivation
196
What are the functions of autophagy?
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
What are the three ways autophagy can occur?
Chaperone Mediated Autophagy
Microautophagy
Macroautophagy
198
What is Chaperone Mediated Autophagy?
Direct translocation of material into the lysosomes via chaperone proteins
199
What is Mircoautophagy?
Inward invagination of the lysosomal membrane, consuming cytosolic materials
200
What is Macroautophagy?
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
What is the first step in the mechanism of autophagy?
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
What is the second step of the autophagy mechanism?
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
What is the third step of the autophagy mechanism?
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
In which cases is autophagy involved in human disease?
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
What are intracellular accumulations?
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
What are the 4 main pathways of intracellular accumulation?
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
What are the presentations of lipid accumulation?
Steatosis (fatty change)
Atherosclerosis
Xanthomas
Cholesterolosis
Niemann-Pick Disease, type C
208
What is Steatosis?
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
What is atherosclerosis?
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
What is Xanthomas?
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
What is cholesterolosis?
Focal accumulation of cholesterol-laden macrophages in the lamina propria of the Gall Bladder
212
What is Neimann-Pick disease, Type C?
Lysosomal storage disease that affects an enzyme involved in cholesterol trafficking.
Results in cholesterol accumulation in multiple organs
NFL
*Neimann-picks Fatty Lysosomes*
213
What is the morphology of protein accumulation?
Intracellular accumulations of proteins appear as rounded, eosinophilic droplets, vacuoles, or aggregates in the cytoplasm
214
What are the causes of protein accumulation?
- 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
How does reabsorption droplets lead to protein accumulation in the proximal renal tubules?
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
What are Russell Bodies?
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
How does defective intracellular trnasport and secretion of critical proteins lead to accumulation?
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
How does accumulation of cytoskeletal proteins occur?
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
How does aggregation of abnormal proteins occur?
Abnormal or misfolded proteins may deposit intracellulary, extracellulary, or both
Amyloidosis
Sometimes called proteinopathies or protein-aggregation diseases
220
What is Hyaline change?
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
How does extracellular hyaline occur?
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
What is glycogen accumulation?
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
How does glycogen accumulation occur in Diabetes Mellitus?
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
What are pigments?
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
What are some endogenous pigments?
Lipofuscin
Melanin
Hemosiderin granules
226
What are some examples of exogenous pigments?
Carbon
Tatooing
227
How is carbon handled as an exogeneous pigment?
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
How are tattoo pigments handled?
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
What is Lipofuscin?
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
What is melanin?
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
What is Homogentisic Acid?
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
What are Hemosiderin Granules?
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
What is Hemosiderosis?
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
How do you explain the cahnging colors of bruising?
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
What is pathologic calcification?
Abnormal tissue deposition of Calcium and Salts (mostly), plus a little Iron and Magnesium
236
What are the two types of pathologic calcification?
Dystrophic Calcification
Metastatic Calcification
237
What are psammoma bodies?
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
What is asbestosis?
Calcium and iron salts gather about long, slender asbestos shards in the lung and create exotic, beaded dumbbell forms
239
What is the morphology of calcification?
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
What is dystrophic calcification?
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
What is Metastatic Calcification?
Deposition of calcium salts in otherwise normal tissues
Almost always the result of hypercalcemia secondary to some disturbance in calcium
242
What causes hyperaclemia due to increased bone resorption?
- 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
What other ways does Hypercalcemia occur?
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
Where does metastatic calcification occur?
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
What regulates cell aging?
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
What is aging?
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
What leads to cellular aging?
DNA damage
ROS (mutations)
Telomere shortening (decreased cellular replication)
Defective protein homeostasis (decreased cellular functions)
248
What counteracts aging?
Decreased insulin/IGF signaling and decreased TOR leads to:
Altered transcription
Increased DNA repair
Increased Protein synthesis
249
What is Werner Syndrome?
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
What two diseases are associated with defective double-stranded breaks repair?
Bloom Syndrome
Ataxia Telangiectasia
251
What is Replicative Senescence?
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
What is Quiescence?
Non-dividing state but can enter cell cycle if the envrionment calls for it
253
What is Telomere Attrition
Progressive shortening of telomeres with each round of cell division ultimately results in cell cycle arrest
254
What is telomerase?
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
How does activation of Tumor Suppressor Genes work?
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
What happens to protein folding with aging?
Normal folding and degradation of abnormally folded proteins decreases with age
The expression of chaperone proteins are positively correlated with longevity.
257
What happens to nutrient sensing with aging?
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
What is rapamycin?
Rapamycin inhibits the mTOR pathway and increases the life span of middle aged mice
