Cell Adaptation and Injury Flashcards
1
Q
What 3 things confine the normal cell to a narrow range of function and structure?
A
- genetic programs of metabolism, differentiation, and specialization
- constraints of neighboring cells
- availability of metabolic substrates
2
Q
Physiologic and morphologic cellular adaptations
A
- achieve new (altered) steady state
- preserve the viability of the cell
- modulate function as cell responds to stimuli
3
Q
When does cellular injury occur?
A
If the limits of the adaptive response to a stimulus are exceeded, or if a cell is exposed to an injurious agent or stress
4
Q
The point of no return
A
If the stimulus persists or is severe enough from the beginning, the cell reaches the point of no return and suffers irreversible cell injury and cell death
5
Q
Common sign of cell injury is _______
A
Cell swelling
6
Q
Standard organelles
A
- synthesis of lipids, proteins, CHO
- energy production
- transport of ions and other molecules
7
Q
Homeostasis
A
Tight control of pH, electrolyte concentration, etc
8
Q
Departure from homeostasis leads to _______
A
Cell damage
9
Q
How do cells respond to homeostatic challenges?
A
Adaptation
10
Q
What happens if a new level of homeostasis can not be achieved?
A
Cell death
11
Q
Stages in the cellular response to stress and injurious stimuli
A
Normal cell –> (injurious stimulus) –> cell injury and cell death
OR
Normal cell –> (stress, increased demand) –> adaptation –> (inability to adapt) –> cell injury/death
12
Q
Examples of cellular adaptations
A
- increase in muscle mass with exercise
- increase in cytochrome p450 mixed function oxidation expression in hepatocytes
- cells respond by either increasing or decreasing content of organelles
13
Q
Atrophy
A
Reduction in mass of a tissue or organ
- loss of cells
- reduction in size of cells within an organ
14
Q
Hypertrophy
A
Increase in the size of cells, resulting in enlargement of organs
15
Q
Hyperplasia
A
Increased number of cells in an organ or tissue
16
Q
Metaplasia
A
Transformation or replacement of one adult cell type with another
17
Q
Adaptive response to altered demands
A
- decreased workload
- decreased nutrition
- loss of hormonal stimulation
- decreased blood supply
- loss of innervation
18
Q
In what scenario is atrophy a good thing?
A
After a cow gives birth, the uterus will shrink back to normal size
- due to loss of cells
19
Q
Cellular atrophy
A
- reversible cellular change
- reduced functional capacity
- continue to control internal environment and produce sufficient energy for metabolic state
20
Q
What happens during adrenal cortical atrophy?
A
Corticosteroid treatment inhibits ACTH –> low ACTH –> atrophy of adrenal cortex –> sudden withdrawal of CS tx = Addisonian crisis
- gradual withdrawal allows cells to return to normal function
21
Q
Prolonged cellular atrophy may lead to _______
A
Death of some of the cells
- atrophy at the organ level may become irreversible at this point (muscle) or may be reversible by hyperplasia (liver)
22
Q
At the organ level, ______ increases organ size without cellular proliferation
A
Hypertrophy
23
Q
Changes in hypertrophic cells
A
- increased protein content
- increased organelle number (myofibrils, mitochondria, ER)
24
Q
____ process > ______ processes
A
Anabolic; catabolic
25
What happens in the liver with induction of hypertrophy?
- response to certain drug administrations (phenobarb, alcohol)
- mixed function oxidases (metabolize compounds, increase water solubility to allow excretion)
26
When is cellular hypertrophy detrimental to an animal?
Heart
- inability to provide adequate energy/contraction, despite hypertrophy
- conformational changes associated (decreased ejection volume)
- may end up with organ failure
27
Induction of the liver
- tolerance to certain drugs/toxins
- more rapid removal of certain drugs/toxins
- may increase susceptibility to some toxins (metabolites may be more toxic than precursors)
28
Do toxins become toxic when they are eaten?
No, they become toxic when the liver metabolizes them
| - addition of charged particle or side group creates a free radical that can damage other molecules
29
Cell injury
Any change that results in loss of the ability to maintain the normal or adapted homeostatic state
30
How does the extent of cell injury vary?
- severity of stimulus
- type of cell involved
- metabolic state at the time of injury
31
Reversible cell injury
Degeneration
| - ex: swelling of endoplasmic reticulum and mitochondria
32
_______ changes lag behind ______ changes
Morphologic; functional
33
Irreversible cell injury
Necrosis
- lysosome rupture
- membrane blebs
- nuclear condensation
- fragmentation of cell membrane and nucleus
34
What are the 11 hallmarks of cell degeneration?
- cell swelling
- fatty change
- glycogen accumulation
- lipofuscin and ceroid
- hyaline changes
- amyloid
- mucinous changes
- calcification
- gout
- cholesterol crystals
- inclusions
35
Lipofuscin and ceroid
Oxidized product from membrane lipids
| - yellow to brown
36
Hyaline changes
Dense, homogenous, glossy, translucent
| - protein leakage most common cause
37
Amyloid
Complex protein that accumulates within cells
| - homogenous, pink material
38
Mucinous changes
Gelatinous, semi-solid, shiny, clear, stringy
| - serous atrophy of fat
39
Calcification
Abnormal accumulation of calcium salts in soft tissue
40
Gout
Occurs in birds and reptiles
| - associated with renal disease due to decreased excretion of urates
41
Cholesterol crystals
Areas of previous hemorrhage or inflammation
42
Inclusions
Viral disease
| - intranuclear or intracytoplasmic
43
What is an early, universal sign of cell injury?
Cell swelling
- loss of control of ions/water with net uptake of water
- compresses adjacent structures
- loss of energy control
- often mild, reversible, but also occurs in lethal injury
44
Loss of sinusoids in liver is due to _______
Cell swelling
45
Staining characteristics of cell swelling
Pale, cloudy appearance (cloudy swelling, hydropic degeneration)
- cytoplasmic vacoules --> distended organelles, lipid droplets
46
Gross appearance of cell swelling
Organ is pale, enlarged, swollen
- rounded margins
- heavy
- wet
- bulges on cut surface
47
Cell swelling - effect on organ
- brain: severe due to pressure necrosis
- liver: decreased blood flow, decreased function
- pharynx: airway obstruction
48
Fatty change
Accumulation of neutral fats (TG) in a cell
- common change in cells that metabolize lots of lipids
- sick cells accumulate TG
49
Does fatty change have anything to do with adipose tissue?
No
| - commonly occurs in: hepatocytes, myocardial cells, renal tubular epithelial cells, diabetes melitus
50
Gross appearance of fatty change
Yellow discoloration (kidney, liver), enlargement (liver)
51
Microscopic appearance of fatty change
- small to large
- clear
- non-membrane bound
- intracytoplasmic vacuoles
- nuclei pushed to cell periphery
52
Pathogenesis of fatty change
```
Overload
- increased mobilization of fats (anorexia), diabetes mellitus
Injury to cells
- toxins, anoxia
Deficiencies
- methionine, choline
```
53
Lipidosis
Normal in young animals (milk diet), normal following fatty meals
54
Pathogenesis of glycogen accumulation
- severe, prolonged hyperglycemia (diabetes mellitus)
- presence of high levels of glucocorticoids (Cushing's)
- lysosomal storage disease , defects in a step of glycogen breakdown
55
Where is the nucleus located during glycogen accumulation?
Center of cells!!
56
Gross appearance of glycogen accumulation
- swollen organ
- rounded margins (liver)
- increased pallor
57
Microscopic appearance of glycogen accumulation
- enlarged cells
- increased pallor
- no nuclear displacement
58
What is the number one cause of increased corticosteroids in animals?
Iatragenic - doctor induced
59
Lipofuscin
Pigment that collects in cells
- gross: brown discoloration of affected organs
- micro: membrane bound, brown pigment, myelin figures
60
What is a phrase for solid, glossy, semi-transparent material?
Hyaline change
61
Hyaline droplets
Cyotplasm contains rounded, eosinophilic droplets, vacuoles, or aggregates
62
Hyaline casts
Protein casts within renal tubules
| - unabsorbed protein: morphologic expression of proteinuria
63
Connective tissue hyaline
Compacted collagen, scar tissue
64
Amyloid
Homogenous, amorphic, eosinophilic matrix/substance deposited along basement membranes and between cells
65
Gross description of amyloid
Enlarged, pale, waxy, translucent organ
66
Serum amyloid A
Acute phase protein that increases during inflammation
| - forms beta pleated sheets that stick together, so proteins are unable to break them apart
67
Calcification
Abnormal deposition of calcium salts (calcium phosphate, calcium carbonate) in soft tissues
68
Gross appearance of calcification
Chalky, white tissue
| - hard, gritty on cut surface
69
Microscopic appearance of calcification
- dark blue staining material
- along basement membrane
- stippled throughout cell
- large clumps
70
Calcinosis
Widespread, excessive calcification
- calcinosis circumscripta: big lumps of calcium
- calcinosis cutis: non lumpy calcification of the skin and dermal connective tissue
71
Calcium in the cavities or lumina
Calculi/calculus
| - ex: urinary calculus, renal calculi
72
Accumulation of urate crystals
Gout
- tophus/topi
- typically seen in birds, reptiles
73
Gross appearance of gout
White, firm, crystal deposites
74
Micro appearance of gout
Granulomas with radiating crystalline material (radiating spicules)
75
Pathogenesis of gout
- disturbance of purine metabolism
- vitamin A deficiency
- kidney failure
76
What are the 2 forms of gout?
- visceral
| - articular
77
Nuclear change
- chromatin clumping
- condensation (pyknosis)
- dramatic nuclear change is usually indicative of necrosis
78
Plasma membrane changes
- loss of surface features (microvilli, cilia)
- desmosome breakdown
- bleb formation
79
Mitochondria changes
- swelling (may rupture)
- loss of dense granules
- calcium deposits
80
ER changes
- dilatation: contributes to vacuolar microscopic appearance
- dissociation of ribosomes
81
Other ultrastructural changes
- phospholipids from damaged organelle membranes accumulate to form myelin figures
- lysosomes: dilation and rupture (late event, terminal cell injury)
82
What are 3 cellular histologic features of necrosis?
- increased eosinophilia: altered protiens, loss of ribosomes, decreased cytoplasmic RNA
- loss of cellular detail
- nuclear changes
83
What are 3 forms of nuclear changes?
- pynkosis
- karyorrhexis
- karyolysis
84
Oxygen depraivation
Hypoxia
- decreased blood oxygen (pulmonary/nonpulmonary)
- decreased blood flow (hypovolemia, vasoconstriction, cardiogenic, shock)
Ischemia
- infarction
- complete/almost complete loss of blood flow
85
Physical agents of cell injury
- trauma
- radiation
- burns
86
Chemical agents of cell injury
- huge variety
- concentration, dose, length of exposure
- variety of actions (injure membranes, interfere with metabolism)
87
Infectious agents
- viruses, bacteria, protozoa, fungi
- elaborate toxins
- host inflammatory responses
88
Nutritional imbalances
- deficiencies
| - excesses
89
Cellular response depends on
- type of injury
- duration of injury
- cell state at the time of injury
- adaptability of the injured cell
90
What 4 intracellular systems are primarily vulnerable to injury?
- cell membrane
- aerobic respiration (mitochondria)
- protein synthesis (rough ER, ribosomes)
- preservation of genetic integrity (nucleus)
91
What are the 2 mechanisms of cell injury?
- interfere with substrates or enzymes
| - produce enzymes or molecules that degrade cell components
92
Most vulnerable systems are _____ production
Energy
- glycolysis
- citric acid cycle
- oxidative phosphorylation
93
What are the 5 components of the common pathway?
- ATP depletion
- oxygen and oxygen derived free radicals
- intracellular calcium loss/loss of calcium homeostasis
- defects in membrane permeability
- irreversible mitochondrial damage
94
ATP depletion
- oxidative phosphorylation of ADP to ATP
- glycolytic pathway --> ATP from glucose in the absence of oxygen
- frequent pathway in ischemic and toxic injuries
95
Organ variation in glycolysis
- brain: no glycolysis, rapid anoxic injury and death (4 min)
- muscle: abundant glycolysis
96
Oxygen and oxygen derived free radicals
Partially reduced reactive oxygen species (damage proteins, lipids, nucleic acid)
- kept under control by scavenging systems --> dead end molecules that absorb free radical energy without passing it on
97
Free radicals are ________
Auto-catalytic
| - especially in membranes!!
98
Normal cytosolic Ca is maintained at ______
Low concentrations
| - Mg/Ca ATP pumps
99
Increased calcium leads to
Increased:
- membrane permeability
- phospholipase activity
- protease activity
- ATPase activity
- endonuclease activity
- also causes self destruction via activation of apoptotic pathways
100
Defects in membrane permeability
- plasma membrane
- mitochondrial membrane
- direct damage: perforin, complement (MAC), inflammation
- indirect damage --> calcium levels, ATP depletion
101
Irreversible mitochondrial damage
Direct/indirect targets of all cell injury
| - damaged by everything from toxin to hypoxia leading to increased Ca, oxygen stress, degradation of phospholipids
102
High conductance channel formation
Mitochondrial permeability transition
| - prevents maintenance of the proton motive force/membrane potential that runs the electron transport chain
103
Hypoxic injury
Decrease in oxygen to affected tissues
- respiratory efficiency
- cardiac function
- tissue demand
- blood flow remains --> substrates for anaerobic metabolism delivered, or glycolytic pathway is used
104
Ischemic injury
Loss of blow flow to affected tissues
- hypovolemia
- infarction
- vasoconstriction
- shock
- loss of oxygen AND loss of substrates --> rapid depletion of ATP, and loss of cell function
- reversible, to a point
105
Reperfusion injury
Paradoxical increase in death of cells after blood flow is restored (shift back from anaerobic to aerobic creates free radicals)
- GDV
- stroke
- myocardial infarction
106
Decrease in oxidative phosphorylation in the mitochondria leads to
ATP depletion, and widespread cellular effects
- Na/K ATPase --> Na accumulates in cell, water follows = cell swelling
- ADP, phosphates, lactate cause further swelling
107
How is energy metabolism altered with hypoxia/ischemia?
Decrease in ATP and ADP leads to glycolysis
- decrease glycogen stores
- increase lactic acid
- increase organic phosphates
- decrease pH
108
Structural disruption of protein synthesis
- detachment of ribosomes from RER
| - dissociation of polysomes into monosomes
109
Functional consequences of ischemia/hypoxia
- heart muscle stops contracting within 60 seconds
| - neurons stop firing or fire erratically leading to loss of consciousness
110
Continuous ATP depletion causes
- cytoskeleton dispersal --> loss of microvilli, formation of blebs
- swelling of mitochondria
- ER dilation
- more cell swelling
111
______ dysfunction leads to membrane damage
Mitochondrial
- decrease ATP --> increase Ca --> activation of mitochondrial phospholipases --> accumulation of FFAs --> change in membrane permeability --> short circuits oxidative phosphorylation, decreasing ATP
112
Loss of membrane phospholipids leads to
Activation of phospholipases
- decrease in membrane phospholipids
- inccrease in Ca
113
How does reaction oxygen species cause membrane damage?
Free radicals!
- return of blood flow --> increase in free radicals
- deactivate/denature enzymes
- deactivate/denature membrane components (*self propagating*)
114
Lipid breakdown products
Unesterified fatty acids, acyl carnitine
- detergent effect on membranes
- increase permeability of membranes
115
Intracellular amino acids have a ______ against free radical damage
Protective
| - loss of intracellular AA leads to membrane damage
116
Loss of membrane integrity causes ____ to enter mitochondria
Ca
117
Hypoxia and ischemia affect ________, causing decreased ______
Oxidative phosphorylation; ATP
118
What is a critical step in the movement of a cell from reversible to irreversible damage?
Membrane damage
119
What is an important mediator of biochemical and morphologic alterations that leads to cell death?
Ca
120
Chemical species with an unpaired electron in their outer orbit
Free radicals
121
What are free radicals reactive to?
Adjacent molecules
- proteins, lipids, carbs, nucleic acids
- especially damaging to membranes
122
Free radical induced membrane damage is _______
Autocatalytic
- molecules that free radicals react with are converted into free radicals
- *self propagating!*
123
How are free radicals formed?
- absorption of radiant energy
- metabolism of chemicals (CCL4)
- byproduct of normal metabolism
- transition metals
- nitric oxide
124
Free radical formation as a byproduct of normal metabolism
Normal respiration molecular oxygen is reduced sequentially to form water
- intermediates produced:
- superoxide anion radical
- hydrogen peroxide
- hydroxyl ions
125
Lipid peroxidation of membranes
Initiated when double bonds of unsaturated fatty acids are attacked (especially by OH)
- yields peroxides (reactive, propagates)
- reaction continues until termination event occurs --> free radical captured by a scavenger (vitamin E)
126
Oxidative modification of proteins
Oxidation of amino acid side chains
- protein-protein cross links
- oxidation of protein backbone --> protein fragmentation
- enhanced degradation/turnover of critical proteins
127
DNA lesions
Reach with thymine to form cross links
- single stranded breaks
- implicated in cell aging
- implicated in malignant transformation of cells
128
Non enzymatic systems to inactivate free radicals
Anti-oxidants
- block formation or scavenge
- vitamin A, E, ascorbic acid, glutathione
Metal transport/storage proteins
- bind to Fe, Cu to prevent them from participating in Fenton rxn
- transferrin, ferritin, lactoferrin, ceruloplasmin
129
Enzymatic systems to inactivate free radicals
Catalase
- peroxisomes
Superoxide dismutases
Glutathione peroxidase
130
Directly toxic compounds
Capable of interacting with critical molecular components or cellular organelles
- ex: mercuric chloride, cyanide, chemotherapeutic agents
131
What pathway does cyanide block?
Oxidative phosphorylation
132
Indirectly toxic compounds
Converted to reactive toxic metabolites by mixed function oxidases (P450)
- SER of liver, lung, etc
- metabolites directly interact with cell membranes/proteins (less common)
- metabolites are/form free radicals (more common)
133
Are most toxins directly or indirectly toxic?
Indirectly
134
Carbon tetrachloride
CCl4
| - oxidation of fatty acids --> autocatalytic rxn
135
Acetaminophen
Sulfonation/glucuronidation in liver
- small amount converted to highly reactive metabolite --> normally scavenged by glutathion scavenger
- GSH system overwhelmed --> massive cell necrosis
136
What is the order of cell changes during prolonged injury?
Cell death --> ultrastructural changes --> light microscopic changes --> gross morphologic changes (takes longest to occur)
137
Morphologic hallmarks of irreversible cell injury and death
- severe mitochondrial swelling
- large flocculent densities in mito matrix
- increased loss of proteins, enzymes, coenzymes
- increased membrane permeability --> leakage of enzymes, initiation of inflammation
138
During irreversible cell injury you have massive influx of _____ into the cell
Ca
- worsens during reperfusion
- Ca functions as a 2nd messenger to activate/deactivate various enzymes
139
Lysosomal membrane permeability
- leakage of lysosomal enzymes
- activation of acid hydrolases
- digestion of cytosolic/membrane constituents
140
1 - 2 punch
Mitochondrial dysfunction and membrane damage
141
What is the central factor in irreversible cell injury?
Membrane damage
