Cell Injury, Death, and Adaptation Flashcards
1
Q
Etiology definition
A
Origin of a disease - including underlying causes and modifiers
The initiating event and its related risk factors
Why a disease occurs
2
Q
Pathogenesis definition
A
Development of disease, from molecular/cellular changes to functional and structural abnormalities
The transition from normal to abnormal
How a disease occurs
3
Q
Cell injury results from what?
A
Disruption of one or more components that maintain viability
Induces a cascade of effects
4
Q
What can happen following cell injury?
A
It may be reversible
May result in cell adaptation
May lead to cell death
5
Q
What happens if cell injury is mild/transient?
A
It is reversible and things can go back to normal
6
Q
What happens if cell injury is severe/progressive?
A
Can cause irreversible injury
Cell death
7
Q
What are the two types of cell death
A
Necrosis = death Apoptosis = programmed death
8
Q
What happens if cell death does not occur properly?
A
Can get sarcomas, carcinomas, cancers
9
Q
Clinical Expression definition
A
Several steps removed from morphologic changes that are preceded by the biochemical changes associated with cell injury
10
Q
What are different causes of cell injury - from the Patient’s persepective?
A
Hypoxia Infectious agents Physical injury Chemicals/drugs Immune response Genetric abnormalities Nutritional imbalance
11
Q
Hypoxia
A
Lack or decrease of Oxygen
12
Q
T/F - Hypoxia effects all cells equally
A
False - some cells are more sensitive to hypoxia than others, ie: heart and brain
13
Q
What are the major targets that cause cell injury/death
A
Cell membrane
Mitochondria
Cell proteins
DNA/RNA
14
Q
How can a disruption in cell membrane cause cell injury/death?
A
Disrupts the balance between electrolytes, cations, protein/enzyme balance
15
Q
How can a disruption of the mitochondria cause cell injury/death?
A
Impairs the cell’s ability to get energy
Function drops off rapidly
16
Q
How can a disruption of cell proteins cause cell injury/death?
A
Don’t get enzymes and structural proteins needed for function
17
Q
How can a disruption of DNA/RNA cause cell injury/death?
A
May take a while for the problem to manifest
Cell lacks an ability to get information
18
Q
What are the different cell injury mechanisms?
A
ATP depletion Generation of ROS Loss of Ca+2 homeostasis Altered membrane permeability Mitochondrial damage DNA and protein damage
19
Q
What is the Hypoxia-Ischemia model of cell damage, and what causes it?
A
Decreased (hypoxia) or no (anoxia) oxygen due to:
- Impaired absorption of oxygen
- Decreased blood flow (Ischemia)
- Disease of blood or blood vessels
- Inadequate oxygenation of the blood
20
Q
How does Hypoxia-Ischemia lead to decreased energy production?
What does the decrease in energy lead to?
A
Decreased oxygen impairs oxidative phosphorylation in the mitochondria
-Reduced ATP reduces the ability of the plasma membrane to maintain homeostasis, leading to a net gain of solute and an isosmotic gain in cytoplasmic water
21
Q
Decreased energy leads isosmotic gain in water leads to what?
A
- Cell swelling with formation of cell surface blebs
- Swelling of the mitochondria
- Dilation of the ER
22
Q
Dilation of the ER leads to what?
A
Detachment of ribosomes from RER and dissociation of polysomes and a decrease in protein synthesis
23
Q
Reduced Oxidative phosphorylation leads to what?
A
Increased glycolysis, producing lactic acid and inorganic phosphates which decreases intracellular pH, leading to chromatin clumping`
24
Q
Hypoglycemia
A
Reduced substrate for ATP producing results similar to the Hypoxia-Ischemia model
25
T/F - ROS are normally generated
True - they're generated by normal endogenous oxidative reactions in the plasma membrane, mitochondria, cytoplasm, and peroxisomes
26
Generation of too many ROS are associated with what?
```
Inflammation
Oxygen toxicity
Chemicals
Irradiation
Aging
```
27
What are the different types of ROS?
```
Superoxide (O2*)
Hydrogen Peroxide (H2O2)
Hydroxyl Radicals (OH*)
```
28
Superoxide
O2*
| Produced by auto-oxidation in the mitochondria and by cytosplasmic oxidases
29
Hydrogen Peroxide
H2O2
| Produced by auto-oxidation in the mitochondria and by cytoplasmic oxidases
30
How are Superoxides (O2*) inactivated?
Spontaneously
OR
By superoxide dismutase (SOD) to form H2O2
31
How is Hydrogen Peroxide inactivated?
By glutathione peroxidase and catalase
32
Hydroxyl Radicals
OH*
Generated by hydrolysis of water by ionizing radiation and H2O2 by the Fenton reaction that utilizes transitional metals (such as Fe++ or Cu++)
33
How do ROS damage cells?
Lipid Peroxidation
Protein Fragmentation
Single strand breaks in DNA
34
Lipid Peroxidation
Oxygen radical comes in and causes the lipids to become radical lipid peroxides
These radical species can react with other species and disrupt the membrane and cause issues with the membrane products
35
What are the major sites of DNA damage via ROS?
Thymidine and Guanine
36
What are the Intracellular antioxidant systems to reduce the effects of ROS?
SOD
Catalase
Glutathione Peroxidase
37
What are the Extracellular antioxidant systems to reduce the effects of ROS?
Vitamins E, A, and C
Glutathione and Cysteine
Serum proteins that reduce/bind iron (transferrin, ferritin) and copper (ceruloplasmin) needed to catalyze the formation of ROS
38
What maintains Cytoplasmic Ca++
Protein sequestration in the cytoplasm, Mitochondria, and ER
39
Increased levels of Ca++ will cause what?
It will activate various degradative enzymes, such as:
- Phospholipases
- Proteases
- Endonucleases
- ATPase
40
What are some 'other' causes of cell membrane injury?
```
Complement C5-C9 membrane attack complex
Cytotoxic T and NK cells - perforin
Virus
Bacterial endotoxins and exotoxins
Drugs
```
41
Reversible Cell Injury
aka Sub-lethal Cell Injury
Acute in nature
Occurs when the cell cannot maintain normal homeostasis due to cell injury of short duration and minimal intensity
42
What are some common causes of Reversible Cell Injury?
Toxins
Infectious Agents
Hypoxia
Thermal Injury
43
What are the morphological changes associated with Reversible Cell Injury
Plasma membrane injury that leads to increased intracellular Na+ that leads to an isosmotic gain in water
Organelles and cells swell, and the organ may appear pale and swollen
44
What occurs first, Biochemical alterations of morphologic changes?
Biochemical alterations
45
The degree of cell injury is determines by what?
- Physiological state of the cell
- Intensity of insult
- Duration of insult
- Number of exposures to the insult
46
What are the different outcomes that can occur from a cell injury?
1) It reverses
2) Results in a cell adaptation
3) Leads to cell death - necrosis or apoptosis
47
What are different types of cellular adaptations?
Changes in cell number, size, or differentiation
| Cellular adaptations associated with abdnormal accumulations
48
T/F - There is one biochemical event that equates with cell death
False - There is no single biochemical event that equates with cell death
49
What are the two types of cell deaths
Necrosis
| Apoptosis
50
What gets released after cell death?
Cellular constituents get released into the extracellular environment
51
What morphologic changes occur in necrosis?
Cell Swelling
Protein denaturation; yielding a glassy, homogenous pink staining cytoplasm
Organelle breakdown may result in vacuoled cytoplasm
Nuclei changes: karylosis, pyknosis, karyorrhexis, or total loss
Inflammation
52
What are the different morphologic types of necrosis
Coagulative Necrosis
Liquefactive Necrosis
Caseous Necrosis
Fat Necrosis
53
Coagulative Necrosis
Most common form
Cytoplasmic proteins are coagulated
Nucleus is lost, but the eosinophilic outline of the cell is retained for a short time prior to being removed by inflammatory response
54
Liquefactive Necrosis
The tissue is totally digested by the release of lysosomal enzymes during the acute inflammatory response
Often associated with focal bacteria or fungal infections (abscesses and wet gangrene)
Also seen in the CNS
Fills with pus
55
Caseous Necrosis
Associated with M. tuberculosis
The tissue has a white and "cheesy" appearance on gross examination
Microscopically characterized by amorphous pink granular material within a ring of granulomatous inflammation and loss of tissue architecture
56
Fat Necrosis
Common in trauma to the breast or in cases of pancreatitis
| Adipose tissue has a chalky white-yellow gross appearance
57
What is the type of Necrosis dependent on?
The patterns of enzymatic degredation of cells and ECM
The type of necrotic debris
Bacterial products when present
58
T/F - Apoptosis is the same as Necrosis
False - It is a morphologically distinct, gene directed form of individual cell death
59
What are some morphologic features of apoptosis?
Cell shrinkage
Chromatin condensation followed by fragmentation
Apoptotic body formation
Phagocytosis of the apoptotic bodies without a significant inflammatory response
60
When is apoptosis useful?
Normal cell turnover
Embryogenesis
Immune function
61
What diseases/pathology cause excessive Apoptosis?
```
AIDS
Ischemia
Neurodegenerative diseases
Myelodysplasia
Toxin-induced liver injury
```
62
What diseases/pathology inhibit apoptosis?
Cancer
Autoimmune diseases
Viral diseases
63
What are the mechanisms of Apoptosis?
1) Intrinsic program - Mitochondria
2) "Death signals" - Fas-ligand binding to Fas receptor (extrinsic)
3) Removal of trophic signals (hormones)
4) ROS, radiation, toxins
5) Effect of Cytotoxic T-cells
64
What are the two pathways to control and integrate
1) Direct Signaling (Fas-ligand, TNF binding)
| 2) Regulation of mitochondrial permeability
65
Bcl-2 gene family
Serve as an 'on/off switch' that regulate membrane permeability of the mitochondria (Bcl-2, Bax, Bak)
66
What do Bcl-2 and Bcl-x products do?
Inhibit apoptosis
67
What do Bax and Bak gene products do?
Stimulate apoptosis
68
What happens when Cytochorme-C is released from the outer mitochondrial membrane?
It disrupts Bcl-2, and therefore favors apoptosis
69
Capspases
Apoptosis signaling pathways converge on an autocatalytic proteolytic cascade of capspaces
Their substrates include: cytoskeletal and nuclear matrix proteins, DNase, and transcription proteins
70
What does the mitochondrial release of Ca do?
Activates various enzymes the execute apoptosis
- Transglutaminases cross-link cytoplasmic proteins
- Endonucleases cleave DNA at the linker regions between nucleosomes
71
What removes cell fragments that underwent apoptosis?
Phagocytosis by neighboring cells and macrophages
| Little or no inflammation associated
72
What stimulates each type of cell death?
```
Apoptosis = Physiologic and pathologic
Necrosis = hypoxia and toxins
```
73
What is the morphology of Apoptosis v Necrosis?
Apoptosis
- Single cells
- Shrinkage
- Condensed chromatin
- Intact plasma membrane
- Apoptotic bodies
Necrosis
- Multiple cells
- Lysed plasma membrane
- Organelle disruption
74
What are the mechanisms of DNA destruction in Apoptosis v Necrosis?
Apoptosis
- ATP dependent
- Gene activation and endonuclease mediated DNA fragmentation
Necrosis
- ATP independent
- Random, Diffuse, Free radicals, Membrane injury
75
What are the tissue reactions of Apoptosis v Necrosis?
Apoptosis
- Minimal inflammaiton
- Phagocytosis of Apoptotic bodies
Necrosis
-Inflammation
76
Chronic (sub-lethal) cell injury leads to what?
Adaptations
77
What are the different types of cellular adaptations?
```
Atrophy = diminishment of cells and functionality
Hypertrophy = Increase in size
Hyperplasia = Increase in number
Metaplasia = Intracellular accumulations
```
78
What occurs alongside cell atrophy?
Concurrent decrease in organ size and/or funciton
79
What can cause Atrophy?
```
Decreased workload
Loss of innervention
Decreased blood supply
Inadequate nutrition
Decreased hormonal stimulation
Aging
Local pressure
```
80
What is the morphologic appearance of atrophic cells
Shrunken
| Reduction in structural components
81
Hypertrophy
Increase in cell size and is associated with an increase in functional capacity
82
What can accompany cellular hypertrophy?
Tissue and/or organ size may increase
AND
It may be accompanied by an increase in cell number (hyperplasia)
83
What are the different etiologies of hypertrophy?
Response to trophic signals (hormonal)
| Response to increased functional demand
84
What are the types of trophic signaling that lead to cellular hypertrophy?
Normal/Physiologic (ie smooth muscle hypertrophy in pregnant uterus)
Abnormal/Pathologic (ie, exogenous anabolic steroids leading to muscle hypertrophy, and increased TSH leading to a goiter)
85
What are some examples of hypertrophy to response of increased functional demand?
Muscle hypertrophy - skeletal muscles get bigger with exercise or myocardial cell hypertrophy due to increased pumping workload
86
Hyperplasia
Increase in the number of cells in a tissue or organ
May involve the proliferation of epithelial and.or stromal cells
May increase the risk for subsequent neoplastic transformation
87
Hyperplasia is stimulated by what
Trophic factors (hormones and cytokines/GF)
88
What are some examples of hormones stimulating hyperplasia
Endometrial glandular cells during the normal menstrual cycle
Gynecomastia (hyperplasia of breast in men) secondary to estrogen treatment of prostate cancer
Erythrocyte hyperplasia can follow extopic production of erythropoeitin renal cell carcinoma
89
Metaplasia
One adult cell type is replaced by another adult cell type in response to chronic stress
90
Intestinal metaplasia
Replacement of normal epithelium with goblet cells and other intestinal mucosa-type cells
-due to prolonged exposure to reflux gastric contents
91
Squamous metaplasia
Conversion of normal columnar epithelium to stratified squamous epithelium
Examples include
-respiratory tract in response to smoking
-Ductal epithelium of various glands due to vitamin A deficiency
-Cervix in response to various agents
92
Mechanisms of intracellular accumulations include what?
Abnormal metabolism
Lack on an enzyme
Abnormal protein folding or transport
Ingestion of indigestible matieral
93
What are the different types of lipid accumulation
Steatosis
| Cholesterol
94
What things can accumulate in cells
Normal constituents (H2O, lipids, proteins, carbs)
Abnormal substances - either endogenous or exogenous
Pigments
Calcium
95
Steatosis
An abnormal accumulation of triglycerides within parenchymal cells of the liver, heart, kidney, and skeletal muscle
96
What is the etiology of Steatosis
```
Obesity
Diabetes
EtOH
Anorexia
Toxins
Protein malnutrition
```
97
Gross appearance of Steatosis
Enlarged, yellow liver
98
Microscopic appearance of Steatosis
Hepatocytes contain clear cytoplasmic vacuoles that displace the nucleus
99
Cholestrol accumulation
Accumulates primarily in macrophages (foam cells)
100
Cholesterol accumulation in skin
In the subepithelial macrophages forming a Xanthoma
101
Cholestrol accumulation in vessels
In Atheromas of atherosclerosis
102
Protein accumulation histology
Eosinophilic cytoplasmic droplets, vacuoles, or aggregates
103
What are some examples of protein accumulation
a1-anti-trypsin deficiency - impaired folding due to a gene mutation
Mallory bodies - impaired secretion due to improper folding or precipitation
Neurofibrilary triangles in Alzheimer's disease
104
What are the different types of pigment accumulation?
Exogenous pigement
| Endogenous pigment
105
What are examples of exogenous pigments
Carbon accumulated in macrophages
| Tattoos
106
What are examples of endogenous pigments
Lipofuscin
Melanin
Hemosiderin
Bilirubin
107
Lipofuscin
"Wear-and-tear" brown-yellow granular pigment
| A lipoprotein complex due to ROS peroxidation of membranes
108
Melanin
Balck-brown pigment
| Produced by melanocytes by accumulated in adjacent epidermal cells and in macrophages
