Exam 1: Cell Injury and Cell Death Flashcards
1
Q
Response to Stress
A
- Cells and organs in homeostasis
- Response to stress ⇒ adaptation or death
- Response dependent on severity and length of stress
2
Q
Adaptations
A
In response to changes in physiologic and pathologic stimuli to maintain homeostasis.
When stress removed, can recover without harm.
Includes:
- Hypertrophy
- Hyperplasia
- Atrophy
- Change in phenotype
- Metaplasia
- Dysplasia
3
Q
Hypertrophy
A
Increase in cellular size and functional activity.
-
Physiologic
- Muscle hypertrophy w/ inc. workload
- ↑ protein synthesis ⇒ ↑ myofilament size ⇒ ↑ force generation
- Ex:
- Bodybuilder ⇒ inc. demand
- Heart ⇒ chronic hemodynamic overload
- Muscle hypertrophy w/ inc. workload
-
Pathologic
- Cancer
- Response to injury
4
Q
Cardiac Hypertrophy
Pathogenesis
A
- Mechanical sensors ⇒ production of growth factors and agonists
- Activation of signal transduction pathways
- Activation of transcription factors
- Inc. synthesis of muscle proteins
5
Q
Hyperplasia
A
Increase in cell number.
- Occurs in response to stimuli
- Can occur with hypertrophy
- Only seen in tissues where cells can divide
- Physiologic vs Pathologic
6
Q
Physiologic Hyperplasia
Examples
A
-
Breast glandular epithelium
- Puberty or pregnancy
-
Liver regeneration
- Regenerate after donation
-
Bone marrow
- Make more RBCs after bleed or hemolysis
7
Q
Pathologic Hyperplasia
Examples
A
-
Endometrial hyperplasia
- Causes abnormal bleeding
- Due to excess estrogen ⇒ imbalance between estrogen/progesterone
-
Benign prostatic hyperplasia
- In response to androgens
- Increases with age
- No increased risk for neoplasm
-
Response to viral infection
- Ex. HPV ⇒ warts
- Viral factors can interfere with host proteins that regulate cell proliferation
- Can be a cancer precursor
- Ex. HPV ⇒ warts
8
Q
Atrophy
A
- ↓ cell size & organelles
- ↓ metabolic demands
- Attempt to prolong survival
- May diminish cell function
- May lead to irreversible injury and death
- ↓ size of organ or tissue
9
Q
Physiologic Atrophy
Examples
A
- Embryonic development
- Shrinkage of uterus after delivery
10
Q
Pathologic Atrophy
Examples
A
-
Decreased workload
- Atrophy of disuse
- Loss of innervation
-
Diminished blood supply
- Seen in brain w/ age
-
Inadequate nutrition
- Marasmus ⇒ cachexia
-
Loss of endocrine stimulation
- Uterus after menopause
-
Pressure
- Enlargeing tumor compresses normal tissue
11
Q
Protein and Organelle
Clearance
A
Two pathways to clear damaged proteins and organelles:
-
↓ protein synthesis
- In response to ↓ metabolic activity
-
↑ protein degradation
-
Ubiquitin-proteasome pathway
- Activation of ubiquitin ligases
- Ubiquitin attached to proteins
- Degraded in proteasomes
-
Autophagy
- Cells “eats” it own components
- Debris may remain as residual bodies ↑ lipofuscin granules
-
Ubiquitin-proteasome pathway
12
Q
Metaplasia
A
One cell type is replaced by another normal cell type.
- Reversible change
- Usually in response to stress
- New cell type more able to withstand stress
- Stem cells ‘reprogrammed’ to differentiate along new path
- Signaled by cytokines, growth factors, ECM components
- Promotes expression of genes that drive differentiation
13
Q
Squamous Metaplasia
A
- Columnar ⇒ squamous epithelium
- Most common epithelial metaplasia
- In areas of chronic irritation
- Ex. bronchi of smokers
14
Q
Barrett’s Esophagus
A
“Intestinal metaplasia”
- Squamous ⇒ columnar epithelium w/ globlet cells
- Due to gastric reflux
- Can lead to cancer
15
Q
Osseous (cartilaginous)
Metaplasia
A
- Production of cartilage or bone in areas of tissue injury
- Causes:
- Chronic irritation
- Stress
- Tissue damage
- Ex:
- Irritation due to dentures
- Injury to muscle ⇒ myositis ossificans
16
Q
Cell Injury
A
Reversible vs Irreversible
- Stimulus
- Limit of adaptive response exceeded
- Exposed to injurious agent or stress
- Deprived of essential nutrients
- Compromised by mutations that affect essential cellular constituents
- Time lag between injury and effects
- Signs of reversible injury takes longer
17
Q
Cellular Injury
Causes
A
-
Oxygen deprivation
- Hypoxia, ischemia
-
Physical agents
- Mechanical, temp, radiation, electrical, pressure
-
Chemical agents
- Pollutants, poisons, drugs, metabolists
-
Infectious agents
- Virus, bacterial, fungi, parasites
-
Immune reactions
- Exogenous, autoimmune
-
Genetic derangements
- Enzymes, structural proteins
- Nutritional imbalance
- Proliferation errors (DNA)
18
Q
Reversible Injury
Changes
A
-
Functional changes
-
↓ oxidative phosphorylation
- Depletes ATP and glycogen stores
-
↓ transporter function
- Loss of membrane activity and integrity
- Defects in protein synthesis
- Cytoskeletal damage
- DNA damage
-
↓ oxidative phosphorylation
-
Morphological changes:
- Cellular swelling ⇒ due to ∆ in ion concentration and water influx
- Mitochondrial swelling & amorphous densities
- RER swelling & ribosome detachment
- Clumping of nuclear chromatin
- Membrane blebbing & loss of microvilli
- Cytoplasmic vacuoles
19
Q
Cell Injury
Mechanisms
A
- Mitrochondrial damage
- ↓ ATP
- ↑ ROS
- Calcium entry
- Membrane damage
- Protein misfolding
- DNA damage
20
Q
Depletion of ATP
Causes
A
- ATP produced through:
- Ox Phos of ADP
- Glycolysis
- ↓ [ATP] caused by:
- ↓ O2 supply
- ↓ nutrient supply
- Mitochondrial damage
- Toxins
21
Q
Depletion of ATP
Effects
A
If [ATP]intracellular falls to 5-10% of normal:
- ↓ Na/K pump activity ⇒ cell swelling
-
∆ cellular metabolism ⇒ shift to anaerobic glycolysis
- Depletes glycogen stores
- Produces lactic acid
- ↓ cellular pH ⇒ ↓ enzyme activity
- ↓ calcium pump activity ⇒ Ca2+ influx ⇒ damage to many cellular components
- Ribosome detach from RER & polysomes dissociate ⇒ ↓ protein synthesis
- ↑ protein misfolding ⇒ accumulation in RER ⇒ activation of misfolded protein response ⇒ cell injury & cell death
- Irreversible damage to mitochondrial & lysosomal membranes ⇒ necrosis
22
Q
Mitochondrial Damage
A
-
Causes:
- ↑ [Ca2+]cytosol
- ROS
- O2 deprivation
-
Types of mitochondrial damage:
- Formation of mitochondrial permeability pore ⇒ failure of ox phos ⇒ ↓ [ATP]
- Abnormal ox phos ⇒ ↑ [ROS]
-
Release of sequestered proteins from intermembrane space ⇒ apoptosis
- Ex. cytochrome C & BCL proteins that activate caspases
23
Q
Loss of Calcium Homeostasis
A
- Caused by ↓ ATP ⇒ influx of calcium
- Key event in cell death
- ↑ [Ca2+]intracellular effects:
- Irreversibly poisons mitochondria
- Inhibits many cellular enzymes
-
Activation of lytic enzymes
- Phospholipases, proteases, endonucleases, ATPases
- Initiates free radical formation
-
Denatures cellular proteins
- Can lead to initiation of unfolded protein response
- Activation of apoptosis
24
Q
Free Radicals
Characteristics
A
- Have a single unpaired e- in an outer orbital
- Extremely reactive with cellular macromolecules
- ROS are a type of oxygen-derived free radical generated within cells
- Build up if not scavenged and disposed of properly
- Initiates autocatalytic rxns ⇒ propagates more free radicals
25
Q
Free Radical
Generation
A
-
Redox rxns during normal metabolism
- Small amount of partially reduced intermediates generated
- Superoxide anion, hydrogen peroxide, hydroxyl ions
-
Absorption of radiant energy (UV, X-rays) and ionizing radiation
- Hydrolyzes water ⇒ free radicals
- Activated WBCs generate ROS during inflammation (respiratory burst)
- Enzymatic metabolism of exogenous chemicals/drugs
-
Transition metals (Fe, Cu) can donate or accept free electrons during rxns
- Can catalyze formation of TOS
- Binding to storage/transport proteins reduces reactivity
- Nitric oxide can act as a free radical
26
Q
Free Radical
Removal
A
- Inherently unstable ⇒ decay spontaneously
- Cells have non-enzymatic & enzymatic mechanisms to remove free radicals
-
Non-enzymatic
-
Antioxidants ⇒ prevent formation or inactivate/scavange free radicals
- Vit E, A, and C
- Glutathione
- Free Fe and Cu
-
Antioxidants ⇒ prevent formation or inactivate/scavange free radicals
-
Enzymatic ⇒ enzymes act as free radical scavening systems
- Catalase, superoxide dismutase, glutathione peroxidase
-
Non-enzymatic
27
Q
Free Radical
Pathologic Effects
A
-
Lipid peroxidation in plasma/organellar membranes
- Attack double bonds in unsaturated FAs of membrane lipids
- Generates peroxide
- Results in autocatalytic chain reaction ⇒ propagation
- Causes membrane damage
-
Oxidative modification of proteins
- Damage enzyme active sites
- Disrupt conformation of structural proteins
- Enhance degradation of misfolded proteins
-
Lesions in DNA
- Single or double stranded breaks in DNA
- Crosslinking of strands
- Implicated in cell aging and malignancy
28
Q
Membrane Permeability
Defects
A
-
Mechanisms of injury:
- ROS ⇒ lipid peroxidation
- ↓ phospholipid synthesis
-
↑ phospholipid breakdown
- Products accumulate & have detergent effect on membranes
-
Cytoskeletal abnormalities
- Due to proteases affected by ↑ cytosolic calcium
-
Results in damage to:
- Mitochondrial membranes ⇒ apoptosis
- Plasma membranes
- Lysosomal membranes
29
Q
DNA and Protein
Damage
A
- Cell initiates suicide program if:
- DNA damage too severe to be corrected
- Level of misfolded proteins too high
- Results in death by apoptosis
30
Q
Ischemic and Hypoxic
Injury
A
- Ischemia results from hypoxia due to ↓ blood flow
- Usually due to blockage in arterial flow
- Can be due to reduced venous drainage
- Worsens hypoxia by also affecting anerobic energy generation
- Reversible if oxygen flow restored in time
- Organs respond differently to hypoxia d/t differences in metabolic activity
31
Q
Organ Response to Anoxia
A
Cell death will begin in:
- Neurons ⇒ 3-5 minutes
- Myocardia ⇒ 20-30 minutes
- Renal tubule cells ⇒ 30-60 minutes
- Hepatocytes ⇒ 1-2 hours
- Skeletal muscle ⇒ many hours
- CT ⇒ many hours
32
Q
Chemical (Toxic) Injury
A
- Direct toxicity
- Chemicals injure cells by combining with molecular components
- Ex. mercuric chloride poisoning, cyanide, chemotherapy
- Conversion to toxic metabolites
- Usually done by cytochrome P-450 mixed function oxidases
- Ex. carbon tetrachloride, acetaminophen
33
Q
___ leads to cell death.
A
Irreversible cell injury
35
Q
Reversible vs Irreversible
Cell Injury
A
36
Q
Cell Death
A
- End result of progressive cell injury
- Many pathologic causes ⇒ ischemia, infection, toxins
- Can be a normal process ⇒ embryogenesis, maintaining homeostasis
- Two pathways ⇒ necrosis & apoptosis
38
Q
Necrosis
Morphological Changes
A
Takes many hours for histologic or gross changes to be visible.
-
Cytoplasmic changes
-
↑ eosinophilia
- Loss of RNA
- Denatured proteins
- Vacuoles
-
Myelin figures
- From damaged cell membranes
- Degraded into FA, may calcify
-
↑ eosinophilia
-
Nuclear changes
- Karyolysis ⇒ nuclear fragmentation
- Pyknosis ⇒ nuclear contration
- Karyorrhexis ⇒ fragmentation of pyknotic nuclei
-
Plasma membrane destruction
- Enzymes & proteins leak out into ECM and blood
- Detectable in blood within 2 hours of necrosis
39
Q
Coagulative Necrosis
A
- Typically caused by ischemia or infarction
-
Dead tissue structure preverved for several days
- Area called an infarct
- Injury denatures enzymes ⇒ no proteolysis of dead cells ⇒ see eosinophilic cells without nuclei
- Dead cells eventually cleared by WBCs via phagocytosis and lysosomal digestion
- Typically seen with MI’s
40
Q
Liquefactive Necrosis
A
- Results from focal bacterial or fungal infections
- PMNs and Mφ degrade necrotic material and pathogen ⇒ pus
- Seen in CNS s/p hypoxic injury
42
Q
Caseous Necrosis
A
- ‘Cheese-like’ central necrotic area of a granuloma
- Seen in tuberculosis and some other infectious
- Caseation appears pink, amorphous, and granular
43
Q
Fat Necrosis
A
- Focal areas of destruction
- Usually specific to the release of pancreatic lipases or trauma to the breast
- Fat reacts with calcium ⇒ saponification ⇒ soap
- Appears chalky-white grossly
- Shows outlines of necrotic fat cells microscopically
45
Q
Apoptosis
Overview
A
- Programmed cell death ⇒ highly regulated
- Serves many normal functions
-
Activated by either an intrinsic or extrinsic pathway
- Relies on sequential activation of proteases through cleavage or caspase cascades
- No inflmmatory reaction triggered
48
Q
Apoptosis
Morphological Changes
A
- Degradation of cellular DNA and proteins
- Organelles tightly packed ⇒ cell shrinkage
-
Chromatin condensation
- Aggregates under nuclear membrane
- Nucleus may break up
-
Formation of cytoplasmic blebs & apoptotic bodies
- Membranes remain intact
- Phagocytosis of apoptotic cells or cell bodies before materials leak out ⇒ no inflammatory response
50
Q
Apoptosis
Intrinsic Initiation Pathway
A
“Mitochondrial pathway”
- Major mechanism
- Results from ↑ permeability of outer mitochondrial membrane
-
Releases pro-apoptotic molecules into cytosol
- Cytochrome C ⇒ initiates apoptosis
-
BCL2 family ⇒ controls release
- Some anti-apoptotic ⇒ BCL-2, BCL-XL, MCL-1
- Some pro-apoptotic ⇒ BAX and BAK
- Some are sensors ⇒ regulate the balance
- Path activates initiator caspase-9
51
Q
Apoptosis
Extrinsic Initiation Pathway
A
“Death Receptor-Initiated Pathway”
- Triggered by activation of death receptors on plasma membrane of some cells
-
Death receptors
- Members of TNF receptor family
-
‘Death domain’ site required
- Protein-protein interactions delivers apoptotic signals
- Type I TNF receptor (TNFR1) ⇒ best known
-
Fas (CD95) receptor ⇒ found on many cells
- Binds Fas ligand (FasL)
- Found on T cells that recognize self-Ag
- Eliminate self-reactive lymphocytes
- Found on some cytotoxic T-cells
- Kill virus-infected and tumor cells
- Found on T cells that recognize self-Ag
- Fas-FasL binding brings together Fas molecules
- Forms binding site for FADD (Fas-associated death domain)
- FADD binds inactive Caspase-8 via death domain ⇒ activation
- Binds Fas ligand (FasL)
- Path activates initiator caspase-8 and caspase-10
55
Q
Apoptosis
vs
Necrosis
A
63
Q
Steatosis
A
“Fatty change”
- Abnormal accumulation of lipids/TAGs in parenchymal cells
- Seen in liver and other organs
- Causes:
- Toxins
- Protein malnutition
- DM
- Obesity
- Anoxia
66
Q
Cholesterolosis
A
Accumulation of cholesterol-laden macrophages in lamina propria of the gallbladder.
69
Q
Protein Droplets
A
Protein resorption droplets in proximal renal tubules.
Found in patients with protein loss via urine.
72
Q
Cytoskeletal Protein
Accumulation
A
- Alcoholic Hyaline
- Made of keratin intemediate filaments
- Accumulates in the liver
- Amyloid
- Accumulates inside and between cells
- Many organs affected
73
Q
Hyaline Change
A
- Homogeneous, glassy pink material
- Accumulates inside or between cells
- Non-specific marker for cell injury
- Extracellular hyaline can be seen in walls of arterioles with chronic HTN
75
Q
Exogenous Pigment
Accumulation
A
- Coal dust (anthracotic pigment)
- Accumulates in lungs and lymph nodes
- Excessive amounts can produce serious disease
- Ex. Coal workers pneumoconiosis
- Tattoos
- Pigments phagocytosed by derml macrophages
77
Q
Lipofuscin
A
- Golden brown fine granules
- ‘Wear and tear’ pigment
- Contains lipid and proteins from membranes
- Does not cause injury
- Increases with age
- Often seen in liver and heart
78
Q
Hemosiderin
A
- Golden-brown granules
- Derived from hemoglobin
- Forms where there is local or systemic excess of iron
- Normally see small amounts in macrophages
- Bone marrow
- Spleen
- Liver
- Local excess can accumulate in areas of bleeding
- Systemic excess causes deposition in many tissues ⇒ hemosiderosis
