Cell Injury and Cell Death Flashcards
1
Q
3 Levels of Pathologist Certainty
A
- Pathognomonic - most certain; finding is unique to specific disease
- Diagnostic - finding is highly linked w/ specific disease
- “Consisten with “ - finding may be associated w/ other diseases too but still helps rules out others
2
Q
Types of Insults (7)
A
- External - physical, chemical (pH, toxins), biological (viruses, bacteria, parasites)
- Internal - energy deficits, genetic, metabolic, neoplasia
3
Q
Stages of Cellular Response to Injury
A
- Adaptation
- 1st- Physio - corrective/ return to homeostasis
- 2nd- Pathological - counterproductive change or side reactive
- Injury (loss of function or damage)
- 1st - reversible- you can repair the damage and regain function
- 2nd- irreversible - too overwhelming or non-repairable
- Cell Death
4
Q
3 Types of Cell Death
A
- Necrotic - overwhelming damage —> degradation —> debris released to surroundings (due to loss of membrane integrity)
- Apoptosis - programmed cell death; regulatory process of enzymatic cell suicide; debris NOT released into surrounding
- Necroptosis - regulated like apoptosis (use death receptors and genetically programmed intracellular signaling BUT does not activate caspases) BUT cellular degradation like necrosis (reduced mitochondrial production of ATP, inc generation of oxidative species, lysosomal membrane permeabilization and cell swelling/rupture)
5
Q
Morphological Signs of Injury (2)
A
- Hydropic Change - ion imbalance —> swelling of vesicular compartments b/c ions and water in cell
- Fatty Change- cannot process lipids —> lipoproteins so accumulate fat droplets in cell
6
Q
Atrophy & Hypertrophy
A
- Atrophy - dec cell size
- Condensed chromatin/less transcription, less cytoplasm volume/less rough ER protein synthesis, loss of apical specialization/ less phagocytosis
- Caused by…nutrient insufficiency, less work demand, less trophic stim, etc - Hypertrophy - inc cell size
- Open chromatin and larger nuclei/more transcription, greater cytoplasmic volume/more rough ER and protein synthesis, greater specialization of apical surface/more phagocytosis
- Caused by…high work demand, hypertrophic stimulation, more nutrient supply - poss adipose tissue?**BOTH regulated by mTOR (protein kinase complex that is central to deciding whether cell size is maintained or inc/dec occurs - receives signals from multiple pathways then phosphorylates targets that directly affect transcription)
7
Q
Hyperplasia
Metaplasia
A
- Metaplasia - replacement of 1 cell type for another
- Squamous metaplasia (epithelium becomes squamous - smokers)
- Intestinal metaplasia (epithelium becomes mutinous columnar - protection from acid)
- Mesenchymal metaplasia (ossification of ligaments) - Hyperplasia - inc # cells (proliferation of resident cells OR decreased regulation of cell death)
8
Q
Hypoxia
Anoxia
Ischemia
Infarction
A
- Hypoxia - decreased or limited O2 delivery
- Anoxia - no O2 delivery (glycolysis can persist)
- Ischemia - insufficient blood supply; so limited O2, no fuel and waste buildup
- Infarction - when one of the above leads to a whole zone or region of cell death
9
Q
What happens to ischemic cells?
A
- Main result is a lack of energy/ATP AND lactic acid buildup so failure of things that use energy…
- No membrane ion pumps …osmotic swelling
- No transcription/translation …dec protein synthesis and loss of heterochromatin
- Actin and myosin need ATP/GTP to remain polymerized …changes in cell shape and membrane blabbing
- MOST IMPORTANT is Na/Ca exchanger (ATP dep) …inc intracellular Ca++ which has multiple effects…
- Ca++ activated proteases (CALPAIN)
- Ca++ activated nucleases
- Ca++ activated lipase —> breakdown of membrane
10
Q
Hypoxia Sensing System
A
- If normal amount of O2…HIF1alpha has hydroxylated prolines - recognized by E3 of Von Hippel Lindau protein and targeted for degradation
- If no O2…HIF1alpha is stabilized and transcription factor for genes needed for glycolysis (energy w/o O2) and VEGF for new caps and erythropoietin for RBC formation in bone marrow
- VHL disease if mutation in VHL protein —> HIP1alpha always stable —> tumors w/ blood vessel proliferation
11
Q
3 Reactive Oxygen Species + Protective Enzymes
A
- 1- hydroxide radical - least stable/most reactive (does not have enzyme b/c normally gone before reacting w/ anything)
- 2- Superoxide - very reactive and short half life (superoxide dismutase)
- 3- hydrogen peroxide - least reactive/longest half-life (catalase OR glutathione peroxidase)
12
Q
Where do reactive species come from?
A
- Damaged mitochondria
- Re-perfusion injuries - resupply O2 to area w/ damaged mitochondria (damaged by ischemia)—> reactive oxygen species
- Released from inflammatory cells (NADPH Oxidase and myeloperoxidase)
- Metabolic Oxidases (ex - CYP450s - oxidation reaction; prostaglandin synthetase)
- Heavy metals (esp Cu and Fe)
13
Q
What kind of damage do reactive oxygen species cause?
A
- Free radical target the plasma membrane directly (unlike hypoxia)
- Also oxidize cytoplasmic proteins, cause DNA mutations, create cross linking compounds, etc
14
Q
Oxidative Stress Response System
A
- Normally…E3 complex w/ KEAP1 binds and targets NRF2 for degradation
- If reactive oxygen species…oxidizes sulfyhdryl groups of KEAP1 so it no longer binds NRF2 —> NRF2 moves to nucleus and acts as transcription factor for antioxidant genes and protective carcinogen metabolizing genes AND regulated heat shock transcription factor and stimulates it to inc transcription of chaperones
15
Q
DNA Damage Response System
A
- Dbl stranded DNA breaks are sensed by ATM (ataxia-telangiectasia mutated) protein complex
- Recruits dbl strand repair enzymes, activates repair complexes (BRCA 1 and 2) and halts DNA replication/cell cycle progression (p53)
- If not effective, ATM can also stimulate apoptotic cell death
