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Cell Adaptation, Injury and Death
pgs 347-354
23
Biology
Professional
12/23/2011

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Term
Using Sickle Cell Anemia as an example, distinguish b/w disease ETIOLOGY and PATHOGENESIS.
Definition
1) Etiology- answers the "why"

Mutation in b-Hb gene, Glu6Val

2) Pathogenesis- answers the "what" question

Polymerization of deoxy Hb, change in RBC shape, capillary blockage.
Term
How can you distinguish b/w necrotic cell death and apoptosis?
Definition
1) Apoptosis is "regulated," without leakage of cytoplasmic constituents into the blood.

2) Necrosis involves overwhelming damage to membranes and organelles leading to cytoplasmic constituent leakage into blood.
Term
Explain the morphological correlates of adaptation to stress in thyroid epithelium.
Definition
Atrophy vs. Hypertrophy determined by nutrient supply, work load, trophic stimulation and mTOR signalling

1) Atrophy

- Condensed chromatin= less transcription
- Less cytoplasmic volume= less RER and synth. of thryoglobulin
- Loss of apical specialization= less phagocytosis of thryoglobulin

2) Hypertrophic

- Open chromatin
- Greater cyt volume
- Greater specialization- more processing of thyroglobulin to thyroid hormone.
Term
Distinguish between Metaplasia and Hyperplasia as they pertain to Adaptation.
Definition
1) Metaplasia is cellular replacement
ex) cig. smoke changes lung respiratory epithelium to squamous
ex) Barret's esophagus where gastric acid induces squamous epithelium to become glandular

2) Hyperplasia- increase cell number arising from either increased proliferation or decreased death.

ex) same pathways regulate proliferation as due Neoplasia, accounting for morphological similarities.
Term
Distinguish between Hypoxia, Ischemia and Infarction.
Definition
1) Hypoxia is decreased O2 delivery

2) Ischemia is decreased blood supply, leading to hypoxia and waste accumulation

3) Infarction is TISSUE death due to ischemia.
Term
What does Calcium entry have to do with ischemic damage?
Definition
If intracellular Ca levels get too high (i.e. mM instead of uM):

Calcium-activated proteases (CALPAIN), nucleases and lipases are deregulated and cause cell damage.
Term
How can you identify necrotic cells produced by infarction or other processes?
Definition
1) Pyknotic nucleus (small and dark blue) becomes pink and then disappears due to Karyolysis

2) cyt-RNA is red as basophilic RNA is digested and partially digested protein fragments aggregate into eosinophilic mass.
Term
What are the 3 main ROS, how do they originate, and what cellular damage do they cause?
Definition
Re-perfusion following ischemia causes issues with ROS

1) Hydroxide Radical (most reactive with shortest half-life), Superoxide and Hydrogen Peroxide

2) Origins

- Released from inflammatory cells from
- NADPH Oxidase (oxidative burst in bacteria)
- Metabolic Oxidase
- Myeloperoxidase (makes peroxide into chloride radical)
- Heavy metals

3) Damage

- Membrane lipid peroxidation (need Vit E)
- DNA mutations
- Plasma- and lipoprotein oxidation (need Vit C)
Term
Name 3 enzymes that are important for protection against ROS.
Definition
1) Catalase- oxidizes peroxides in peroxisomes

2) Glutathione peroxidase

3) SOD- converts -O2 into peroxide in Cytoplasm and Mitochondria.

NOTE- get rid of superoxide with SOD and then oxidize it further with GP and Catalase.
Term
A patient presents with numerous tumors with prominent proliferation of blood vessels.

What is going on? How could you confirm?
Definition
Von Hippel Lindau Disease

This is a genetic issue with the hypoxia sensing system in which mutations in the Von Hippel Lindau protein (VHL) disrupt hydroxyproline binding site that usually binds HIF1-a targeting it for degradation.

HIF1-a is stabilized ("perceives" situation as hypoxic) and causes abnormal vascular proliferation.
Term
How does the normal hypoxia-sensing system work?
Definition
1) High O2 causes HIF1-alpha hydroxylation at P residues, which is recognized by E3 enzyme Von Hippel Lindau protein (VHL)

2) Low O2, HIF1-a is stabilized, and acts as nuclear t-factor, where it up-regulates genes involved in glycolysis, VEGF (capillary formation) and Erythropoiten (RBC formation from marrow)
Term
How to ROS elicit an oxidative stress response?
Definition
1) ROS oxidize sulfhydral groups on KEAP1 (E3 enzyme), preventing it from targeting NRF2 for degradation.

2) NRF2 goes to nucleus where it stimulates antioxidant genes, phase 2 enzymes (protective carcinogen metabolizing) and HSF1 (stimulates transcription of HSP chaperones)
Term
Why might a mutation in Ataxia-Telangiectasia Mutated (ATM) be a clinical concern?
Definition
ATM-complex phosphorylates and activates components of repair complex including BRCA2 and p53, and can also cause apoptosis as a last resort.

Mutations cause CANCER syndrome, because DNA replication and cell cycle progresses without repair or death, thereby increasing mutation prevalence.
Term
Why might mutations in HSP90 be of clinical interest?
Definition
HSP is part of the cytoplasmic heat shock inducible pathway involved in "adaptation to acquired cellular damage."

SHORT- too much unfolded protein, HSP90 releases HSF. HSP90 prevents aggregation and HSF regulates transcription.

Cytoplasmic HSP90 binds Heat Shock transcription Factor (HSF) until denatured cytoplasmic proteins increases and compete HSF off.

HSF diffuses to nucleus and transcribes inducible HSPs and HSP90 binds denatured proteins, preventing aggregation.
Term
How does the ER react when it is overloaded by increase secretory protein synthesis (viral infection) or mutant non-refoldable protein?
Definition
ERAD!

1) Transmembrane ATF6 keeps BiP in ER. When Bip is used up in response, ATF6 goes to Golgi, where it is cleaved and beomces a transcription factor of ER chaperone and machinery proteins.

2) Transmembrane PERK (eIF2a kinase) interacts with Bip. When Bip is occupied, luminal domains dimerize and activate kinase activity, phosphorylizing eIF2a to turn of mRNA translation and Nrf2 to release it from KEAP causing an oxidative response.

3) Transmembrane IRK-1 has luminal domains that dimerize without BiP. This does 4 things.

-Activates RNAse domain that splices mRNA of t-factor HAC-1/XBP-1 (making a more active form) for ER chaperone proteins

- Inhibits traction of 2-% of genes mostly in metabolic pathways

- Activates its own transcription (CONDITIONING)
Term
How is IRK-1 activity an example of "conditioning"?
Definition
Remember, when BiP is tied up, IRK-1 dimerizes and activates RNAse domain to splice HAC-1/XBP-1 into a more active form that will transcribe ER chaperone proteins.

IRK-1 actually activates its own transcription to create a feed forward amplification loop called "conditioning."
Term
Generally, how does the Ubiquitin Proteasome System (UPS) repair cellular damage?
Definition
26S multi-subunit complex
19S (catalytic with protease activity)
6S (regulatory with ubiquitin tag recognition, protein unfolding activity and tag removal)

1) E1 (ATP-dependent), ubiquitin activating enzyme binds Ub.

2) E2 takes Ub from E1 and donates it to substrate protein

3) E3 ligase recognizes substrate and catalyzes E2-Ub transfer to target
Term
What are Mallory Hyaline and Lewy Bodies?
Definition
Hyaline Inclusions (eosinophilic, homogenous bodes), which are UPS-resistant aggregates of damaged protein that stain with Ab against Ub.

Mallory Hyaline is keratin-rich aggregate found in hepatocytes

Lewy Bodies are a-synuclein rich aggregates in dopamine neurons.
Term
How does Autophagy occur in response to cellular damage?
Definition
1) APG proteins activate smooth ER fragment by linking membrane phosphotidyl ethanolamines to LC3 (ubiquitin-like).

2) Created double-membrane organelle called "autophagosome" engulfs damaged organelles, fusing with lysosomes that digest material and leave yellow/brown granules of Liofuscin
Term
Explain the 4 Morphological Correlates of Necrotic Cell Death providing an example for each.
Definition
1) Selective Vulnerability- Purkinje neurons in cerebellum are especially sensitive to Hypoxia.

2) Coagulative Necrosis- solid dead tissue consisting of anuclear ghost cell remnants with basic outlines (stain with Reticulin) and eosinophillic interiors.

3) Liquifactive Necrosis- Digestive enzymes have remained active and is seen in tissues with minimal basement membranes (like brain) and abundant digestive enzymes (pancreas).

4) Caseous/Caseating Necrosis- tissue with small foci of liquifactive necrosis that have been walled off by viable inflammatory cells and fibrosis (seen in TB infection!)
Term
Which intracellular organelles are particularly sensitive to reperfusion injury and why?
Definition
The unsaturated membranes of mitochondria are particularly susceptible to damage by ROS.
Term
How does insulin signaling regulate the hypertrophy/atrophy balance?
Definition
mTOR signaling!

1) Insulin binds to and inhibits TSC1/TSC2 (EGFRs), preventing them from inhibiting mTOR (i.e. indirectly activates mTOR)

2) mTOR phosphorylates and activates S6K1 kinase and inhibits 4EP1 (the "off switch)

3) S6K1 phosphorylates key players, leading to increased cell growth.

** ATP inhibits mTOR activation (no energy means no hypertrophy!) **
Term
How can meningitis arise?
Definition
Too much bacteria causes oxidases to attack membranes, leading to ROS release and infection (brain meningitis)
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