LMP200 MIDTERM

Reversible cell injury

loss of cell funtion

Irreversible cell injury

cell death, ultrastructural changes, light microscopic changes, gross morphologic changes

When do morphological changes occur

After the cell is already dead

Metabolic internal stress

Metabolic imbalances, nutritional deficiencies or excesses

Genetic internal stress

Genetic abnormalities and DNA

Acquired derangements internal stress

hypoxia, ischemia

hypoxia

Insufficient oxygen

Ischemia

lack of blood supply

external stress on cell

physical agents, drugs

Examples of physical agents

heat, cold, radiation, blunt force

Paracelsus

father of toxicology, everything depends on the dose

What are the 3 cell responses to injury

recovery, adaptation, death

What cells are susceptible to hypoxia and ischemia

Brain and heart cells

How long can brain cells last with out oxygen

only 4 minutes

What cells are susceptible to chemical injury

Liver cells

Why are liver cells more susceptible to chemical injury

Liver cells metabolize substances

How long do calf cells muscles tolerate ischemia

2-3h

How long can cardiac muscle tolerate ischemia

20-30 minutes

What cells are more susceptible to cigarette smoke

highly differentiated surface epithelial cells of respiratory tract

How do glycogen levels effect hepatocyte response to ischemia

Glycogen replete hepatocyte is more resistant to ischemia than depleted one

4 vulnerable systems

account for all injury and death cells are exposed to

What are the 4 vulnerable systems of cells

cell membrane integrity, ATP generation/mitochondrial function, protein synthesis/enzyme function, genetic integrity

What are the 6 general mechanisms in response to injury

ATP depletion, oxygen I (ischemia hypoxia), oxygen II (ROS), loss of Ca2+ homeostasis, plasma membrane integrity, mitochondrial damage

Infarction

area of necrosis due to ischemia

ATP depletion

ischemia leads to decreased ox phos and therefore ATP

What happens during anaerobic glycolysis

Lactic acid builds up and causes low pH and clumping of nuclear chromatin

What happens with decreased activity of the Na+ pump

Influx of Ca2+, H2O and Na+; efflux of K+

What does the Na+ pump do?

Pumps Na+ out and K+ in to maintain gradient

What happens when the ER swells

Loss of microvilli

What does increased intracellular Ca2+ do

loss of Ca2+ homeostasis- activates various enzymes

phospholipase

destroys phospholipids

protease

disruption of membrane and cytoskeletal proteins

endonuclease

nuclear damage

ATPase and mitochondrial permeability

decreased ATP

Mitochondrial damage

decreased O2 supply and toxins lead to mitochondrial damage and necrosis

Decreased survival signals

causes leakage of mitochondrial proteins and apoptosis

4 characteristics of adaptive responses

1. expressed on demand

2. reversible when demand ceases

3. would have survival advantage for the cell , organ and organism

4. should cause least disturbance in homeostasis of the system

Metallothionien

part of general response to cell injury, work with heat shock proteins

heat shock proteins

produced in response to many stimuli

heat shock stimuli

heat shock, ischemia, hypoxia, exposure to toxic metals, radiation

An example of heat shock responsive injury

Myocardial and neuronal ischemic injury

high molecular weight heat shock proteins

HSP60 and HSP70

What do HSP60 and HSP70 do

-Help new and distorted proteins fold into shape, essential for function

- Shuttle proteins from one compartment to another

- Transport damaged proteins to lysosomes for disposal

Low molecular weight heat shock protein

Ubiquitin

Ubiquitin

involved in protein degradation by proteosomes

E1

activating enzyme

E2

ubiquitin carrier protein

E3

ubiquitin protein ligase adds ubiquitin to damaged proteins

atrophy

cell shrinkage by loss of substance, tissue shrinkage by loss of mass of cells

Causes of atrophy

starvation, decreased function, reduced blood flow, loss of innervation, loss of endocrine stimulus, insufficient nutrition, old age

Starvation

decreased anabolic activities and increased catabolic activities

decreased function example

bone atrophy in bed ridden patients and in astronauts

What happens with a bone fracture

muscle atrophy because muscles aren't used

Why do astronauts undergo atrophy

osteoclasts and osteoblast imbalance

Mechanisms of atrophy

cell shrinkage and loss of cells

cell shrinkage

accelerated normal catabolic functions

Lysosomal enzymes

degrade cellular components

Non lysosomal enzyme example

ubiquitin pathway that involves proteosome

Example of dietary restriction prolonging life span

Spiders fed fewer spiders live longer

Example of calorie restriction prolonging life span

it being ideal to burn less glucose

hypertrophy

increase in cell and hence organ size

Where is hypertrophy mostly seen

In skeletal and cardiac muscle --\> unable to divide

Phenobarbital

induces hypertrophy of hepatocytes through SER cytochrome p450

What muscle is enlarged in a marathon runner

soleus muscle

Where does exercise induce hypertrophy

In cardiac muscle and skeletal muscle, myocardial cells

How does hypertrophy relate to cardiomyocytes

B1 integrins transduce biochemical signals triggering mechanical stress- induced hypertrophic program

B1 integrins

membrane spanning receptors

Mellusin

striated muscle protein, binds to the B1 integrin cytoplasmic region and induces mechanical stimulus into biochemical signals

Akt pathway

cell survival pathway activated by mellusin

- responsible for increased global protein synthesis and cardiomyocyte hypertrophy

Other melusin functions

- regulates compensatory hypertrophy and maintains contractility

- if we remove mellusin, there is no cardiomyocyte hypertrophy and non contracting

What happens during human aortic stenonsis

Decreasing levels of mellusin correlate with increasing cardiac impairment

Aortic stenonsis

narrow heart valve which affects heart function

Phosphatidylinositol-3-kinase

activates Akt pathways

hyperplasia

increase in cell number

Phenobarbital and other drugs

induces hyperplasia

persistent cell injury example

ill fitting shoe causes hyperplasia of skin of foot

secondary polycythemia

increase in red cell number

How many types of hyperplasia does the liver and kidney undergo

3 types of hyperplasia

direct hyperplasia

phenobarbital and other drugs

compensatory hyperplasia

liver regeneration following exposure to chemicals, parasites, surgery

nodular hyperplasia

following exposure to chemicals and radiation --\> neoplasia

neoplasia

the new and abnormal development of cells that may be benign or malignant

Which types of hyperplasia do not demonstrate change in cellular architecture

Direct and compensatory hyerplasia

Which type of hyperplasia DOES demonstrate architectural and/or organizational changes

nodular hyperplasia

metaplasia

replacement of one differentiated cell by another differentiated cell

metaplassein

to cast into new mold, plasticity of tissue

transformation

usually applied to cancer cells

differentiaion

usually refers to precursor cells

adult mammal metaplasia

occurs within varieties of epithelia and within varieties of mesenchyme

dogmas of metaplasia

1. no protein metaplasia across germ layers

2. metaplasia occurs in cells that can proliferate

3. If cells proliferate, cells can de differentiate and be replaced

Example of metaplasia that can not occur across germ layers

from bone to nerve, from connective tissue (mesenchyme) to intestinal tissue