L1 - A Kelly Flashcards
Virchow proposed that ___ ____ is the basis of disease
Virchow proposed that cell injury is the basis of disease.
list some things which can inflict cell injury:
extremes of oxygen tension or pH; lack of ATP; exposure to toxins, drugs and chemical agents (xenobiotics); cold and heat; prolonged deprivation of vital nutrients;
trauma; and aging.
can acute and chronic inflammation affect host cells engatively?
yep
give some cellular responses to injury:
- Hypertrophy – can adapt to stresses
- Hyperplasia – increase in number of cells
- Atrophy – reduction of complexity, and diminishing cell volume
o Digestion of cytoplasm proteins
o Autophagy – where organelles are encapsulated by intracytoplasmic membranes and digested by lysosomes
describe some reversible cell injury that may be seen:
Reversible injury may be seen as fatty deposits or cell swelling
what cause cell swelling?
Cell swelling is commonly caused by Na+/K+-ATPase (sodium/potassium pump) shut down leading to an influx of Na+ and hence H2O into the cell/mitochondria.
2 main methods by which cells die?
apoptosis
necrosis
describe apoptosis?
- Requires cell to have control over its own metabolism
- Common in tissue development and repair
- Cell blebs and buds, and cytoplasm shrinks in volume.
- Critical proteins cleaved by site specific protein caspases
- Cell signals nearby phagocytes (macrophages) for immediate phagocytosis
- Rarely induces inflammation
describe necrosis:
- Loss of cell volume homeostasis – swelling
- Rupture of membranes
- Cellular contents can leak into blood stream
- Will induce acute inflammation
- Neutrophil activation may itself cause local cell injury.
- Necrosis = poorly controlled process - tends to spread and involve sheets or groups of adjacent cells
the following lead to death by which mechanism?
- loss of metabolic control
- membrane damage
- cytoskeletal damage
- increased ROS
- DNA damage
what are free radicals?
molecules with unpaired electrons – eg Nitric oxide
- Created by:
how are free radicals created?
o Ionising radiation
o Many xenobiotics
why are free radicals dangerous?
o Highly reactive
o Cause DNA strand scission
o Create more free radicals
are free radicals exclusively produced by pathogens?
nope - also used by neutrophils and macrophages to attack microorganisms – but they can damage host cells too
describe the process of Free radical production?
O2
O2*
H2O2
OH*
how are free radicals removed?
glutathione
Catalase
SOD
describe hypoxia reperfusion injury?
Period after ischaema when blood flow is restored – ROS production increases and leads to tissue damage – destruction of endothelium of the blood vessels – recruits neutrophils = more damage, and thrombosis
how can as a loss of cell energy metabolsim lead to cell death? (4)
- Less ATP, reduced Na/K pump activity, Na+ accumulates in the cell, causing swelling
- Increased lactic acid from increased glycolysis = decreased pH, decreased enzymatic activity
- Influx of Ca2+ = increased activity of intracellular proteases, phospolipases, endonucleases and ATPases.
- Ribosome detachment (or lack of attachement) and loss of protein synthesis
_____ _____ are created by ionising radiation and also by many
xenobiotics
Free radicals
free radicals are the normal by-products of reactions catalysed by many _____ ______
oxidase enzymes
is the heat shock respone only to heat?
nope
also to other stresses
Describe the heat shock response:
- HSF form inactive complexes with HSP in cytosol
- stress causes dissociation
- HSF migrate to nucleus (also arent allowed to leave nucleus)
- HSF trimerise
- Supresses lots of generic gene transcription
- Activate heat shock protein transcription
what do heat shock proteins do?
– chaperone proteins which help refold partially denatured proteins.
why dont heat shock proteins denature?
- Unlike other proteins Hsps do not denature under conditions of stress as they have better hydrophobic packing, enhanced secondary protein structure, stronger hydrogen bonds and helix dipole stabilization.
how are HSPs responsible for preconditioning?
where cells exposed to minor injury become resistant to more major stresses.
HSP picture
Describe the purpose of the unfolded protein response
- ensures that the rate of protein synthesis does not exceed the cell’s capacity to complete the folding process.
- ER protein conc can reach as high as 100mg/ml – if not folded and chaperones – can precipitate
How does the unfolded protein response helpt to prevent protein precipitation in the ER
o increase synthesis of folding chaperones,
o enhances proteasomal protein degradation
o slows down protein translation
o usually reversible and is part of a process termed ‘host cell shut-down’.
what is meant by ‘cell shut down’
Cell shut-down is a primitive reversible response to injury and is initiated within minutes. RNA and DNA synthesis is supressed and many enzyme-catalysed reactions are inhibited
describe what activates the stress kinase pathway
(osmotic stress, oxidative stress, heat, UV, DNA cleavage)
what does the stress kinase pathway ultimately modulate -
DNA transcription
the stress kinase pathway activates _____ _____ _____ that reprogram transcription
heterodimeric transcription factors (e.g. AP1) that re- programme transcription
important examples of stress kinase pathways
o Jun N-terminal Kinase (JNK)/stress-activated protein kinase pathway (SAPK) pathway
o P38 kinase pathway
does the stress kinase pathway have a definitive outcome / answer?
nope - it just modulates discisions towards a stress response.
stress kinase image
Fat
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