1.2 - Cell Injury + Cell Death Flashcards
What is cell injury
- cells have effective mechanisms to deal with mild environmental changes
- more severe changes lead to cell adaptation, injury or cell death
- injured cell will either adapt, revert back to normal or lead to cell death
- degree of injury depends on type, severity, duration of injury and the type of tissue
Example of cell response to injury – heart
initial insult = myocytes having to work harder
adaptation = cardiac myocyte hypertrophy
continued insult and adaption = ventricular hypertrophy
continuing insult = myocytes require more oxygen (as they are bigger)
second insult = hypoxia
irreversible cell injury + death = myocardial infarction / arrythmia
*there are many treatments that would help at different stages of this path, eg valve replacement, heart failure medications (to increase O2 delivery to the heart), stents, bypass, anti-arrythmics, ICDs etc)
Causes of cell injury – environmental and non-environmental (details on separate cards)
environment
- hypoxia
- toxins + poisions
- immune mediated
- physical agents
- infection
- nutrition + dietary
non-environmental
- genetic
- aging
Causes of cell injury: Hypoxia + it’s different causes
oxygen deprivation
- hypoxaemic hypoxia - arterial content of oxygen is low
- anaemic - decreased ability of haemoglobin to carry oxygen
- ischaemic interruption to blood supply
- histiotoxic inability to utilise oxygen due to disabled oxidative phosphorylation enzymes (much rarer)
different tissues are affected in different ways by hypoxia ie neurones are affected very quickly, leading to cardiac arrest, however skeletal muscle can tolerate up to a few hours.
☞ cause needs to be determined in order to treat effectively
Causes of cell injury: Examples of some toxins
- Poisions
- Pollutants
- Insecticides
- Herbicides
- Asbestos
- Alcohol
- Drugs
Causes of cell injury: immune mediated
Two types of mechanism
hypersensitivity
- Excessive immune response to a non-self antigen
- Eg anaphylaxis
autoimmune
- Immune system over reacts to a self antigen
- Eg Grave’s disease
Causes of cell injury: physical agents
- Trauma
- Extreme temperatures eg burns + frostbites
- Electric currents
- Radiotherapy
also, infections: viral, fungal, bacterial, parasitic
Causes of cell injury: nutritional
- Obesity
- Anorexia
- Any dietary deficiencies or excess eg B12, folate, vit D, salt, fat etc
Causes of cell injury: genetic + ageing
- Inborn errors of metabolism
- Enzyme deficiencies
- Dysfunctional proteins
What are the main different mechanisms of cell injury
lots of different types, but most result in a lack of ATP
- Depletion of ATP
- Direct mitochondrial damage
- Direct membrane damage
- Disruption to calcium homeostatis
- Oxidative stress (ie free radicals)
- Direct damage to DNA and proteins
Mechanisms of cell injury: cellular reduction in ATP
cells deprived of oxygen → reduction in oxidative phosphorylation → mitochondrial ATP production stops
Cellular reduction in ATP has multiple effects:
- anaerobic glycolysis: intracellular glycogen stores depleted → inc lactic acid + phosphates → decreased pH in cell → denaturation → activity of enzymes effected
- Na/K pump: sodium + water enter cell → swelling of cell/organelle → potassium leaves cell → ER + cell swelling, loss of microvilli + blebbing → calcium also enters cell
- ribosomes detach from ER: reduced protein synthesis → altered metabolism → intracellular accumulations eg lipid deposition + denatured proteins
How does calcium influx cause irreversible cell damage
Excess calcium can activate the following enzymes
- ATPases: reduces ATP in the cell further
- Phospholipases: break down cell and organelle membranes (and lysosome enzymes, so cell digests itself)
- Proteases: breaks down proteins, leading to dysfunctional proteins
- Endonucleases: breaks down DNA in cell
Mechanisms of cell injury: free radicals
- aka oxidative stress
- free radical is atom with unpaired electron, highly reactive + chemically unstable
- formation can be pathological or physiological
some common free radicals (aka reactive oxygen species, ROS
hydroxyl OH*
superoxide O2-
hydrogen peroxide H2O2
Some examples of how free radicals are generated (no detail)
- chemical/radiation injury
- ischaemia-reperfusion injury
- cellular aging
- anti-microbial killing by phagocytosis
How do free radicals damage lipids, proteins + DNA
lipid damage
- Free radicals target unsaturated fatty acids
- Causes cell membrane + DNA damage
- Results in calcium influx + damage to Na/K pump etc
protein damage
- Promotes protein-protein cross links (ie disulphide bonds)
- Promotes oxidation of proteins
- Causes protein fragmentation and therefore cell damage
DNA damage
- Free radicals target nuclear and mitochondrial DNA
- Cause single + double strand breaks in DNA
- This can cause cell aging and malignant transformation of cells
Body control of free radicals (ie how do we get rid of them)
free radicals are so unstable that they commonly decay spontaneously in the presence of water or via
- Anti-oxidants: eg lipid soluble vitamins, ascorbic acid, glutathione
- Transport proteins: iron binds to transferrin, copper binds to ceruloplasmin (metals can cause free radical formation, but this is prevented by them binding to transport proteins)
- Enzymes: superoxide dismutases (SODs) and glutathione peroxidase
- Heat shock proteins eg ubiquitin: they help repair + refold damaged proteins, or label them for degradation
What transport protein binds to iron and copper
- Iron binds to transferrin
- Copper binds to ceruloplasmin
What are some reversible and irreversible damage to cells (and what are they due to, broadly speaking)
reversible
- Swelling (due to Na/K+ pump failure, so water into cell)
- Clumped chromatin (due to reduced pH)
- Ribosome dispersion (lack of ATP to hold them together)
- Cytoplasmic blebs (symptomatic of cell swelling)
☞ cell membrane is intact
irreversible
- Nuclear changes
- Lysosome rupture (reflects membrane damage)
- Membrane defects
- Lysis of endoplasmic reticulum (due to membrane defects)
What is the difference between apoptosis and necrosis
apoptosis
- Cell suicide
- Individual programmed cell death
- Pathological or physiological
- Cells shrink, no inflammation
- Cell membrane preserved
necrosis
- Cell murder
- Cells swell
- Pathological
- Inflammation due to release of cell contents
Physiological vs pathological apoptosis
physiological
- Embryogenesis
- Involution of hormone dependent tissue
pathological
- Cell death in viral infection
- Cells with damaged DNA
Intrinsic vs extrinsic apoptosis
intrinsic (mitochondrial)
Mitochondria release cytochrome C → which activate caspases (enzymes) → induce apoptosis
extrinsic (death receptors) death receptors are released from T-killer cells → recognise damaged cells → attach to cell membrane → activate caspases → lead to cell death
What is necrosis
in a living organism, the morphological changes that occur after a cell has been dead some time
- Seen after 12-24 hours
- See both macroscopically + microscopically
- Cells swell
- Causes lots of inflammation due to emptying of cell contents
Different subtypes of necrosis
- coagulative occurs in solid organs, retains ghost outline of cells + tissue architecture. Protein denaturation prominent in the cell injury/death.
- liquefactive damage of ‘loose’ tissue, complete loss of architecture, release of enzymes that break down tissue.
- caseous seen in the lung (and sometimes lymph nodes) infected with TB. Cheese like.
- fat necrosis direct trauma to fatty areas. Acute pancreatitis.
- fibrinoid necrosis death of cells in small blood vessels
