MoD Session 1: cell injury Flashcards
Causes of cell injury and death
Hypoxia Toxins Radiation Microorganisms Immune mechanisms (autoimmune, hypersensitivity) Dietary deficiency or excess Genetic abnormalities Physical agents: trauma, extreme temperature, pressure, electric current
What is the result of hypoxia and how does tolerance vary between cells?
Reduced aerobic respiration.
Fibroblasts can tolerate it for a few hours, neurones only a few minutes
What are the causes of hypoxia?
- Hypoxaemic hypoxia: at altitude or reduced oxygen absorption in lungs
- Anaemic hypoxia: less ability of Hb to carry oxygen due to anaemia or carbon monoxide poisoning
- Histiocytic anaemia: problem with oxidative phosphorylation enzymes e.g. cyanide poisoning
- Ischaemic hypoxia: interruption to arterial blood supply or decreased venous drainage. Reduces oxygen and metabolic substances so injury more rapid and severe
What toxins can cause cell injury?
Glucose and salt in hypertonic solutions High oxygen Insecticides, herbicides, pollutants etc Asbestos Narcotics, alcohol, medicines
Hypersensitivity reactions?
Host tissue damaged after overly vigorous immune reaction, e.g. urticaria (hives)
Autoimmune reactions?
Immune system fails to distinguish self from non-self, e.g. Grave’s disease
What are the targets for cell damage?
Membranes
Nucleus
Proteins
Mitochondria
Describe the events in reversible hypoxic injury
Decreased oxidative phos so decreased ATP
Loss of activity of Na+/K+ ATPase (as needs ATP)
[Na+]i increases, water enters, cell swells
Ca2+ enters, damages cell components
Anaerobic glycolysis produces lactate-affects enzymes as low pH
Ribosomes detach from ER causing disrupted protein synthesis
Describe irreversible hypoxic injury
Not known exactly when injury becomes irreverible
Accumulation of Ca2+ causes activation of enzymes
Lysosomes are broken down and release more lytic enzymes
All cell membranes are damaged and start to show blebbing, and at some point die
Which enzymes does Ca2+ activate in irreversible hypoxic injury?
ATPases (decreases ATP further)
Phospholipases (more membrane damage)
Proteases (break down membranes and cytoskeletal proteins)
Endonucleases (damage DNA)
Ischaemia-reperfusion injury?
Blood flow returned to tissue that has had ischaemia but not yet necrotic, damage can be worse than if blood not restored
May be due to:
1. Increased production of free radicals with the reoxygenation
2. More neutrophils causing more inflammation and injury
3. Activation of the complement pathway
What are free radicals and when are they produced?
Molecules with a singular unpaired electron (so unstable)
Produced in: chemical/radiation injury, cellular ageing, ischaemia reperfusion, high oxygen concentrations
OH radical (hydroxyl radical): most dangerous
O2- (superoxide)
H2O2 (hydrogen peroxide)
Produced in Fenton reaction: Fe2+ + H2O2 –> Fe3+ + OH- + hydroxyl radical
Also in Haber-Weiss reaction: O2 radical + H+ + H2O2 –> O2 + H2O + hydroxyl radical
Effects of free radicals?
Chain reactions causing production of more free radicals Lipid peroxidation of cell membranes Damaged proteins, CHOs and nucleic acids Kill bacteria Used in cell signalling
Antioxidant system
Superoxide dismutase: makes O2- into H2O2 so less damaging
Catalases and peroxidases: make H2O2 into O2 + H2O
Free radical scavengers: vitamins A,C,E and gluathione
Storage proteins
Heat shock proteins
Unfoldases or chaperones
E.g. ubiquitin
Mend misfolded proteins and maintain cell viability
Triggered by any form of injury
Dye exclusion technique
Morphological criteria for light microscopy to see if cell dead: put dye in cells medium and if cell takes it up cell is dead because membrane is permeable to something it wouldn’t normally be
Cytoplasmic changes seen with cell swelling from oncosis light microscope
Decreased staining of cytoplasm due to H2O accumulation (reversible)
then
Increased staining due to loss of ribosomes from the ER (irreversible)
May also see abnormal intracellular accumulations