MoD - Cell injury Flashcards
What is hypoxia?
Oxygen deprivation that leads to reduced oxidative phosphorylation in mitochondria. This reduced aerobic respiration leads to decreased ATP
What are the seven causes of cell injury/death?
Hypoxia Physical agents Chemical agents Microorganisms Immune mechanisms Dietary insufficiency Genetic abnormalities
What is hypoxaemic hypoxia?
This is where there is reduced arterial O2
What is anaemic hypoxia?
This is the decreased ability of haemoglobin to carry O2
What is ischaemia?
This is interruption to the blood supply to tissues.
Can be due to reduced venous drainage or arterial supply.
Leads to loss of O2 and loss of metabolic substrates
What is histiocytic hypoxia?
The inability to utilise O2 e.g cyanide
What are the two immune mechanisms of cell injury?
Hypersensitivity - tissue is injured secondary to a vigorous immune reaction (e.g hives)
Autoimmune - immune system fails to distinguish self from non self e,g graves.
What are the 4 targets of cell injury?
Cell membranes (plasma and organelle)
Nucleus (genetic material)
Mitochondria (ATP)
Proteins (structure and metabolism)
What are the consequences of hypoxia?
The reduced ATP reduces the action of the sodium/potassium pump
The increases intracellular Na+ which causes water to move into the cell leading to swelling.
Also low ATP leads to increased aerobic glycolysis leading to more lactate = low pH… This causes clumping of chromatin, and reduced enzyme activity.
The low ATP leads to the detachment of ribosomes from the ER. This reduces protein synthesis.
What are the features of irreversible hypoxic injury?
Profound disturbance in membrane permeability
Influx of Ca2+ from outside and release from calcium stores in mitochondria and ER.
This leads to increased production of -
ATPases (decreased ATP)
Phospholipases ( decreased phospholipids) - lysosomal membranes
Proteases (decreased membrane stability)
Endonucleases (damage DNA)
Also intracellular substances leak out - detected in blood samples (ie AST/ALT - liver)
What is ischaemia reperfusion injury?
If blood returns to hypoxic tissue before it becomes necrotic the damage can be worse -
- Increased free radical production
- Increased no. If neutrophils
- Delivery of compliment proteins
What are free radicals?
Unstable configuration of outer electrons react with lipids and damage proteins.
What is the most dangerous free radical?
*OH
How is *OH formed?
Radiation of water
Fenton reaction - iron plus H2O2
Haber Weiss - superoxide radical and H2O2
What do heat shock proteins do?
These recognise misfolded proteins and ensure they are correctly folded. When cells are submitted to stress they increase HSPs.
What is oncosis?
Cell death with swelling, this is the spectrum of change that occurs prior to death.
What is apoptosis?
Cell death by shrinkage. Induced by intracellular processes. That activate enzymes to destroy cellular DNA. Often called cell suicide.
What is necrosis?
The morphological changes that occur after a cell has been dead some time
What is diagnosis of cell death by dye exclusion?
This is when dye is applied to a cell and if it doesn’t enter the cell the cell is live. If the dye enters the cell it is dead.
What are the features of the light microscope view of oncosis?
Reduced pink stain of cytoplasm due to increased water swelling.
Then an increased pink stain due to detached ribosomes
Nuclear changes - clumped chromatin.
Abnormal intracellular accumulation
What are the features of an electron microscope view of oncosis?
Reversible changes - swelling, cytoplasmic blebs, clumped chromatin, ribosome separation.
Irreversible changes - nuclear changes, pykosis (shrinkage), karryohexis (fragments), karryolysis (dissolution)
Swelling and rupture of lysosomes
What are the principle molecules that leak out of cells?
Potassium - stops heart
Realised from severe necrosis (burns, MI, tumour lysis syndrome)
Enzymes - indicate organ involved
Myoglobin - realised from dead myocardium or striated muscle.
What are the two types of pathological calcification?
Dystrophic -
Metastatic
What is dystrophic calcification?
Occurs in areas of dying tissue. Local disturbance in tissue favours hydroxyapatite crystals to lay down. Causes organ disfunction - ie atherosclerosis in great vessels leads to heart failure
What is metastatic calcification?
Body wide calcification due to hypercalcaemia (caused by increased PTH or bone turnover) hydroxyapatite crystals are deposited in normal tissues throughout the body.
Why do cell’s ability to replicate diminish with age?
Every replication the telomere is shortened
What are the two main types of necrosis?
Coagulative
Liquefactive
Why does coagulative necrosis occur?
Ischaemia in tissues. Proteins undergo denaturation and these denatured proteins then coagulate.
Tissue appears white and solid to the naked eye
Histologically the cellular architecture is preserved (ghost outline)
Explain the pathophysiology of Liquefactive necrosis
This is seen in infection of infarction of the brain (fragile tissue)
Protein undergoes autolysis (dissolution by proteases)
Tissue becomes a viscous mass and in acute inflammation pus is present.
Histologically lots of neutrophils and cell debris
Where is caseous necrosis seen?
In TB infections
White soft cheese looking material.
What is fat necrosis?
Destruction of adipose tissue
Mainly seen in pancreatitis (inflammation of acinar cells lead to lipase release)
Chalky white areas of combined fat with calcium (saponification) looks like wax
Microscopically - outline of adipose cells and bluish cast from calcium deposits.
What is gangrene?
Necrosis that is visible to the naked eye
What is the difference between dry and wet gangrene?
Dry gangrene is when air results in dry hardened dead skin
Wet gangrene is when the dead cells are infected with bacterial culture.
What is an infarction?
Area of tissue death (necrosis) caused by ischaemia. Mostly due to thrombosis or embolism.
What is a red infarction? And why does it occur?
This is when there is extensive haemorrhage into the dead tissue.
Can be due to -
- Organ having dual blood supply so occlusion of main artery leads to necrosis yet secondary arterial supply allows blood to enter. -
- Or when capillary bed of two arterial supplies merge.
- Or loose tissue where there is poor support for fro capillaries.
What is a white infarction and why does it occur?
Occurs in solid organs after occlusion of end artery solid nature limits the amount of haemorrhage that can occur.
What is apoptosis?
Cell death shrinkage - opposite to mitosis
DNA is cleaved non randomly by capsizes
When is apoptosis see ?
When cells are no longer needed
Embryogenesis - sculpting of features ie hands
Or when cell is damaged ie toxic injury or tumours.
What is seen microscopically in apoptosis?
Light - cells are shrunken, eosinophilic, chromatin condensation
Electron - cytoplasmic budding - membrane bound apoptosis bodies
No inflammation due to no loss of content
What are the 4 abnormal cellular accumulations?
Fluid
Lipids
Protein
Pigments
Why do abnormal cellular accumulations occur?
If a cell can’t metabolise something, it remains in the cell
How does fluid accumulate in cells?
Can appear as vacuoles or due to osmotic disturbance the while cell swells.
This means the cells are enlarged but not hypertrophic
What is accumulation of TAGs in cells known as?
Steatosis, (often seen in the liver, common causes alcohol, obesity)
What is Mallory’s hyaline?
Damaged protein that is seen in hepatocytes in alcoholic liver disease die to accumulation of altered keratin filaments
What is a1-antitrypsin deficiency?
Genetically inherited disorder where the liver produces a misfolded a1-anti trypsin protein. This cannot be packaged in the ER so accumulates .
What are exogenous pigments?
Outside source e.g coal, soot, tattoo ink
What are endogenous pigments ?
Pigments naturally produced by the body (e.g lipofuscin, haemosiderin, bilirubin)
What is haemosiderin? And what is the condition associated with it?
Is an iron storage molecule derived from haemoglobin and is yellow /brown. It forms due to and excess of iron (e,g bruise)
Haemochromatosis is genetically increased iron absorption. Leads to iron deposition in skin, liver, pancreas etc ..symptoms include liver damage, endocrine failure,
