Cell Injury Flashcards
What is hypoxia?
Oxygen deprivation resulting in decreased aerobic oxidative respiration
How can cell injury occur?
Hypoxia
Physical agents eg trauma, extremes in temperature
Chemical agents
Drugs
What does hypoxaemic mean?
Arterial content of oxygen is low
What can cause someone to be hypoxaemic?
High altitude
Lung disease
Definition of anaemia?
Decreased ability of haemoglobin to carry oxygen
What is ischaemia?
Interruption to blood supply causing lack of oxygen and metabolic substrates to tissue
What is oncosis?
Cell death with swelling
What is necrosis?
The morphological changes that follow cell death in living tissue
What is apoptosis?
Cell induced death by a regulated intra-cellular programme where a cell activates enzymes that degrade its own DNA and proteins
What is liquefactive necrosis?
Release of active enzymes is the dominant feature and tissue tends to liquefy - common with neutrophils
When does liquefactive necrosis commonly occur?
Bacterial infection due to neutrophils releasing proteolytic enzymes.
In the brain
What is coagulative necrosis?
When coagulative denaturation is the dominant feature and proteins clump together leading to solidity of the dead cells and tissue
What is fat necrosis?
Destruction of adipose tissue. Fatty acids released which react with calcium to form calcium soaps
When does fat necrosis often occur?
Trauma to fatty tissue eg in the breast - irregular scar is left which can mimic a nodule of breast cancer
Acute pancreatitis
Causes of infarction?
Thrombosis
Embolism
External compression of a vessel
Twisting of vessels
When and where does a white infarct occur?
After occlusion of an end artery in a solid organ
Solid nature limits the amount of haemorrhage from adjacent capillaries
Tissue dies and appears white
Which organs is a white infarct common in?
Heart
Spleen
Kidneys
When does a red infarct occur
Occurs in organs with a dual blood supply
Organs with numerous anastomoses
In loose tissue where there is poor stromal support for capillaries
What reversible changes occur in hypoxic cell injury?
Na/K pump failure so cell swells. Due to a lack of oxygen and therefore ATP
Calcium enters and damages cell components
Accumulation of lactic acid which lowers pH, affecting enzymes and chromatin clumping
Ribosomes detach from the ER, disrupting protein synthesis
Intra cellular accumulations of fat and denatured proteins
Effects of high cystolic calcium ion concentration?
Activates ATPase
Activates phospholipase which damages membranes
Activates proteases which break down membranes and cytoskeletal proteins
Activates endonucleases which damage DNA
What is ischaemia-reperfusion injury?
When blood flow is returned to tissue which has been subject to ischaemia but isn’t yet necrotic. Can cause tissue injury to be worse
Why does ischaemia-reperfusion injury occur?
Increased production of oxygen free radicals with reoxygenation
Increased neutrophils ➡️ more inflammation and tissue injury
Delivery of complement proteins and activation of complement pathway
What damage do free radicals cause?
Attack lipids in cell membranes
Damage proteins and nucleic acids
Mutagenic
What cells produce free radicals to kill bacteria?
Leukocytes
Which enzymes are involved in defence systems against ROS?
- SOD catalyses O2- to H2O2
- catalases and peroxidases convert H2O2 to oxygen and water
What are the free radical scavengers?
ACE vitamins
Glutathione
What do heat shock proteins do?
Ensure proteins are refolded correctly
Maintains protein viability and maximises cell survival
What are the main causes of cell injury and death?
Hypoxia Chemical agents Physical agents Microorganisms Immune mechanisms - hypersensitivity and autoimmune Dietary deficiency Genetic abnormalities
When are free radicals often produced?
Chemical and radiation injury
Cellular ageing
Ischaemia-reperfusion injury
High oxygen concentrations
Name the three important free radicals
Superoxide
Hydroxyl
Hydrogen peroxide
When are heat shock proteins important?
When the folding step in protein synthesis goes wrong
When proteins become denatured during cell injury
What nuclear changes occur during cell injury?
Chromatin clumping
Pyknosis
Karryohexis
Karryolysis
What does pyknosis mean?
When the nucleus shrinks and chromatin clumps
What is karryohexis?
Fragmentation of the nucleus
What is karryolysis?
Dissolution of the nucleus
What cytoplasmic changes occur under the light microscope during cell injury?
- Reduced pink staining due to increase in water in cytoplasm
- Increased pink staining due to increase in denatured proteins and detachment of ribosomes from the ER
When does coagulative necrosis commonly occur?
In most solid organs, where the cause of death is ischaemia
How does caseous necrosis appear?
Amorphous debris
What is caseous necrosis often seen with?
Granulatomous inflammation
What is gangrene?
A clinical term used to describe necrosis which is visible to the naked eye.
What type of necrosis is it if the gangrene is dry?
Coagulative necrosis
What can wet gangrene lead to?
Septicaemia
What is wet gangrene often due to?
Infection
Is an MI normally liquefactive or coagulative?
Coagulative
Is a cerebral infarction normally coagulative or liquefactive?
Liquefactive
What does the outcome of ischaemia depend on?
If there is an alternate blood supply
How quickly ischaemia has occurred - may be time for other perfusion pathways to develop
How vulnerable a tissue is to hypoxia
Oxygen content of the blood - in anaemic patients may be more serious
Examples of when physiological apoptosis might occur
Embryogenesis
Body needs to remove cells to maintain a steady state
Cells infected by a virus
Cancerous cells
During apoptosis, what changes occur which can be seen under the light microscope?
Shrunken Appear very pink (intensely eosinophilic) Chromatin condensation Pyknosis Fragmentation of nucleus
What changes occur that can be seen under the electron microscope during apoptosis?
Cytoplasmic blebbing which progresses to fragmentation into membrane-bound apoptotic bodies - contain cytoplasm, organelles and often nuclear fragments
Apoptotic bodies are removed by macrophages in phagocytosis
Why does apoptosis not induce inflammation?
No leakage of cell contents
What are the three phases of apoptosis?
Initiation
Execution
Degradation
What are caspases?
Proteases that mediate the cellular effects of apoptosis
How do caspases work?
Cleave proteins to break up the cytoskeleton
Initiate the degradation of DNA
Why is the intrinsic pathway called intrinsic?
All of the apoptotic machinery is inside the cell
What are some triggers for intrinsic apoptosis?
DNA damage
Withdrawal of growth factors or hormones
Which protein is important in triggering intrinsic apoptosis?
p53
After being triggered, what happens in intrinsic apoptosis?
Membrane permeability of mitochondria increases
Release of cytochrome C from mitochondria
Interacts with APAF1 and caspase 9 to form an apoptosome that activates various downstream caspases
What are triggers of extrinsic apoptosis?
External ligands such as TRAIL and Fas
They bind to ‘death receptors’ which activate caspases
What does p53 do?
‘Guardian of the genome’
Mediates apoptosis in response to DNA damage
Which three proteins make up the apoptosome?
Cytochrome C
APAF 1
Caspase 9
What does bcl-2 do?
Inhibits apoptosis by preventing cytochrome c from being released from mitochondria
Name a death ligand and a death receptor
TRAIL
TRAIL-R
What is pathological calcification
The abnormal deposition of calcium salts within tissues
What is steatosis?
Accumulation of triglycerides in cells
What are common causes of liver steatosis?
Alcohol abuse
Diabetes mellitus
Obesity
Toxins
What type of cells can cholesterol accumulate in? What are these cells known as?
Smooth muscle cells and macrophages in atherosclerotic plaques
Foam cells
What is it called when cholesterol is deposited in the skin of people with hyperlipidaemia?
Xanthomas
What is Mallory’s hyaline seen in?
Alcoholic liver disease
What is Mallory’s hyaline caused by?
Accumulation of altered keratin filaments
What is the pathology of α1-antitrypsin deficiency
Liver produces a version of α1-antitrypsin that is incorrectly folded. Cannot be packaged by the ER so accumulates within it. Therefore not secreted by the liver.
How does α1-antitrypsin defence affect the lungs?
Proteases within the lung can act unchecked and patients develop emphysema as lung tissue is broken down.
What happens of someone has a high exposure to urban pollutants such as coal/coal dust?
Lungs can become fibrotic or emphysematous.
What happens to coal dust when it is inhaled?
Phagocytosed by macrophages within lung tissue and is seen as blackened tissue or blackened peribronchial lymph nodes.
Give some examples of endogenous pigments
Bilirubin
Lipofusin
Haemosiderin
How is lipofusin produced?
Sign of previous damage by free radicals and lipid peroxidation.
Seen in ageing cells
Brown pigment
When does haemosiderin form?
When there is localised or systemic excess of iron.
Eg bruises
What is haemosiderin derived from?
Haemoglobin
What colour is haemosiderin
Yellow/brown
What is haemosiderosis and what damage can it cause?
When haemosiderin is deposited in many organs.
Can damage the liver, pancreas and heart.
What conditions is haemosiderosis seen in?
Hereditary haemochromatosis
Haemolytic anaemias
Blood transfusions
What does dystrophic calcification occur in?
Dying tissues Atherosclerotic plaques Ageing Damaged heart valves Tuberculus lymph nodes
When does metastatic calcification occur?
As a consequence of hypercalcaemia secondary to disturbances in calcium metabolism.
Four main causes of hypercalcaemia?
Increased PTH secretion due to parathyroid tumours or ectopic secretion of PTH-related protein by malignant tumours
Vitamin D related disorders
Destruction of bone secondary to primary tumours of bone
Renal failure
List some things that accumulate in cells as they age
Damage to DNA
Abnormally folded proteins
Lipofuscin
What is telomerase and which cells have it?
An enzyme which prevents the shortening of telomeres so cells can divide many times
Stem and germ cells
What is ethanol broken down into and by which enzymes?
Ethanol ➡️ acetaldehyde dehydrogenase
Alcohol dehydrogenase
a cytochrome P450 enzyme - CYP2E1
catalase
What happens to acetaldehyde?
Acetaldehyde ➡️ acetic acid
Acetaldehyde dehydrogenase
Which enzyme involved in alcohol metabolism do women have a lower concentration of than men
Alcohol dehydrogenase
Which enzyme do about half of oriental people have reduced activity of? What does this result in?
Aldehyde dehydrogenase
Build up of acetaldehyde
Facial flushing
Toxicity of alcohol affects the liver by causing a fatty change. What is this?
Steatosis which can cause hepatomegaly.
It is reversible and generally asymptomatic.
What happens in acute alcoholic hepatitis?
Focal hepatocytes necrosis
Mallory body formation
Neutrophilic infiltrate
Symptoms of acute alcoholic hepatitis?
Fever
Liver tenderness and jaundice
What changes occur to the liver in cirrhosis?
Hard and shrunken liver
Micronodules of regenerating hepatocytes form surrounded by bands of collagen.
How is paracetamol detoxified?
Glucaronidation and sulphonation
Which enzyme in metabolism of paracetamol leads to the production of the toxic metabolite? What is it called?
When cytochrome P450 is used
NAPQI
How is NAPQI detoxified?
Interaction with glutathione
What does NAPQI do?
Binds sulphydryl groups on hepatocytes membranes, causing necrosis and liver failure
What can cause people to have lower reserves of glutathione?
If they drank alcohol with the paracetamol overdose If they are alcohol dependent If they are malnourished On enzyme inducing drugs HIV positive/AIDS
What is the antidote to paracetamol overdose?
N-acetylcysteine
What is measured to decide whether or not to give NAC
Serum conc of paracetamol
4 hours after over dose
What is used to assess liver damage by paracetamol overdose?
The pro-thrombin time 24hrs after overdose
What does aspirin do?
Acetylates platelet cyclooxygenase
Blocks platelet ability to form thromboxane A2, a substance which activates platelet aggregation
What are the consequences of an aspirin overdose?
Stimulates respiratory centre ➡️ respiratory alkalosis
Causes metabolic acidosis to compensate
Interferes with carbohydrate, fat and protein metabolism and oxidative phosphorylation ➡️ production of lactate, pyruvate and ketone bodies ➡️ acidosis
Deceased platelet aggregation
Acute erosive gastritis and GI bleeding
What damage can free radicals cause?
Cross link proteins
Oxidise membrane lipids
Describe what is seen in fatty change of the liver after alcohol
Steatosis from toxicity of alcohol
Hepatomegaly
Acute, reversible and asymptomatic
Explain what is seen in acute alcoholic hepatitis
Alcohol and acetaldehyde are directly toxic Acute hepatitis Focal hepatic necrosis Mallory body formation Neutrophils infiltrate Fever, liver tenderness and jaundice
Explain changes seen in cirrhosis
Shrunken, hard liver
Micro nodules of regenerating hepatocytes surrounded by bands of collagen
Irreversible, serious, sometimes fatal
