Pathological Processes 1+2 Flashcards
Cell injury
Cell injury results when cells are stressed and can no longer adapt
3 things that degree of injury depends on :
- Type of injury = physical/chemical
- Severity of injury
- type of tissue
Process of responding to injury
• Homeostasis
• Cellular adaptation – to the change
• Cellular injury
• Cell death = when injury is irreversible
—> Cell injury results when cells are stressed and can no longer adapt
Causes of cell injury
• Hypoxia – lack of oxygen • Toxins • Physical agents – Direct trauma – Extremes of temperature – Changes in pressure – Electric currents • Radiation • Micro-organisms - infection • Immune mechanisms – macrophages, neutrophils • Dietary insufficiency and deficiencies, dietary excess – cell energy sources
What is hypoxia?
—-> Hypoxia is a deficiency of oxygen that can result in a reduction in aerobic oxidative respiration. Extremely important common cause of cell injury/cell death.
What do hypoxia tumours snow ?
- Increased aggressiveness
- Resistance to therapy
- Increased metastasis - cancer spreads to different part of body
- Poor prognosis
4 types of hypoxia
Hypoxaemic hypoxia – arterial content of oxygen is low
Anaemic hypoxia – decreased ability of haemoglobin to carry oxygen
Histiocytic hypoxia – inability to utilise oxygen in cells due to disabled oxidative phosphorylation enzymes
Ischaemic hypoxia - interruption to blood supply
Ischaemia
—> ischaemia = insufficient blood flow to provide adequate oxygenation
Examples of injury causing toxins
- Glucose and salt in hypertonic solutions – change cell homeostasis
- High concentration of oxygen – can form free radicals
- Poisons
- Pollutants
- Insecticides
- Herbicides
- Asbestos
- Alcohol
- Narcotic drugs
- Medicines
How does immune system cause cell injury?
- Hypersensitivity reactions
- host tissue is injured secondary to an overly vigorous immune reaction, e.g., urticaria (= hives)
- Autoimmune reactions
- immune system fails to distinguish self from non-self, e.g., Grave’s disease of thyroid
What are free radicals?
Reactive Oxygen Species
• Single unpaired electron in an outer orbit – an unstable configuration hence react with other molecules, often producing further free radicals
Production of free radicals - 5 methods
- Normal metabolic reactions: e.g., oxidative phosphorylation
- Inflammation: oxidative burst of neutrophils
- Radiation: H2O OH• = break bounds = free radicals
- Contact with unbound metals within thebody: iron (by Fenton reaction) and copper
• Free radical damage occurs in haemachromatosis and Wilson’s disease - Drugs and chemicals: e.g., in the liver during metabolism of paracetamol or carbon tetrachloride by P450 system
3 things that control free radicals
- Anti-oxidant scavengers: donate electrons to the free radical
• vitamins A, C and E - Metal carrier and storage proteins
• (transferrin, ceruloplasmin): sequester iron and copper - Enzymes that neutralise free radicals
• Superoxide dismutase
• Catalase
• Glutathione peroxidase
Free radicals mechanism of cell injury
- –> number of free radicals overwhelms the anti-oxidant system = oxidative imbalance
- -> tend to attack bonds specifically double bonds
- Most important target are lipids in cell membranes.
- Cause lipid peroxidation.
- This leads to generation of further free radicals → autocatalytic chain reaction.
- Also oxidise proteins, carbohydrates and DNA
- These molecules become bent out of shape, broken or cross-linked
- Mutagenic and therefore carcinogenic
How does cell protect itself against injury?
—> aim to correct the mistake
• Heat shock proteins – try to correct misfolded proteins
Heat shock protein
- Heat shock proteins – try to correct misfolded proteins
- In cell injury heat shock response aims to ‘mend’ mis-folded proteins and maintain cell viability.
- Unfoldases or chaperonins.
- An example – ubiquitin.
Diagnosing cell death - staining
The diagnosis of cell death in short time is best measure on their functional capability rather than morphologic criteria, e.g., increased permeability of the cell membrane.
1. Add dye to cell mixture 2. Dye can only go into cells if there are pores and gaps in membrane 3. So dye only passes into membrane of damaged cells 4. Only dead cells are stained as blue 5. Live cells are intact and remain unstained
Necrosis definition
—> Necrosis: in a living organism the morphologic changes that occur after a cell has been dead some time. Damage to intracellular organelles
• Seen after 12-24 hours
→ protein denaturation and enzyme release
4 types of necrosis
Coagulative
Liquefactive
Caseous
Fat
Coagulative necrosis
•Denaturation of proteins dominates over release of active proteases.
•Cellular architecture is somewhat preserved, “ghost outline” of cells.
1. Protein starts to get denatured
2. Ghost outline of cell is present
- see lots of neutrophils
Shape of cell can be seen but proteins have been denatured
→ check image on 1.1
Liquefactive necrosis
- Complete dissolution of necrotic tissue
- Most commonly due to massive infiltration by neutrophils (abscess formation).
- Release of reactive oxygen species and proteases = further degrade tissue
- Enzyme degradation is substantially greater than denaturation.
- Leads to enzymatic digestion (liquefaction) of tissues
→ mainly in the brain due to very high concentration of lysosymes
Caseous necrosis
Contains amorphous (structureless) debris. (no ghost outline like seen in coagulative necrosis).
• Structureless debris
•Particularly associated with infections, especially tuberculosis.- lung
→ tissue almost looks smooth , no cell outlines as original tissue architecture is lost
Fat necrosis
- Results from action of lipases released into adipose tissue.
- Free fatty acids accumulate and precipitate as calcium soaps (saponification).
- These precipitates are grossly visible as pale yellow/white nodules
- Seen on the slide 2.1
- Common in adipose tissue
Gangrene
Necrosis visible to the naked eye
- appearance of necrosis
Oncosis
cell death with swelling, the spectrum of changes that occur in injured cells prior to death
Infarction
-necrosis caused by reduction in arterial blood flow
• A cause of necrosis
• Can result in gangrene
Infarct
- an area of necrotic tissue which is the result of loss of arterial blood supply
An area ischaemic necrosis
3 types of gangrene
Dry gangrene
Wet gangrene
Gas gangrene
Dry gangrene
= necrosis modified by exposure to air (coagulative necrosis)
If there’s mostly coagulation necrosis, (i.e., the typical blackening, desiccating foot which dried up before the bacteria could overgrow), we call it dry gangrene.
Wet gangrene
= necrosis modified by infection (liquefactive necrosis)
If there’s mostly liquefactive necrosis (i.e., the typical foul-smelling, oozing foot infected with several different kinds of bacteria), or if it’s in a wet body cavity, we call it wet gangrene.
Gas gangrene
A type of a wet gangrene where the infection is with anaerobic bacteria that produce gas.
White infarcts
Anaemic infarcts
• ‘Solid organs’, occlusion of an end artery
• Often wedge-shaped
• Coagulative necrosis
Red infarcts
haemorrhagic infarct • Loose tissue • Dual blood supply • Numerous anastomoses • Prior congestion • Raised venous pressure • Re-perfusion – other blood goes to supply infarct area but then accumulates
Consequences of infarction depends on:
- Alternative blood supply
- Speed of ischaemia
- Tissue involved
- Oxygen content of the blood
What is apoptosis
Programmed cell death
cell activates enzymes that degrade it’s own nuclear DNA and proteins, packaged and engulfed by macrophage
How many cells does apoptosis affect?
Single cell or groups of cells
When does apoptosis occur?
• Pathological or physiological
When does apoptosis occur physiologically
• In order to maintain a steady state
• Hormone-controlled involution = breast gland epithelium after lactation, in which the number of cells in the epithelium becomes reduced. By apoptosis
• Embryogenesis
a. Removal of tissue = tadpole losing tail to be frog
b. Organ sculpting – removing web between fingers
When does apoptosis occur pathologically
4 times
- Cytotoxic T cell killing of virus-infected cells
- Removal of neoplastic cells – cell need to be destroyed
- When cells are damaged, particularly with damaged DNA
- Graft versus host disease – organ transplant, foreign organ
5 steps of apoptosis
- Nucleus condense
- Nucleus break into fragments
- Nucleus dissolved
- Packaged into apoptotic bodies
- Macrophages phagocytose apoptotic bodies
How do apoptotic cells look under a microscope
Single cells Shrinkage Lysis-broken Dna fragmentation Intact cellular contents - released in apoptotic bodies No adjacent inflammation
How do necrotic cells look under a microscope
- Continuous groups of cells
Enlarged, swelling
Nucleus = pyknosis _ karyorrhexis _ karyolysis
Disrupted plasma membrane - lysis
Frequent inflammation
Always pathological
Two mechanisms in the initiation and execution of apoptosis
Intrinsic
Extrinsic
—-> Both result in activation of caspases
Capases
Enzymes that control and mediate apoptosis
• Cause cleavage of DNA and proteins of the cytoskeleton
Activated by intrinsic and extrinsic pathways
Intrinsic pathway - apoptosis
- Initiating signal comes from within the cell
- p53 protein is activated and this results in the outer mitochondrial membrane becoming leaky 3.Cytochrome C is released from the mitochondria and this causes activation of caspases by activating apoptosome
Eventually cells to shrink and break up into apoptotic bodies
2 triggers of Intrinsic pathway - apoptosis
- Most commonly irreparable DNA damage
* Withdrawal of growth factors or hormones
Extrinsic pathway - apoptosis
- Initiated by extracellular signals
2.One of the signals is TNFα
• Secreted by T killer cells
• Binds to cell membrane receptor (‘death receptor’)
• Results in activation of caspases
Eventually cells to shrink and break up into apoptotic bodies
Triggers of extrinsic pathway - apoptosis
• Cells that are a danger, e.g., tumour cells, virus-infected cells
Clearance of apoptic bodies
- The apoptotic bodies express proteins on their surface
- They can now be recognised by phagocytes or neighbouring cells
- Finally degradation takes place within the phagocytes
Abnormal cellular accumulation
- Accumulation of an abnormal amount of something in a cell
—> Seen when metabolic processes become unbalanced
• Often occur with sublethal or chronic injury
• Can be reversible
• Can be harmless or toxic
3 places where abnormal cellular accumulations are derived from
- Cell’s own metabolism
- The extracellular space, e.g., spilled blood
- The outer environment, e.g., dust
5 main types of abnormal intracellular accumulation
- Water and electrolytes
- Lipids
- Carbohydrates
- Proteins
- ‘Pigments
Fluid accumulation in cells
• -> maintain osmotic presure
- Hydropic swelling
- Occurs when energy supplies are cut off, e.g., hypoxia at cellular level
- Indicates severe cellular distress
- Na+ and water flood into cell
Problem with fluid accumulation
- Particular problem in the brain-cerebral edema
* Edema is recognized as an area of lucency or hypodense or hypoattenuation by CT imaging
Lipid accumulation in cells
—> Steatosis (accumulation of triglycerides)
• Often seen in liver (major organ of fat metabolism)
• If mild - asymptomatic but when severe can lead to liver failure
4 Causes of lipid accumulation
- Alcohol (reversible in about 10 days)
- Diabetes mellitus
- Obesity
- Toxins (e.g., carbon tetrachloride)
Lipid accumulation - cholesterol
Cholesterol Cannot be broken down and is insoluble = Can only be eliminated through the liver
• Excess stored in cell in vesicles
- Accumulates in smooth muscle cells and macrophages in atherosclerotic plaques = foam cells
- Present in macrophages in skin and tendons of people with hereditary hyperlipidaemias = xanthomaserol
Protein accumulation
- –> Seen as eosinophilic droplets or aggregations in the cytoplasm
1. Alcoholic liver disease: Mallory’s hyaline (damaged keratin filaments)
Alpha 1 anti trypsin deficiency
- Liver produces incorrectly folded α1-antitrypsin protein (a protease inhibitor)
- Cannot be packaged by ER, accumulates within ER and is not secreted
- Systemic deficiency – proteases in lung act unchecked resulting in = emphysema
Alpha 1 anti trypsin deficiency - view under microscope
–> The Periodic acid–Schiff stain (PAS) with diastase stain shows the diastase-resistant pink globules that are characteristic of this disease
2 Examples of exogenous pigments accumulation in cells
- Carbon/coal dust/soot – urban air pollutant
* Tattooing – pigments pricked into skin
Carbon/dust - exogenous pigment accumulation
Inhaled and phagocytosed by alveolar macrophages
• Anthracosis and blackened peribronchial lymph nodes – black colour
• Usually harmless, unless in large amounts = fibrosis and emphysema = coal worker’s pneumoconiosis
Tattooing - exogenous pigment accumulation
- Phagocytosed by macrophages in dermis and remains there = some inflammation but they remain as they are harmless
- Some pigment will reach draining lymph nodes
Endogenous pigment accumulation
- Haemosiderin = iron storage molecule
- Derived from haemoglobin, yellow/brown
- Forms when there is a systemic or local excess of iron, e.g., bruise
- With systemic overload of iron, haemosiderin is deposited in many organs = haemosiderosis
- Seen in haemolytic anaemias, blood transfusions and hereditary haemochromatosis
Hereditary haemochromatosis
–> Genetically inherited disorder - results in increased intestinal absorption of dietary iron
• Iron is deposited in skin, liver, pancreas, heart and endocrine organs - often associated with scarring in liver (cirrhosis) and pancreas.
• Symptoms include:
• liver damage
• heart dysfunction
• multiple endocrine failures, especially of the pancreas.
• Treatment is repeated bleeding
