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
Accumulation of bilirubin - jaundice
—> bilirubin = Breakdown product of heme, stacks of broken porphyrin rings that is formed in all cells of body (cytochromes contain heme) but must be eliminated in bile
• Taken from tissues by albumin to liver, conjugated and excreted in bile
* If bile flow is obstructed or overwhelmed, bilirubin in blood rises and jaundice results = yellow * Deposited in tissues extracellularly or in macrophages = yellow skin colour
2 types of abnormal deposition of calcium
localised (dystrophic)
generalised (metastatic)
Dystrophic calcification
—> No abnormality in calcium metabolism, or serum calcium or phosphate concentrations
• Local change/disturbance favours nucleation of hydroxyapatite crystals
• Can cause organ dysfunction, e.g., atherosclerosis, calcified heart valve
Occurs in an area of dying tissue, atherosclerotic plaques, aging or damaged heart valves, in tuberculus lymph nodes, some malignancies
Metastatic calcification
- Due to hypercalcaemia secondary to disturbances in calcium metabolism
- Hydroxyapatite crystals are deposited in normal tissues throughout the body
- Usually asymptomatic but it can be lethal
- Can regress if the cause of hypercalcaemia is corrected
Hypercalcaemia - high levels of calcium
Increased secretion of parathyroid hormone (PTH) resulting in bone resorption – secretion and resorption balance :
• Primary - due to parathyroid hyperplasia or tumour
• Secondary – due to renal failure and the retention of phosphate
• Ectopic - secretion of PTH-related protein by malignant tumours (e.g., carcinoma of the lung)
4 causes of bone tissue destruction
- Primary tumours of bone marrow, e.g., leukaemia, multiple myeloma
- Diffuse skeletal metastases
- Paget’s disease of bone – when accelerated bone turnover occurs
- Immobilisation
Cellular aging
—> As cells age they accumulate damage to cellular constituents and DNA
•After a certain number of divisions they reach replicative senescence - related to the length of chromosomes
Telomeres and cellular aging
- Ends of chromosomes are called telomeres, with every replication the telomere is shortened. When the telomeres reach a critical length, the cell can no longer divide
- Cancer cells = overactive telomerase repairs the telomere many times = can continue to divide
Replicative senescence
Irreversible arrest of cell proliferation and altered cell function
- controlled by multiple dominant acting genes
- Depends on number of cell divisions, cell type, species and age of donor
Elevated proteins/ enzymes in hepatitis
Transaminases -ACT/AST
- Alanine aminotransferase
- Aspartate aminotransferase
Elevated proteins/ enzymes in acute pancreatitis
Amylase
Lipase
Elevated proteins/ enzymes in myocardial infarction
Troponin
Myoglobin
Creatine kinase
Inflammation
—> natural response body has to injury
Acute Inflammation - features
- Immediate
- Short term – approx 2 weeks
- Driven by innate immune system – neutrophil, macrophages
- Stereotyped – same process happens every time, same cells, same steps, same order
- Limits damage – aims to stop damage getting worse, or organism to cause more damage
3 features of inflammation
Vascullar and cellular involvement
• Vascular alters to allow accumulation of exudate(aims to expel toxins but let in good things and neutrophils in tissues)
Controlled by variety of mediators
• Derived from plasma or cells
Protective
• But can cause local and systemic complication
• Loss of function
• Some tissue damage cuased by protective cells
Mediators in inflamation
- Cytokines
- Chemokines
- Macrophaes – release mediators
4 causes of acute inflammation
→ cause does not affect process of inflamation - process is always the same
* Hypersenstitivity = allergy, try to instigate a normal immune response to something abnormal e.g. pollen * Physical trauma = stabbing, acid attacks etc * Other ilnneses – crohn's disease of Gi tract (in image), autoimmune disease * Micro-organisms
Prolonged acute inflammation
- Bursts of acute inflammation
* 2 weeks inflammation at random times
Steps of acute inflammation
- Bacteria sits outside tissue
- Something happens – breaking barrier – bacteria enters tissues
- Activiation of complement, happens at the same time as macrophage senses bacteria
• Complement (C3) - drives mast cells, eiosinophils and basophils to release histamine, porstaglandins, leukotrines
• Those 3 things ( histamine, porstaglandins, leukotrines) cause vasculature to become more permeable, allows pores to form
• changes in vasculature allows Bad things move out good things move in (neutrophil can cross vasculature) - • When macrophages figure out bacteria they release IL8 – to attract neutrophils accumulation
- and release cytokines (IL1 beta, TNF alpha, IL6) act on vasculature to prepare it for influx of other cells - IL1 beta, TNF alpha, IL6)
• changes in vasculature allows Bad things move out good things move in (neutrophil can cross vasculature) - Neutrophils enter cell and capture bacteria
Macrophage
tissue resident, moniter and maintain tissue
4 clinical signs of acute inflammation
- Rubor – redness
- tumour - Swelling
- dolor- Pain
- calor - Heat
All cause a loss of function
3 changes in vessels and surrounding tissues - acute inflarrimation
- Changes in blood flow – vasculature
- Movement of fluid into tissue
• Vascular phase - Infiltration of inflammatory cells into tissues
- cellular phase
- Movement of fluid into tissue
Changes in blood flow - acute inflammation l vascular phase
- Vasconstriction (Seconds) - initially to prevent bleeding
- Vasodilation (minutes)
• Enter neutrophils into cells
• Heat and redness - Permeability increase
- influx of plasma and things to help response
• Odeoma formation
- influx of plasma and things to help response
- Vasodilation (minutes)
- Red cell stasis → slowing down of blood flow
Starling’s law
– Fluid movement controlled by balance between:
• Hydrostatic pressure (pressure exerted on vessel wall by fluid – pushes fluid away…)
• Oncotic pressure (pressure exerted by plasma protein – draws fluid towards…)
Balance between what moves in and out
Increased capillary hydrostatic pressure = Increased fluid flow out of vessel
Increased interstitial oncotic pressure = Increased fluid flow out of vessel
Movement of fluid into tissue - acute inflammation
– Vasodilatation
= increased capillary hydrostatic pressure
– Increased vessel permeability = loss of plasma proteins into interstitium (increased interstitial oncotic pressure)
Presusre outside is greater and so pushes things into tissue
– Net flow of fluid OUT of vessel INTO interstitium – OEDEMA (swelling – TUMOR)
THINGS MOVE OUT OF BLOOD VESSELS CAUSING
– Increased viscosity of blood = due to more rbc and less fluid
– Reduced flow through vessel = STASIS (allows neutrophil to enter)
Changing pressure to allow neutrophil enry
2 types of interstitial fluid
Exudate → gets good things to desired area
Transudate → build up of fluid constricts tissue
Exudate
– Occurs in inflammation
– Increased vascular permeability = vasodilation and stasis
– Protein rich and some red and white blood cells (delivering proteins to area of injury)
Transudate
– Fluid loss due to increased capillary hydrostatic ‘ pressure or reduced capillary oncotic pressure
– No change of vascular permeability = just caused by fluid loss from tissue forced into interstitum - fluid leakage
– Occurs in heart failure/hepatic failure/renal failure – cardiac tampernade
4 mechanisms of increased vascular permeability
- Endothelial contraction
- (gaps between endothelial cells)
- Driven by = Histamine, leukotrienes (cause permeability within membrane
- Endothelial cytoskeleton reorganisation
- caused by Cytokines IL-1β, TNFα - reorganisation to create conditions for cell capture (neutrophil capture)
- Direct injury
- Chemical, toxic burns – injury to vasculature
- Some changes in vasculature permeability may restrict movement of toxins and bacteria to prevent spread around body
- Leucocyte dependent injury
- Enzymes and toxic oxygen species from leucocytes
Neutrophil
- • The primary white blood cell involved in acute inflammation
- • distinct Trilobed nucleus
- • A granulocyte
- • (aka neutrophil polymorph)
- Dark blue stain
- Contains a lot of genetic info
Neutrophil infiltration (chemotaxis) - acute inflammation
Stasis
- Stasis causes neutrophils to line up at the edge of blood vessels along the endothelium = MARGINATION
- Neutrophils then roll along endothelium, sticking to it intermittently until they find a point to get into tissue = ROLLING
- Then stick more avidly = ADHESION
- Followed by EMIGRATION of neutrophils through blood vessel wall
Chemotaxin – cell movement
2 adhesion molecules
Selectins
Integrins
Selectins - adhesion molecules
– On endothelial cell surface
– Upregulated by chemical mediators – Il1 beta and TLF alpha
Integrins - adhesion molecules
– On neutrophil surface
– Bind to receptors on endothelial surface
Chemotaxis - neutrophil movement through interstitium
– Movement along a chemical gradient of chemoattractants
• Bacterial peptides, C5a, LTB4
• IL8
• Rearrangement of neutrophil cytoskeleton – to squeeze through vasculature by using pseudopod formation
• Pseudopod formation – neutrophil clws, squeezes its way through
Older people and neutrophil chemotaxis
• Older people have loss of immune function
• As neutrophils lose their sense of direction and start to tunnel their way through healthy tissue to get where they need to be
• Neutrophils don’t respond to IL8 in the same way
–> chemotaxis breaks down in older people
What do neutrophils do - steps
- Phagocytose bacteria
- Package bacteria in phagosome
- Produce lysosomes filled with ros and enzymes
- Fuse phagosome and lysosome = phagolysosome
- Destry bacteria with things
- Remove bacteria or keep it internally but neutrophil starts to dye due to toxins
Dead neutrophils – cleared by macrophages
= pus is a build up of dead neutrophils
2 killing mechanisms that neutrophil do
Oxygen dependent
Oxygen independent
Neutrophil - oxygen dependent killing
- Reactive oxygen intermediates – kill bacteria
- O. (superoxide anion)
- OH. (hydroxyl radicals)
- H2O2 (hydrogen peroxide)
- reactive nitrogen intermediates
Neutrophil - oxygen independent killing
- Enzymessss
- Lysozyme
- Hydrolytic enzymes
- Defensins
- Neutrophil Extracellular Traps (NETs)
4 ways that inflammatory cells limit damage
- Removal of toxins and pathogenic organisms ‘
- Removal of necrotic tissue – evry quickly
- Release of chemical mediators stimulates and regulates further inflammation - limit spread of toxins
- Stimulates pain – Encourages rest and limits risk of further damage
2 reasons why acute inflammation is effective
- . Vascular phase
– (move fluid into tissue Exudation of fluid into interstitium (oedema)
Brings proteins and good things in it- Cellular phase
– Infiltration of neutrophils
Clearing and capturing
- Cellular phase
Oedema - how does it limit damage
• Dilutes toxins
• Delivers plasma proteins to area of injury
– Fibrin (mesh limits spread of toxin-limits movementof bacteria out of tissue )
– Inflammatory mediators enter
– Immunoglobulins – opsonins
• Increased lymphatic draining from area of injury – lymphatics are where adaptive immune system is
– Delivers antigens to lymph nodes (inducing adaptive immune system
• Need opsonisation to clear infection
Chemical mediators
—> overlap, they work at the same tie, not in sequence, overlap of process
• Varying chemical structure – some are present in tissue
• Some circulate in an inactive sate in blood – activate when infection start
3 things that release chemical mediators
- Activated infammatory cells – e.g. macrophages
- Platlets
- Endothelial cells
Chemical mediators that cause • Vasodilatation
– Histamine, Serotonin, Prostaglandins, Nitric Oxide
Chemical mediators that cause • Increased vascular permeability
– Histamine, Bradykinins, Leukotrienes, C3a and C5a
Chemical mediators that cause • Chemotaxis
– C5a, LTB4, TNF-a, IL-1β, IL8, Bacterial Peptides
Chemical mediators that cause • Fever
– Prostaglandins, IL-1β, TNF-α, IL-6
• Fever limits functionality of invading organism (increase temp increases microorganism function)
Chemical mediators that cause • Pain
– Bradykinin, Substance P, Prostaglandins
• Loss of function
3 local complications of acute inflammation
• Swelling
– Blockage of nearby tubes and ducts(bile duct/intestines)
• Swelling of unaffected tissue
• Exudate
– Compression of organs – Eg cardiac tamponade (swelling of sac around heart
• Limit contraction
• Pain and loss of function
– Muscle atrophy – become week
– Psycho-social consequences of chronic pain = lifestyle impacted by pain
5 Systemic complications of acute inflammation
- Fever
- pain
- leucocytosis
- acute phase proteins
- septic shock
Fever -Systemtic complication of acute inflammation
– Endogenous pyrogens (prostaglandins, IL-1β, TNFα)
– Act on hypothalamus to alter baseline temperature control
– Take NSAIDS to reduce temperature
– This is a bit counter-intuitive for viral infections.
Pain -Systemtic complication of acute inflammation
• IL6 produced by the immune system causes systemic muscle pain.
Leucocytosis - Systemtic complication of acute inflammation
– IL-1β and TNFα act on bone marrow to increase production
– Bacterial infection = more neutrophils
– Viral infection = more lymphocytes
– Clinical use of lymphocyte levels : can measure blood levels of these in patient (e.g. c reactive protein)
Acute phase proteins -Systemtic complication of acute inflammation
– Release of proteins from inflammatory cells:
* C-Reactive Protein (commonly used blood marker; is an opsonin) * 1 antitrypsin * Haptoglobin * Fibrinogen * Serum amyloid A protein
- Cause “acute phase response” – Malaise, reduced appetite, altered sleep, tachycardia
- Acute inflammation wants your body to rest
Septic shock -Systemtic complication of acute inflammation
– Overwhelming infection – Huge release of chemical mediators – Widespread vasodilatation – Hypotension, tachycardia – Multi-organ failure – Death
4 sequelae of acute inflammation
- Complete resolution = switch off inflammation
- Continued acute inflammation with chronic inflammation -> abscess
- Chronic inflammation and fibrous repair, with some tissue regeneration
- No resolution = Death
Acute Inflammation - complete resolution
- Exudate drains away via lymphatics
- Fibrin is degraded
- Neutrophils die, break up and get phagocytosed
- Damaged tissue may be able to regenerate, if architecture is preserved
- Mediators are diluted/inactivated/degraded
Netosis
Netosis
• -> done by neutrophils where they expel a net of genetic information that captures bacteria
• This net is difficult to break down and you must inactivate captured bacteria
• Netosis also kills neutrophils so must form new one
→ neutrophils are destroyed by macrophages
Examples of acute inflammation
- Appendicitis
- Pneumonia
- bacterial meningitis
- abscess
- inflammation of serious cavities
Refer-to 2.1
Histology
—> study of tissue and structure
And how they are related to function
Haemotoxylin
purple/blue nuclei
• Basic dye
• Stains acididc components of cells
Eosin
pink
• Acidic dye
• Stains protein in cytoplasm, extracellular matrix and membrane
Protein analysis
- Look for unique histological features to determine tissue
- Determine if it is normal or not
• If it is not normal is it inflammatory or neoplasmic
• Is inflammation acute or chronic
• If neoplastic is it benign or malignant
• If malignant is it primary or secondary
- Determine if it is normal or not
Orientation and position of a section
→ well positioned section
- sectioning at angle - does not show a clearimage
Magnification
Higher magnification = detailed image
Lower magnification = bigger overall image
Cytology
—> study of individual cells or small cluster of cells on the body not the tissue, study structure of cell
• Look at abnormal changes in individual cells – nucleus, cytoplasm, body of cell
• Diagnostic and screening purposes
Cytology - tests
Tests
• Fine needle asparation
• Body fluid cytology
• Cervical scrap test
Lymphocyte - cytology
- Large nuclear to cytoplasmic ratio
* Blue
Neutrophil - cytology
- Most abundant WBC
- Multiple lobe nucleus - tribobe
- Light pink granules in cytoplasm (packed with enzymes that fight pathogen)
Monocyte - cytology
- Precursor of macrophages
* Kidney shapes nuclei
Eosinophil - cytology
- Round red cells
- Used in fighting pathogens
- Large bright red acidiphilic granules – destructive and toxic proteins
4 types of tissue
- nervous
- muscle
- epithelial
- connective
Nervous tissue
→ internal communication
- brain
- spinal cord
- Nerves
Muscle tissue
→ contracts to cause movements
Skeletal
Cardiac
Smooth
Epithelial tissue
- Lining of external and interanl spaces
- Digestive trac
- Skin - epidermis
Connective tissue
Supports, protects, binds other tissues together
- Bones
- tendons
- fat and other soft padding tissue
3 functions of epithelium
- Secretion
- Absoption
- Protection
Classifications of epithelieum
= one layer
• Stratified = multiple layers
Cell shapes
• Squamous – flat shaped body and nuclei
• Cuboidal – square shaped, large round nuclei in middle
• Columnar – tall with oval shaped nuclei in bottom of the cell
Simple squamous
Kidney – single squamous cells in podocytes in bowmans capsule
• Allow quick filtration
Single cuboidal cells
- Apical surface facing lumen
- Section and absorption
- Found in pancreas and small collecting ducts of kidney
Simple columnar
Excretory ducts of pancreas
Stratified squamous
- Regions of mechanical abrasion
- Oesphagus
- Mutiple layers
- Apical surface facing lumen
Stratified cuboidal
- Protection and secretion
- Organs that so absorption or secretion
- Seperate organs from outside environemnt
- Sweat and mammary gland
Stratified columnar
• Found in eyelid
Transitional epithelieum
dome shaped
• Found in bladder
Liver tissue - microscope
- Hepatocytes – liver epithelial cells
* Arranged in rows radiating out from central vein
Thyroid gland tissue
- Simple cuboidal epithelail cells form follicles
* Clear cells in parafollicular tissues – clear cytoplasm
Lung tissue
• Thin walled alveoli – simple squamous epithelial cells = exchange
Skeletal muscle tissue
- Bundles of muscle fibre
- Stripey striated due to sarcomere
- Multiple nucleus at peripehral side of cells
Atherosclerosis → microscope
- Extracellular lipids
- Fibrous cap
- Necrotic wall
- Blue stained area
Liver cirrohisis → microscope
- Alcholc consumption
- Chronic inflammation
- Hepatocytes connected by fibrous connective tisseu
Tumour grade
Lower grae tumour – grows slower
Higher grade tumour grows faster
Low grade
• Cells resemble normal cuboidal epithelial cells
High grade
• No grandular structure seen
• Cells are fully differentiated
• Can clearly see mitotic activity
4 pathological stages of lobar pneumonia
- Congestion = infectious fluid in lungs, looks red due to increase blood flow to lungs
- Red hepatisation = dry, granular , airless - airways clogged by rbc and wbc , debris
- Grey hepatisation = grey colour because rbc disintegrate
- Resolution = breakdown and reabsorption
Macrophage clear debris normal function
Inherited angio- oedema
Recurrent episodes of severe swelling in :
- limbs, face, airway etc
Unknown trigger - maybe stress
Chronic granulomatous disease
Phagocytes unable to kill certain types of bacteria and fungi
-Immune deficiency disease
Defects in napph oxidase.
abscess
Acute inflcmation
→ formed when neutrophils engulf bacteria infiltration of neutrophils
