W12 Acute inflammation Flashcards
What is acute inflammation?
Initial rapid response to tissue injury
minutes/hours to develop
short duration (hours, days)
Acute inflammation is an innate immune response
Relatively non-specific: several types of injury
Triggers of acute inflammation - infections
bacteria, viruses, parasites, fungi, toxins
Triggers of acute inflammation - Tissue damage due to:
Physical agents
frost bites, burns, radiation (ionising, UV)
Chemical agents
chemical burns, irritants
Mechanical injury & ischemia
trauma, tissue crush, reduced blood flow
Triggers of acute inflammation - foreign bodies
splinters; sutures; dirt; swallowed bones; dentures
Acute inflammation - purpose
Alert the body
Limit spread (of infection and/or injury)
Protect injured site from becoming infected
Eliminate dead cells/tissue
Create the conditions required for healing
Acute inflammation is a beneficial response
If acute inflammation didn’t exist
No control of infections
Impaired wound healing
Injured tissues would not be repaired
Acute inflammation – the 5 Rs
Recognition of injury Recruitment of leucocytes Removal of injurious agent Regulation (closure of inflammatory response) Resolution/Repair of affected tissue
Signs of acute inflammation - redness
Redness (rubor)
increased blood flow (hyperaemia) to injured area
Signs of acute inflammation - swelling
Swelling (tumor)
fluid accumulation <= permeability of vessels
Signs of acute inflammation - heat
Heat (calor)
increased blood flow and metabolic activity
Signs of acute inflammation - pain
Pain (dolor)
release of pain mediators; pressure on nerve ends
Signs of acute inflammation - loss of function
Loss of function (functio laesa)
excessive swelling and pain
Acute inflammation – systemic changes
Acute inflammation = local response
symptoms and reactions take place in affected tissue
Can have some systemic manifestations
Fever
<= endogenous pyrogens (IL-1, TNF-alpha); <= exogenous pyrogens (microbial components)
Neutrophilia
<= G-CSF stimulation of bone marrow
replenish dead neutrophils
release of immature neutrophils
Acute phase reactants
C-reactive protein (CRP), fibrinogen, complement, serum amyloid A protein (SAP)
produced in the liver
induced by IL-6, IL-1, TNF-alpha
↑ fibrinogen => stacking of RBCs (rouleaux) => faster sedimentation rate (↑ESR)
Rare cases (systemic changes)
systemic inflammatory reaction => sepsis
widespread, severe manifestations
form of Systemic Inflammatory Response Syndrome (SIRS)
Vasodilatation (small vessels)
histamine, serotonin; released by injured cells, macrophages, mast cells
Increased blood flow to injured area
results in influx of white blood cells, fluid, oxygen, nutrients
- Increased vessel permeability (microvessels)
due to contraction of endothelial cells (histamine, serotonin, other)
results in leakage of fluid and cells in injured tissue
endothelial cell activation: increased adhesion molecules
What is the overall effect of the vascular events
Overall effect: leucocytes and plasma proteins exit vessels and enter inflammation site to deal with infection/damage
Inflammation summary
endothelial cell contraction
(histamine, serotonin, other)
leakage of fluid and cells in injured tissue
Inflammatory exudate
Inflammatory exudate (due to increased vessel permeability)
water, salts, small plasma proteins (fibrinogen)
=> get out of vessels and enter tissues or serous cavities
Transudate
fluid leaks due to altered osmotic/hydrostatic pressure; vessel permeability normal
Exudate
High protein content, and may contain some white and red cells
Migration and accumulation of cells
first step – neutrophils
involves a complex process of exit from blood vessels
Removal of pathogens/injured/dead cells
neutrophils phagocytose pathogens and dead tissue
neutrophils live briefly => dead neutrophils = pus
- Migration and accumulation of monocytes
monocytes differentiate into macrophages
phagocytosis => clearance of injured site
release factors that promote tissue repair (TGF-beta)
Acute inflammation - Neutrophil recruitment
Multistep process
Adherence to luminal surface of endothelium
Migration through vessel wall
Neutrophil recruitment
- Margination & rolling
- Integrin activation by chemokines
- Firm adhesion to endothelium
- Transmigration through endothelium into tissue
- Chemotaxis to inflamed site
Molecules involved in neutrophil recruitment (adhesion molecules)
- Selectins
- Integrins
- Immunoglubulin superfamily cell adhesion molecules
(CAMs)
E-selectin
induced by IL-1 and TNF-alpha (cytokines produced by macrophages, mast cells, endothelial cells at site of inflammation)
L-selectin
Leucocytes (neutrophils, monocytes, lymphocytes) express L-selectin; ligands on endothelium
Endotelial selectins
Endotelial selectins bind to ligands on neutrophils
Ligands – carbohydrates (PSGL-1, sialyl-Lewis^x)
Low affinity interaction => disrupted by flowing blood => repetitive binding and detaching => rolling; slow down
Endotelial selectins
Endotelial selectins bind to ligands on neutrophils
Ligands – carbohydrates (PSGL-1, sialyl-Lewis^x)
Selectins mediate rolling
Low affinity interaction => disrupted by flowing blood => repetitive binding and detaching => rolling; slow down
Integrin activation by chemokines
Neutrophils rolling slows them down => endothelial contact
Neutrophils express integrins (LFA-1)
Integrins in low affinity configuration; no binding to ligands
Activated endothelial cells produce/bind
chemokines
Chemokines bind to receptors on
neutrophils
=> integrin activation => high affinity configuration
Integrins bind to ligands on endothelium
integrin ligands: ICAM-1, VCAM-1integrin ligands induced by IL-1 and TNF-alpha (cytokines produced by macrophages, mast cells, endothelial cells at site of inflammation)
=> Firm adhesion of neutrophils to endothelium
ICAM-1
intercellular adhesion molecule-1
VCAM-1
vascular cell adhesion molecule-1
Neutrophil transmigration
Neutrophils migrate through interendothelial spaces
Neutrophils pass through vessel wall and enter tissue
Migrate (chemotaxis) through tissue towards inflamed site
Gradient of chemoattractants guides migration in tissues
Neutrophil chemotaxis
Movement of cells through tissue towards inflamed sites
Neutrophil chemotaxis - chemoattractants
Guided by chemoattractants:
produced at site of infection/damage
diffuse into adjacent tissue and form a gradient
bacterial components (peptides containing N-formyl-methionine-leucine-phenylalanine; lipids)
chemokines (IL-8)
complement components (C5a)
leukotriene B4 (LTB4)
Cells at inflammation site change over time
neutrophils (6-24h); short lived; die in tissues (24/48h)
monocytes (24-48h); survive longer, proliferate
monocytes use similar mechanisms to leave blood vessels and enter sites of inflammation
monocytes differentiate into macrophages in tissues
Other types of inflammatory responses:
eosinophils (allergies, parasite infections)
lymphocytes (viral infections)
Pathogen destruction
Once at sites of inflammation immune cells (neutrophils, monocytes/macrophages) destroy & clear pathogens and dead cells
Neutrophils - pathogen destruction mechanisms
Recognition of microbes/dead cells to oxygen-independent and oxygen-dependent killing
Mechanisms involved: (pathogen destruction)
Release of granule content
Phagocytosis
Generation of reactive oxygen/nitrogen species
Formation of Neutrophil Extracellular Traps (NETs) (netosis)
Neutrophil Extracellular Traps - NETs
Mesh of nuclear content (chromatin)
Mesh traps microbes
Contains anti-microbial molecules
Specific granules (small)
lysozyme, collagenase, gelatinase, lactoferrin, alkaline phosphatase
Azurophil granules (large)
myeloperoxidase, lysozyme, defensins, acid hydrolases, proteases (elastase, cathepsin G, collagenases, proteinase 3)
Granule content can cause
Granule content can cause tissue damage
Corticosteroid drugs
inhibit transcription of many inflammatory genes
Acute inflammation - termination
Anti-microbial mechanisms
Inflammatory mediators
not specific to microbes/dead tissues
normal tissues can get damaged during inflammation
Termination of acute inflammatory reaction – IMPORTANT !
Outcomes of acute inflammation
Inflammatory trigger eliminated => inflammation resolves
recruited cells die (neutrophils – short life span in tissue)
inflammatory mediators degraded (most short-lived)
activation of regulatory mechanisms (anti-inflammatory)
activation of tissue repair mechanisms
Lost tissue replaced: cell regeneration / connective tissue
Outcomes of acute inflammation - summary
- Complete resolution
affected tissue restored to normal state - Repair
lost tissue replaced by connective tissue (scarring, fibrosis) - Chronic inflammation
acute inflammation cannot be resolved => chronic
Outcomes of acute inflammation - summary
- Complete resolution
affected tissue restored to normal state - Repair
lost tissue replaced by connective tissue (scarring, fibrosis) - Chronic inflammation
acute inflammation cannot be resolved => chronic
Acute inflammation – resolution/tissue repair - complete resolution
damaging agent removed
injured tissue replaced by cells of the same type
no change in tissue structure/function
Restoration of normal tissue structure only if residual tissue is structurally intact
Extensive tissue damage (infection/inflammation) => structure affected => incomplete regeneration & scarring
Acute inflammation – resolution/tissue repair - Repair by replacement (fibrosis)
injured tissue replaced with connective tissue
scarring => can alter tissue function
TGF-beta released by macrophages promotes fibrosis
Abscess
mass of necrotic (dead) tissue
caused by pyogenic (pus-forming) bacteria
can become chronic if not reabsorbed/drained
High regeneration ability
(labile tissues; divide continuously)
epithelial cells (e.g. skin, airways, gut; blood cells)
sometimes perfect regeneration, no scarring
Intermediate regeneration ability
(stable tissues)
normal state: quiescent cells (G0/G1); injury => division
may regenerate when injured
e.g. liver, kidney, pancreas; endothelial cells, fibroblasts
if extensive injury => scarring
No/little regeneration ability
(permanent tissues)
neurons, myocardium, skeletal muscle
heal with fibrosis, scarring, loss of function
Factors that favour tissue resolution
- Minimal destruction
- Minimal cell death
- Good regeneration ability of injured tissue
- Fast clearance of infection
- Quick removal of dead tissue (debris)
- Removal of foreign material (sutures, bone fragments)
- Immobilisation of wound edges (sutures)
Factors that prevent tissue healing
Infection
Diabetes
Poor general health/nutrition (protein/vitamin C deficiency)
Old age
Drugs: corticosteroids
Extensive injury
Poor vascular supply
Extensive haemorrhage
Foreign bodies (steel, glass, bone fragments)
Pressure/torsion/movement on wound edges => dehiscence
