Inflammation and repair (2) Flashcards
Describe the sequence of events in WBC activiation
- margination
- pavementing
- emigration
- chemotaxis
- phagocytosis & synthesis of biochemical mediators (cytokines)
Describe margination and pavementing
Haemodynamic changes - venule congestion → wbcs move to endothelium
Adhesion molecules on the endothelium i.e. selectins, ICAMs attach to adhesion molecules on wbcs i.e. β-integrins
Length of time of adhesion depends on strength of inflammatory response
Layer of wbcs stick to endothelium (pavementing)
Describe emigration
Wbcs squeeze through inter-endothelial cell junctions in venules → perivascular spaces
Circulating neutrophils diam approx. 10υm can reduce width to 1 υm
Describe chemotaxis
Directional migration of wbcs along a chemical gradient
Chemo-attractants i.e.
Complement fragments
Fibrinogen degradation products
Chemokines – small protein molecules produced at the inflammatory site by damaged resident cells i.e. IL-8, MIP (macrophage inflammatory protein), NAP-2 (neutrophil activating peptide) many more
Describe phagocytosis
Engulfing of large (i.e. bacteria / damaged cells) particles and destruction intracellularly
Surface attachment & engulfment
Formation of phagocytic vacuole & fusion to form phagolysosome
Digestion in phagolysosome
Debris extrusion
Process enhanced by opsonisation i.e. antibodies, complement fragments
Also by elevated body temperature – fever
Describe phagocytosis (particle destruction)
O2-dependent killing
“Respiratory burst” of phagocytosis
Increased O2 & energy utlisation by cell → creation of reactive O2 species (H2O2, O2-, HOCl∙)
Oxidant damage & peroxidation of membrane lipids
Normally occurs inside phagolysosome
Molecular scavengers of oxyradicals – SODs occur in circulation - ↓ effect extracellularly
Name chemical mediators
Histamine (& Seratonin)
Kinins
Neuropeptides
Arachidonic acid metabolites
Lipoxygenase (LO) pathway
Nitrous oxide
Describe the effects of histamine and seratonin
contraction of smooth muscle and ↑ bv permeability (Mast Cells)
Describe the effects of Kinins
i.e. bradykinin, leukokinin (precursors present in plasma)
Vasodilation, ↑ bv permeability
Stimulate release of histamine from Mast cells
Activate arachidonic acid cascade (for PG and leukotriene production)
Believed to be major mediator of pain in acute inflammation; effects on afferent nerve fibres
Describe the effects of neuropeptides
i.e. substance P, neurokinin from sensory nerves → pain, vasodilation & increased bv permeability
Describe the effects of arachdonic acid metabolites
Vasodilation, ↑ bv permeability, pain
Arachidonic acid cascade
Describe the effects of lipoxygenase (LO) pathway
lipoxins & leukotrienes
Enhance chemotaxis
Cause lysosomal enzyme release
Generate O2-
↑ wbc adhesiveness
Describe the complement system
Multicomponent system – “compliments” action of antibodies in killing pathogens
“Classical” and “alternate” pathways
Classical Ab related / alternate not Ab related
By-products of cascade i.e. C5a, C3a have direct inflammatory roles
↑ bv permeability
chemotactic
degranulation
↑ phagocytosis (opsonisation)
Describe the effects of nitrous oxide
Inflammatory stimulated endothelial cells generate NO (Ca++ dependent)
Cause net vasodilation
Also NO production from stimulated macrophages & monocytes
NO inhibitory and destructive to many pathogens
As well as previously mentioned cytokines and chemokines
What is the difference between repair and regeneration?
Difference between the two?
Healing by parenchymal tissue regeneration
Healing by CT replacement (scarring)
What does regeneration capability depend on?
Capability of the cells (labile or stable not permanent)
Maintenance of CT framework
What tissues have ‘very good’ regeneration capabilities?
connective tissue, blood vessels, lymph vessels, bone marrow, fat, ovarian tissue, liver
Which tissues have ‘good’ regeneration capabilities?
intestinal and gastric epithelium, bone (remodellng and periosteal growth)
What tissues have ‘limited’ regeneration capabilities?
cartilage, ligament, tendon, kidney, pancreas
What tissues have no regeneration capabilities?
seminiferous tubulus, neurones, cardiac muscle, eye
Describe neuronal regeneration
Following peripheral nerve injury
If neurone body affected → whole neurone necrosis
If axonal →
Axon below damaged area degenerates
Above damaged area degenerates to proximal node of Ranvier (Wallerian degeneration)
As long as axonal tube / membrane intact axon will regenerate approx. 5mm/day
nb. Traumatic neuroma following limb amputation
What are the different categories of tissue and wound repair?
Bleeding
Inflammation
Proliferative stage
Reorganisation / remodelling – MMPs very important in remodelling
Describe repair
nitiated by the proliferation of fibroblasts and endothelial cells (2 - 3 days following tissue damage)
Fibroblasts develop from resident fibrocytes, becoming hyperplastic.
very large, active nuclei with little cytoplasm
They then start to lay down a matrix consisting of collagen fibres and mucopolysaccharide.
Define primary intention
Following surgery and proper wound apposition healing
Define secondary intention
If there is a deficit in the wound then healing is by secondary intention and granulation tissue will fill in this gap
Describe CT repair
Fibroblastic response → collagen-rich scar tissue
Initially “granulation tissue” – fibro-vascular CT
Consists of fibroblasts, endothelial sprouts & capillaries, phagocytic cells (neutrophils & macrophages)
Re-epithelialisation from wound edges (if on surface) & islands of squamous epithelium
Describe fibroblasts
Most widespread of mesenchymal tissues
“stable cells retaining proliferative capability”
In repair fast multiplication and synthesis of ECM components i.e. collagen
Activation by activated macrophages (MDGFs)
Produce growth factors at site of repair
Specialised fibroblast → myofibroblast
Describe endothelial cells and macrophages
endothelial cells and the capillaries formed in repair tissue→ very permeable “leaky”
Easily leak exudate high in protein content (plasma protein) and wbcs into repair site
Wet appearance & scab on surface wounds
Also produce growth factor – PDGF (platelet derived growth factor)
Macrophages very important in healing
Phagocytic function
Also secrete growth factors
Describe remodelling
Refinement of collagen and ECM
Chemical mediated but also affected by physical stress
Active process
may take months → year for final healing
State the extracellular matrix components (and describe)
Collagen
Primarily Type I & Type III in fibrovascular CT (fibrillar types)
Type III finer random fibrils; eventually replaced by Type I
Higher tensile strength than other collagen fibres
Increase in strength takes time – not only related to amount of collagen at site but eventual remodelling
Can take weeks → months
In relation to growth factors, what can protein stimulate?
cell proliferation & differentiation
synthesis of ECM
Some are chemotactic
