4. Acute inflammation Flashcards
What is inflammation
reaction of a vascularised living tissue to a local injury
- eliminate the initial cause of cell injury and the necrotic cells and tissues arising from the injury
- intimately associated with repair process
Objectives of inflammation
- localise and eliminate the causative agent
- limit tissue injury
- begin the process of healing
Causes of inflammation
- infectious agent
- physical agent
- chemical agent
- immune reaction
- necrotic tissue
Characteristics of acute inflammation
- immediate and early response to injury
- accumulation of fluid and protein
- accumulation of polymorphonuclear cells (neutrophils)
Characteristrics of chronic inflammation
- inflammation of prolonged duration
- accumulation of mononuclear cells (macrophages, lymphocytes, plasma cells)
Components of acute inflammation
- vasodilatation
- endothelial permeability
- extravasation of neutrophils
5 classic local signs of acute inflammation
heat - vasodilatation redness - vasodilatation swelling - vascular permeability pain - inflammatory mediator release loss of function - pain/oedema
Two major events in acute inflammation
- vascular response
- vasodilatation
- increased vascular permeability - cellular response
- extravasation of neutrophils at site of infection
Vascular response in acute inflammation
- vasoconstriction - transient (few sec)
- vasodilatation
- increased vascular permeability -> exudation of protein rich fluid
- loss of fluid -> concentration of red cells and increased viscosity -> blood stasis
Increased vascular permeability is due to
- increased hydrostatic pressure
- decrease in intravascular osmotic pressure
- changes in endothelial cells:
a) endothelial cell contraction
b) junctional retraction
c) endothelial injury
Increased hydrostatic pressure
Vasodilatation -> increased blood flow -> increased hydrostatic pressure
-transudate
What is transudate
- extravascular fluid with low protein concentration
- specific gravity <1.012
- hydrostatic imbalance
- ultrafiltrate blood plasma
Decreased osmotic pressure
osmotic pressure of interstitial fluid increases
-exudate
What is exudate
-extravascular fluid with high protein concentration and cellular debris
-specific gravity >1.012
-alteration in vascular permeability
fluid emitted by an organism through pores or a wound
Cellular response to acute inflammation
- margination
- endothelial activation
- rolling
- adhesion/pavementing
- transmigration
- chemotaxis
What are the main effector cells in acute inflammation
Neutrophils
What is margination
- leukocytes moving from the centre of the vessel towards the periphery
- Normal flow - RBC and WBC flow in the centre of the vessel
- a cell poor plasma is flowing adjacent to endothelium
- as blood flow slows, WBC collect along the endothelium, -> margination
What is endothelial activation
the underlying stimulus cause release of mediators which activate the endothelium causing selectins and other mediators to be moved quickly to the surface
What is rolling
neutrophils bounce or roll along endothelial cells
- transiently adhere to endothelial cells
- mediated by selectins molecules
What is adhesion (pavementing)
leucocytes firmly adhere to endothelial cells
-mediated by integrins, ICAM-1 and VCAM-1
What is transmigration
- mediated by PECAM-1
- diapedesis - the passage of blood cells through the intact walls of capillaries
What is chemotaxis
movement towards the site of injury
- recognition of microbes and dead tissues
- Toll-like receptors: recognise components of different type of microbes -> upregulation of NF-κB
Leucocyte activation leads to
opsonisation - coating a bacterium or a particle to facilitate its phagocytosis
- immunoglobulins
- C3b (complement)
Group of chemical mediators of inflammation
- Plasma-derived
- circulating precursors
- have to be activated - Cell-derived
- sequestered intracellularly
- synthesized de novo
Examples of chemical mediators of inflammation
- vasoactive amine
- plasma proteases
- phospholipid-derived products
- cytokines
- nitric oxide
- lysosomal enzymes
- oxygen derived free radicals
Effects of vasoactive amines
vascular dilatation and leakage
a) Histamine
- found in mast cells, basophils and platelets
- released in response to stimuli
- promotes arteriolar dilation and venular endothelial contraction
- results in widening of interendothelial cell junctions with increased vascular permeability
b) Serotonin
- found in platelets
- released when platelets aggregate
Effects of plasma proteases
- complement system
- kinin system
- clotting system
How does the complement system works
a) classical pathway
- require antibodies to activate
- C1 binds to IgG or IgM that is bound to antigen
b) alternative pathway
- dose not require antibody to activate
- microbial surface
Complement system role
- in immunity
- C5-9 complex
- membrane attack complex (MAC C5-9)
- punches a hole in the membrane - in inflammation
- C3a and C5a
- vascular effects: increase vascular permeability and vasodilation
- cellular effects: leucocyte activation, adhesion and chemotaxis (C5a), phagocytosis (C3b)
How does Kinin system works
leads to formation of bradykinin
What does bradykinin cause
- increased vascular permeability
- arteriolar dilatation
- smooth muscle contraction
- pain
How does the clotting system works
activation key is factor XII (F12)
- Hageman factor
- end result is fibrin
What are the examples of phospholipid derived products
- arachidonic acid derivatives
- platelet activating factor
What is arachidonic acid
complement of cell membrane phospholipids
- occur in 2 major pathway:
a) lipoxygenase - produce leucotrienes
- LTB4 - attract and activate neutrophils
- LTC4, LTD4, LTE4
- vasoconstriction, vasospasm, bronchospasm, and increased permeability
b) cyclooxygenase - produce prostaglandins and prostacylins
- prostaglandins: PGI2, PGD2, PGE2
- vasodilation and permeability
- PGE2 - fever
- prostacylin vs TXA2 = vasodilatation vs vasoconstriction
- platelet aggregation: inhibit vs promote
What does Phospholipase A2 do and how is it blocked
cleave fatty acid in position two of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule into arachidonic acid
-blocked by Steriods
What does cyclooxygenase do and how is it blocked
converts arachidonic acid to prostaglandins
-blocked by aspirin and NSAIDS
What does platelet activating factors do
- induces aggregation of platelets
- causes vasoconstriction and bronchoconstriction
- enhance leucocyte adhesion, chemotaxis and degranulation
Effects of nitric oxide
- toxic to bacteria
- vasodilation
- tissue damage
Effects of oxygen derived free radicals
- elimination of bacteria
- tissue damage:
a) direct injury to endothelial cells
b) injury to ECM
c) injury to other cell types
What causes vasodilatation
- vasoactive amines
- prostaglandins
- bradykinin
- complemet (C3a and C5a)
- NO
What causes vascular leakage
- vasoactive amines
- bradykinin
- complement
- tissue damage
- leucotrienes
- PAF
What causes chemotaxis
- complement (C5a)
- leucotrienes
- cytokines
- bacterial products
What causes pain
- prostaglandins (PGE2)
- bradykinin
- oedema
What causes tissue damage
- lysosomal enzymes
- oxygen metabolites
- NO
What causes fever
- cytokines
- prostaglandins
- pyrogens cuse macrophages to release IL-1 and TNF
- increase cyclooxygenase activity on perivascular cells of hypothalamus -> PGE2
Beneficial effects of inflammation
- dilution of toxins
- arrival of antibodies on the site of inflammatiokn
- drug transport
- delivery of nutrients and oxygen
- fibrinogen -> fibrin (delays bacterial spread)
- destruction of microbial agents
- removal of tissue debris
- stimulation of immune response
Harmful effecrts of inflammation
- mechanical effects: e.g. epiglottitis
- impaired blood flow: e.g. acute meningitis
- impaired function
- tissue destruction due to effect of inflammatory mediators and activation of clotting system that activates microthrombi
Outcome of acute inflammation
- resolution
- abscess formation - walled off collection of pus
- progression to chronic inflammation
- healing and repair
