Download Inflammation

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Inflammation
1
Inflammation is a local
reaction of blood
vessels, connective
tissue and nervous
system to any kind of
damage.
Inflammation includes three
stages:
1. Alteration – injury of
tissues
2. Exudation - local
vascular reaction
3. Proliferation – reaction
of connective tissue cells.
* Inflammatory reactions components ratio
exudation
Injurious factor
alteration
2
1
1 –primary alteration; 2 – secondary alteration
proliferation
- cellular injury;
- local vasodilation and increased blood
flow, increased capillary permeability,
cellular adhesion, and exudation to
bring inflammatory cells and chemical
mediators to the injured area;
- destruction of injurious agent by
phagocytes;
- clearing away of cellular debris;
- deposition of protein framework for
tissue healing.
Etiology of inflammation.
 Extrinsic injurious agents:
mechanical, physical, chemical,
biological etc.
 Intrinsic injurious agents:
excess of immune complexes,
metabolic products, necrotic
tissues, stones etc.
Primary and secondary alteration.
Primary alteration or injury
of tissues by etiologic
agents initiates the
inflammatory response
Secondary alteration is damage
by following factors:
 1.
inflammatory mediators,
 2. lysosomal enzymes,
 3. local acidosis,
 4. increased osmotic and
oncotic pressure in
inflammatory area.
Chemical mediators and their role
in inflammation.
Preformed
mediators in
secretory granules
Newly synthesized
mediators :
source:
histamine
serotonin
lysosomal
enzymes
mast cells, basophils, platelets
platelets
neutrophils, macrophages
all leucocytes, platelets, endothelial
prostaglandins
cells (ECs)
plateletall leucocytes, ECs
activating factors all leucocytes
activated oxygen macrophages, ECs
species
all leucocytes, ECs
nitric oxide
cytokines
Arachidonic acid
metabolites.
Cyclooxigenase pathway
prostaglandin H2 products: PGE2,
PGF2α, prostacycline (PGI2) ,
thromboxane A2(TXA2).
Lipoxigenase pathway
leukotrienes:
LTB4 (chemotactic agent), LTC-D-E4
(bronchoconstrictor/vasoconstrictors),
lipoxins: LXA2,LXB2 (possibly are natural
ingibitors of LT actions).
Cytokines
1. cytokines have a wide spectrum of effects,
2. each cytokine may be produced by several
cell types,
3. each leukocyte produces several
cytokines,
4. all interactions between cells during an
inflammatory process are due to
cytokines.
Sequences of cytokines releasing in area of inflammation
bacteria
LPS
LPS
LPS
macrophage
IL-1
macrophage
TNF
IL-1
IL-1
TNF
LPS – lipopolysacharide of microbes cell; IL-1 – interleukin-1; TNF – tumor necrosis factor
A)
produced by:
action:
α-interferon
β-interferon
γ-interferon
leukocytes
firoblasts
T-cells
-
B)
IL-1
IL-2,IL-3, IL-4, IL-5
IL-6
IL-7
macrophages
T cells
macrophages
fibroblasts
bone marrow cells
fever
activation many other cells
activation many other cells
activation many other cells
C)
TNF-α
macrophages
like IL-1
D)
PDGF (platelet-derived
growth factor)
platelets
ECs
proliferation of vascular smooth
muscle cells
antiviral
induces MHC-I expression
antiviral
induces MHC-I expression
activates macrophages
induces MHC-II expression
(on macrophages)
* Effects of cytokines IL-1 in inflamed area
Positive feedback loop
hypothalamus
liver
fever
Production
of acute
phase
proteins
Antibody
production
Proliferation
Of fibroblast
Lymphokines
production
IL-2 production
* «Cascade of cytokines», providing interaction of Т - и В lymphocytes in area of inflammation
antigen
IL-1, IL-2, IL-4 – IL-6
Т-lymphocyte
IL-1
В-lymphocyte
IL-2
IL-4
IL-2
IL-5
Т-helper
IL-6
antibodies
Cytokines as inductors of acute phase proteins production
in area of inflammation
Hypothalamus, pituitary,
adrenals
+
glucocorticoids
IL-1
Increased temperature
+
TNF
–
g- inter
feron
IL-6
IL-11
LIVER
–
insulin
Acute phase
proteins
(+) – activation
( - ) – inhibition
Systemic mediators (plasmaderived).
The major source - liver:
Factor XII (Hageman factor) activation
activation of:
- kinin system
bradykinin
- coagulation (hemostatic) system
fibrin,
fibrinopeptide, fibrin degradation products
- fibrinolitic system
plasmin
- complement system
C3a,C5a,
C3b, C56789
Complement
“Classical” pathway
“Alternate” pathway
triggered by antigenantibody complex:
C1: C2
C2a+C2b
C4 C4a+C4b
by contact with
microbial surfaces:
Properdin+ D: C3
C3a+C3b
B
Ba+Bb
C4b2a
(convertase)
C3bBb
(alternate
convertase)
chemotactic
anaphylotoxic
(opsonin)
C5a
C56789
chemotactic
bacteriolytic
anaphylotoxic
membrane attack
complex (MAC)
Role of inflammatory mediators:
Fever
IL-1, prostaglandins
Vasodilatation
histamine, nitric oxide,
prostaglandins, bradykinin
Exudation
Chemotaxis
histamine, bradykinin, LT
C4,D4,E4, platelet-activating
factor
C5a, IL-8, LTB4
Phagocytosis
C3b (opsonin)
Pain
prostaglandins, bradykinin
Vascular changes ( or
microcirculatory response)
1. Transient short vasoconstriction due to increased
vasoconstrictor’s nerve supply and release of
noradrenalin.
2. Vasodilation under action of inflammatory mediators.
a) arterial hyperemia with increased blood flow and
hydrostatic pressure in microcirculation,
b) venous hyperemia with increased vessel permeability,
slow blood flow and increased blood viscosity.
3.stasis with very sluggish blood flow due to impairment
microrheological properties of blood cells.
Vascular changes in inflammation
vasospasm
Arterial hyperemia
(neurotonical)
Arterial hyperemia
(neuroparalytic)
Venous
hyperemia
*Vascular permeability
А
Б
А. Early (transient)
В
Б. Immediate (prolonged)
В. Delayed type of
increased permeability
0
1/2
1
2
3
time (hours)
4
5
6
Cardinal signs of
inflammation:
Cardinal signs of inflammation
Local signs
1. rubor - redness due to hyperemia;
2. tumor – swelling or edema due to exudation;
3. calor – increased local temperature (heat or warmth)
due to hyperemia, release and activation of cellular
enzymes, increased oxygen uptake and production of
free radicals by neutrophils during phagocytosis;
4. dolor - pain due to action of mediators, accumulation
of exudate and acidosis;
5. functio laesa - loss of function due to pain, swelling
and tissue destruction.
Systemic signs
1. Reaction of immune system (release of
cytokines)
2. Production of acute-phase proteins in the
liver (C-reactive protein, fibrinogen,
complement proteins, ceruloplasmin,
haptoglobin):
3. Malaise, fatigue, decreased appetite;
4. Fever
5. Leukocytosis;
6. Increased erythrocyte sedimentation rate.
Neutrophils in acute inflammation
Skin: Bee sting with acute
inflammation
Acute inflammation-stasis
Bone: acute osteomyelitis
(suppurative inflammation)
Face: erysipelas due to group A
streptococcus (Streptococcus
pyogenes, cellulitis)
Pseudomembranous inflammation