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General Pathology
Basic Principles of Cellular and Organ
Pathology
Inflammation - I
Jaroslava Dušková
Inst. Pathol. ,1st Med. Faculty, Charles Univ. Prague
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Inflammation I- table of contents
Definition
Classifications (sense, time view…)
Causes
Macroscopy features
Phases of inflammatory response
Pathogenesis of inflammation – hyperemia
– inflammatory mediators
– immune response
Cells in inflammation
Systemic inflammatory response
Inflammation development
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InflammationDefinition:
complex reaction of organism to damage
(aim: homeostasis maintenance)Jaroslava Duško
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InflammationSense
defensive – agent elimination
reparative – damage reparation
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Inflammation - Classification:
Time view
acute (days)
subacute (weeks)
chronic (months-years)
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Inflammation - Classification:
Causes:
nonliving
physical
chemical
living
viral
bacterial
mycotic
parasitic
AUTOIMMUNE
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Inflammation Celsus´ features:
rubor
tumor
calor
dolor
functio laesa
Aulus Cornelius Celsus
25 BC – 50 AD;
De Medicina
Galenos, Sydenham, Virchow?
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Erysipelas
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Laryngitis haemorrhagica et pseudomembranosa
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Phases of Inflammatory
Response
alteration
exsudation
proliferationJaroslava Duško
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Anthrax
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Meningitis purulenta
CSF
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Colitis pseudomembranosa
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Cholelithiasis. Empyema vesicae felleae chronicum.
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Phases of Inflammatory Response
Alteration Exsudation ProliferationJarosla
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Phases of Inflammatory Response
AlterationExsudation
Proliferation
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Vascular Changes in Inflammation
Flux hyperemia - axonal reflex
Peristatic hyperemia
Stasis
Increased permeability - exsudation
Inflammatory edema
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The reflex arc of axon reflex has neither an
integration center nor any synapse
Def.: a reflex resulting from
a stimulus applied to one
branch of a nerve, which
sets up an impulse that
moves
centrally to the point of
division of the nerve, where
it is reflected down the other
branch to the effector organ
• Blood vessels, sweating
glands and mast cells are
most important effectors of
axon reflex in the skin
Mevlut YAPRAK: The axon reflex. Neuroanatomy (2008) 7: 17–19
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Active Hyperemia
vasodilatation
slowing of the circulation
increased microvasculature
permeability – leakage
----------
leucocyte emigration
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Mast Cell ruling the process
Degranulation (immediate response)
– histamin-vasodilation-permeability-
exsudation
– neutrofil chemotactic factor
(micro)fagocytosis
– eosinophil chemotactic factor -
modulation of the vascular effect
Synthesis (long-term response)
– leukotriens (SRS-A) –vasodilation-
permeability-exsudation
– prostaglandins - vasodilation-
permeability-exsudation- PAIN
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Active Hyperemia
vasodilatation
leakage
Chemical mediators:
Cells: histamine , serotonin, catecholamins,
lysosomal enzymes
Plasma: complement, kinin system,
coagulation/fibrinolysis system
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Active Hyperemia
vasodilatation
– slowing of the circulation
– increased microvasculature permeability -
leakage
leucocyte emigration
chemotaxis:
soluble bact. products
complement components esp. C5a
products of lipoxygenase pathway of arachidonic
acid (esp.leukotriene B4)
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Recognition of the dead cells
Phagocytes and dendritic cells express
pattern recognition receptors that recognize
structures common to many microbes and
dead cells
Activation of the inflammasome –
multiprotein cytoplasmic complex – reacts to
necrosis, urates, cholesterol….
Activation of Il-1 – recruitment of neutrophils
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axial flow
quiet capillary
vasoconstriction
vasodilation
flux hyperemia
peristatic hyperemia
flux hyperemia
peristatic hyperemia
increased
permeability
increased
permeability endothelium
swelling
erythro- &
leucocytodiape
desis
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Main Inflammatory Mediators
Vasodilation prostaglandins, NO
Permeability vasoactive amins, C3,C5, bradykinin
Chemotaxis C5a, bacterial products, leucotriens,
cytokins
Fever interleukin 1,6, TNF, prostaglandins
Pain prostaglandins, bradykinin
Tissue damage lysosomal enzymes…
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Lipids in Cell Signaling - 1
Many of the lipids involved as second messengers in cell signaling pathways arise from the arachidonic acid (AA) pathway.
AA is an unsaturated fatty acid
a normal constituent of membrane phospholipids
released from the phospholipids by the actions of phospholipase A2 (PLA2).
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Lipids in Cell Signaling - 2
Prostaglandins (PG) are generated by the cyclooxygenase (COX).
Constriction or dilation in vascular smooth muscle cells
Aggregation or disaggregation of platelets
Sensitize spinal neurons to pain
Decrease intraocular pressure
Regulate inflammatory mediation
Regulate calcium movement
Control hormone regulation
Control cell growth
Short half-life. Therefore, they exert only a paracrine(locally active) or autocrine (acting on the same cell from which it is synthesized) function
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Lipids in Cell Signaling - 3
Leukotrienes (LT) and lipoxins (LP), are
derived directly from AA without the mediation
of a cyclic endoperoxide.
LT induce inflammation by their chemotactic
and degranulating actions on
polymorphonuclear leucocytes (PML)
the amino acid containing LTs induce
vasoconstriction and bronchoconstriction and
are involved in asthma and anaphylaxis.
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Acne conglobata
Alteration
Exsudation
Proliferation
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Mechanisms and
Morphological
Features of Immune
ReactionJaroslava Duško
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Mechanisms
of Immune Response
nonspecific
antigen specific humoral
cellular
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Barriers
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nonspecific PHAGOCYTOSIS
bactericid substances (lysozym)
complement
interferon
proteins distinguishing general microbial structures
Mechanisms
of Immune Response
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complement
proteins C2-C9
chemotactic
phragments
C3a,C5a
antibody
bacterium
Lytic pore
C5-C9
Complement
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particle
particle
Superficial
phagocyte
membrane
Superficial lectinsFc receptors of antibodies
Phagocytosis
&
Opsonisation
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„Natural“ antibodies starting the immune response
Superficial
immunoglobulin
Natural AB
Antigen
particle
Follicular dendritic
cell
B-lymphocyte
immune complex Jaroslava Duško
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Cytokines
Def.:
polypeptides and proteins - regulatory
molecules participating by autocrine,
paracrine & endocrine function in
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Cytokines
Source:
• macrophages
• APC
• T- lympho
Types:
• growth fcs.
• colony stim. fcs.
• chemokins
(interleukins)
• TNFα, TNF β – LT
• interferonsJarosla
va Dušková
Zhang X, Mosser DM.
Macrophage activation by
endogenous danger signals.
Most microbes have Pathogen Associated
Molecular Patterns (PAMPS) that are
recognized by macrophages and trigger this
activation response.
J Pathol. 2008 Jan;214(2):161-78.
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Interleukin 4
Th2 stimulation – antibody mediated
immune response
Th1 + interferon γ suppresion
inhibition of the T-lymphocytes proliferation
inhibition of TNF α +Il6 secretionJaroslava Duško
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antigen specific humoral B– lymphocytes
cellular T– lymphocytes
INTERACTIONB-lympho–Th – affinity maturation – plasmocyte
Mechanisms
of Immune Response
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signal cell
input (arrows)
mature Th clone
Th precursor
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B-lymphocyte
T- helpers
signals
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NK- cell, macrophage,
neutrophil, heparinocyte
Antibodies attached to
infected cells or invading
pathogens
FC receptors
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virus
Il-2 receptor
mature Tc clone
creation
cytotoxic vesicules
infected
cell
cytotoxic
vesicules
injection
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Granzyme B
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infected
macrophage
activated
macrophage
intracellular
parasites
mature Th clone
creation
cytokins & bactericid subst.
secretion
interferon γ
interferon
receptor
interferon
receptor
Macrophage
activation
IFN-γ is secreted
by T lymphocytes
and NK cells
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Inflammatory cells
neutrophile granulocytes
eosinophil granulocytes
basophil granulocytes & heparinocytes
lymphocytes & plasmocytes
monocytes – macrophages
erythrocytes
platelets
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Heparinocytes
IgE receptors
mediators production (heparin, histamin,
serototnin, catecholamins…)
cytokin production IL4, TNF α
chemotactic factors for neutrophils &
eosinophils
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Heparinocytus
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Heparinocyte Degranulation
IgE receptors
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Heparinocytes
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Heparinocyte degranulation
physical
– heat, mech.,UV light, x-rays
chemical
– venoms, enzymes
immune
– IgE binding, complement
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ICAM
ELAM
VCAM
TNF
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Neutrophilic granulocytes
pavementing (selectins,
integrins)
emigration (chemotactic
factors from bacteria,
complement 3a, 5a, kinins,
histamin….)
fagocytosis (both non
specific without opsonisation
and specific IgG + compl.)
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ingestion & digestion of bacteria
H2O2 & myeloperoxidase
lysozyme - mucopeptide digestion
DEATH in a few hours
elastase, colagenase
plasminogen activator
complement activation
neutrophil extracellular traps - NETs
Neutrophilic granulocytes
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Neutrophil (polymorphonuclear) granulocyte
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Neutrophil (polymorphonuclear) granulocyte
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NG disorders 1.
migration & chemotaxis
– lazy leucocytes syndrome
– diabetes (locomotion)
– Chédiak - Higashi syndrome (bacteria killing,
lack of elastase, locomotion)
– β2-integrin defect (adhaesion)
locomotion– serum changes
– corticoids
– phenylbutazone
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NG disorders 2.
phagocytosis
– opsonins & IgG in sickle cell anaemia
– morphin abusers
– lysosom fusion (corticoids, antimalaric drugs, CH-H sy…
bactericid effect
– chronic granulomatosis in children
cytochrom oxidase & H2O2 defects
recurences of staphylococcus and aspergillus infectionJarosla
va Dušková
Eosinophilic Granulocytes
alergic response
IgA receptors
anti parasites defence
peroxidase, histaminase, acid
phophatase, cytokins Jarosla
va Dušková
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Mechanisms of
Immune Response
antigen specific cellular T– lymphocytes
APC – CD8+ precursors – Th,Tc
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Plasmocyte
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Inflammatory cells
neutrophile granulocytes
eosinophil granulocytes
basophil granulocytes & heparinocytes
lymphocytes & plasmocytes
monocytes – macrophages
erythrocytes
platelets
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Macrophage
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CSF
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Macrophages - Function
phagocytosis
bacteria killing
mediators production
antigen processing & presentation
modulation of fibroblast proliferation – IL-1
modulation of endothelia proliferation –
TNFα
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Macrophages - secretion
acid & neutral proteases
cytokins IL-1 , TNF
O2, NO
complement componentsJaroslava Duško
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Granuloma lipophagicum
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Sinus pilonides
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Giant cells - I
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Giant cells - II
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Megakaryocytes & Plateletes
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Thrombocytes
mediators production
– vasoactive substances, thrombosis,
mesenchymal cell proliferation
– granules: serotonin, ADP, acid
phophatase, thromboxan, Ca cationic
protein…
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Colla
gen f
ibre
s c
reation
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Collagen fibres
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ILM & EMM
ILM
M
M
F
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lymphatic tissue activation
fever – IL 1, prostaglandins
leucocytosis
lymfocytosis in viral infections
eosinophilia in parasitic diseases
Systemic Inflammatory Response
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No – death
Complete resolution - ad integrum
vessel permeability normalized
migration stopped
necrosis resorption
tissue regeneration
Healing with a defect - per defectum
regeneration impossible – extensive necrosis
granulation tissue – scar
Progression towards a chronic inflammation
Inflammation Development
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