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

homeostasis maintenanceJaroslava Duško

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Cytokines

Source:

• macrophages

• APC

• T- lympho

Types:

• growth fcs.

• colony stim. fcs.

• chemokins

(interleukins)

• TNFα, TNF β – LT

• interferonsJarosla

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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

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Eosinophilic Granulocytes

alergic response

IgA receptors

anti parasites defence

peroxidase, histaminase, acid

phophatase, cytokins Jarosla

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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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