INFLAMMATION

INFLAMMATION

Complex reaction

Dispose damaged/dead tissue

Eliminate foreign substances

Components - Vascular, Cellular & Plasma proteins

Deliver the WBC & plasma proteins

CARDINAL SIGNS

CELSUS

Rubor ,Tumour, Calor, Dolor

Functio laesa (Virchow)

Acute & Chronic

SEQUENCE OF EVENTS

Inflammatory stimulus

Microbes, dead tissue, hypoxia

Soluble factors generated / activated

Trigger vascular & cellular events

Initiate. Sustain. Broken down

Removal of offending agent

Anti inflammatory mechanisms

CUTE INFLAMMATION

VESSEL CALIBER

Vasoconstriction

Vasodilation

1.Increased blood flow

2.Calor, erythema,

HISTAMINE, NITRIC OXIDE Smooth muscle

Stasis

REACTION OF LEUCOCYTES

Recruitment

Migration

Chemotaxis

Recognition

Removal

RECOGNITION
1.Toll like receptors
2.G protein coupled receptors

N formyl methionyl residues

N acetyl galactose amine

N acetyl glucose amine - lysozyme

3.Receptors for opsonins

Ig G ab, C 3, lectins

C3a, C5a - anaphylatoxins

4.Receptors for cytokines

REMOVAL OF OFFENDING AGENT

Phagocytosis

Recognition & attachment receptors

Engulfment phagosome phagoysosome

Polymerization of actin

KILLING & DEGRADATION

Activation of phagocytes

Reactive oxygen & nitrogen species

NADPH Oxidase / Phagocyte oxidase

Oxidises NADPH

Reduces oxygen to superoxide anion

RESPIRATORY BURST

Assembles at phagosome membrane

H2O2 MPO HALIDE SYSTEM

Superoxide anion hydrogen peroxide

Myeloperoxidase & halides

Hydrogen peroxide hypochlorite

Halogenation

Lipid peroxidation

Hydroxy radical

Nitric oxide

Arginine & NO synthase

NO & superoxide peroxynitrite

Secretion is controlled

Material difficult to ingest

Unable to surround & ingest FRUSTRATED PHAGOCYTOSIS

LEUCOCYTE FUNCTION DISORDERS

INHERITED DISORDERS

Leucocyte adhesion deficiency type 1

Leucocyte adhesion deficiency type 2

Chediak Higashi syndrome

Chronic granulomatous disease

G6PD deficiency

MPO deficiency

ACQUIRED DISORDERS

BM suppression

DM

Sepsis

Anemia

Leukemia

Malignancy

Malnutrition

LEUCOCYTE ADHESION DEFICIENCY

LAD 1, LAD 2 & LAD 3

Most common is LAD 1

Deficiency in -2 integrin or CD 18

LAD 2- absence of Sialyly Lewis X

LAD 3 defect in integrins, Glanzmanns thrombasthenia

CHEDIAK HIGASHI SYNDROME

Rare AR disorder

Mutation in a lysosomal trafficking

LYST protein

Defective decrease in phagocytosis

Recurrent infections
CHRONIC GRANULOMATOUS DISEASE

Defective respiratory /oxidative burst

X linked membrane component, gp 91 phox

Recessive - cytoplasmic component, gp 47 &67 phox

Macrophage rich inflammatory infiltrate

1.Nitroblue tetrazolium test

2.Dihydrorhodamine test
3.Cytochrome C reduction assay

MPO DEFICIENCY

Quantitative or qualitative defect in MPO

Defective intracellular killing of microbes

Must be differentiated from chronic granulomatous disease

HISTAMINE

Preformed mediator

Sources of histamine

Mast cells, basophils, platelets

Stimulus mast cell degranulation

SEROTONIN

Preformed mediator

Platelets, NE cells

ARACHIDONIC ACID METABOLITES (EICOSANOIDS)

Linoleic acid

Phopspholipases (A2) act on membrane phopsholipids

Cyclooxgenases & lipooxgenases

1.Prostaglandins
2.Leukotrienes
3.Lipoxins

ARACHIDONIC ACID METABOLITES

PROSTAGLANDINS

COX 1 & COX 2

LEUKOTRIENES

Secreted by & act on leucocytes

Lipooxygenase enzymes

5- Lipooxgenase

12- Lipooxygenase Lipoxins

15 Lipooxygenase
LEUKOTRIENES
LIPOXINS

12- Lipoxygenase

INHIBITORS OF INFLAMMATION

Synthesis - Neutrophils & platelets

Lipoxin A4 & Lipoxin B4

Inhibit leucocyte recruitment endothelial adhesion & chemotaxis

Activation of moncytes
PLATELET ACTIVATING FACTOR

Derived from cell membrane phospholipids

Produced by platelets, basophils, mast cells, endothelila cells

Cell bound & secreted

Causes platelet aggregation

Smooth muscle vasoconstriction & bronchoconstriction

Cellulra events of inflammation adhesion, chemotaxis, degranulation,oxidative burst

REACTIVE OXYGEN SPECIES

Production depends on NADPH oxidase

Increase expression of chemokines, cytokines

Endothelial adhesion molecules

Killing & degradation of microbes

Vascular permeability

ANTIOXIDANT MECHANISMS

Antioxidants vit E, A, C, glutathione

Superoxide dismutase superoxide anion

Catalase hydrogen peroxide

Glutathione peroxidase- hydroxyl ion

Ceruloplasmin - copper

Transferrin iron

Peroxiredoxins - peroxynitrite

NITRIC OXIDE

L- arginine & NO synthase

eNOS, nNOS, iNOS

Vasodilation

Reduces platelet aggregation& adhesion

Microbicidal action peroxynitrite

CYTOKINES

Tumour Necrosis Factor, IL-1

Produced by macrophages

Endothelial ACTIVATION

Endothelial adhesion

Synthesis of chemical mediators

Matrix remodelling

Thrombogenicity

Systemic acute phase responses

CHEMOKINES

Chemoattractant cytokines bind to G protein coupled receptors

Chemotaxis

Normal migration of cells

C chemokines

CC chemokines

Monocytes, eosinophils, basophils, lymphocytes

MCP-1, Eotaxin, MIP 1, RANTES

CXC chemokines

Lymphocytes, Lymphotactin

Neutrophils, IL 8

CX3C chemokines

Monocytes, T cells

Fractalkine

NEUTROPHIL GRANULES

COMPLEMENT SYSTEM

Proteins are in inactive form in plasma

Activated into proteolytic enzymes

Proteolysis of C3 most abundant component

Innate & adaptive immunity

Inflammation C3a, C5a, C4a, (Anaphylatoxins)

Chemotaxis C5a

Phagocytosis-C3b

Cell lysis - MAC

COAGULATION & KININ SYSTEM

In inflammation endothelial surface thrombogenic & anticoagulation

KININS

Vasoactive peptides

Derived from kininogens by the action of kallikreins ( chemotactic)

Bradykinin

Vascular permability

Vasodilation

Pain

Contraction of SM

Inactivated by

Kininase, ACE

FIBRINOLYTIC SYSTEM

Hageman factor / factor XII

Induces clot formation

Activates the fibrinolytic system

ACTIVATED HAGEMAN FACTOR

Kinin system

Clotting system

Fibrinolytic system

Complement system

OUTCOME OF ACUTE INFLAMMATION

Resolution

Fibrosis

Chronic inflammation
PATTERNS OF ACUTE INFLAMMATION

SEROUS INFLAMMATION

Plasma or secretion of cells lining cavities

EFFUSION

PATTERNS OF ACUTE INFLAMMATION

FIBRINOUS INFLAMMATION

Increase in permability

Procoagulant stimulus

Deposition of fibrin in extravascular space

Fibrinolysis

Organisation

PATTERNS OF ACUTE INFLAMMATION

SUPPURATIVE INFLAMMATION

Purulent exudate or pus

Abscess formation localised collection of pus

CHRONIC INFLAMMATION

Persistent infections

Immune mediated diseases

Allergic reactions

Autoimmune diseases

Prolonged exposure to causative agent

Features

Mononuclear infiltrate

Growth of BV & lymphatics

Tissue destruction

Healing connective tissue replacement

MACROPHAGES

Mononuclear phagocyte system/ RES

Kupffer cells

Sinus histiocytes

Alveolar macrophages

Microglia

Osteoclasts

Half life

Monocyte : 1 day

Macrophage : months - years

Activated macrophages

Eliminate injurious agents

Initiate healing

Classically activated macrophages M1

Interferon gamma

Phagocytosis

Killing of bacteria & fungi

Inflammation

Inhibited by IL13, IL4

Alternatively activated macrophages- M2

IL-13, IL-4

Anti inflammtory effects

Wound repair

Fibrosis

Inhibited by Interferon gamma

OTHER CELLS IN CHRONINC INFLAMMATION

GRANULOMATOUS INFLAMMATION

Morphologic pattern of chronic inflammation

Granuloma formation

Central caseous necrosis

Epitheloid cells & giant cells

Rim of mononuclear infiltrate

TUBERCULOSIS

Caseating granulomas

Acid fast bacilli

SARCOIDOSIS

Non caseting granulomas

Asteroid bodies

Phospolipid derivatives

Schaumann bodies

fvd

Calcium & protein inclusions