acute inflammation

ACUTEINFLAMMATION

Pramodkumar pamuAss i stant Professor

ES IC MEDICAL COL LEGE

• Inflammation is a complex reaction to injurious agents such as microbes and damaged, usually necrotic, cells that consists of vascular responses, migration and activation of leucocytes, and systemic reactions

or

• Inflammation is the cellular and vascular response or reaction to injury characterized by pain, redness, swelling, heat, and disturbance of function

or

• Inflammation is the reaction of a part of the body to injury or infection, characterized by swelling, heat, redness, and pain. The process includes increased blood flow with an influx of white blood cells and other chemical substances that facilitate healing.

or

• Inflammation is a signal-mediated response to cellular insult by infectious agents, toxins, and physical stresses

Inflammation is fundamentally a

protective response

The berlin papyrus 3038 (1300 bc)

RuborTumorCalorDolor Functio laesa Celsus

(2nd century Greek philosopher)

John Hunter (1728-1793)

“Inflammation was a general phenomenon, with stages, which might

resolve, or progress and suppurate.”

Julius Cohnheim (1839-1884)

In the veins "..the originally plasmatic zone becomes filled with innumerable colourless corpuscles...A pointed projection is seen in the external contour of the vessel wall..this grows longer and thicker, throws out fresh points, and gradually withdraws itself from the vessel wall, with which it is at last connected only by a long thin pedicle. Finally ...there lies outside the vessel ..a colourless blood corpuscle."

He described the diapedesis of leucocytes as follows

Elie Metchnikoff (1880s)and his drawings of bacterial phagocytosis by macrophages and microphages

Paul Ehrlich and his drawings of the formation and effector functions of antibodies according to the side-chain theory

Inflammation is a complex reaction to injurious agents such as microbes and damaged, usually necrotic, cells that consists of vascular responses, migration and activation of leucocytes, and systemic reactions

• Acute– Rapid in onset, lasting for min/hrs/days– Exudation of fluid and plasma proteins (edema)– Emigration of leukocytes predominantly neutrophils

• Chronic– Longer duration– Lymphocytes and macrophages– Proliferation of blood vessels, fibriosis and tissue

necrosis

• Acute inflammation is a rapid response to an injurious agent that serves to deliver mediators of host defense- leukocytes and plasma proteins- to the site of injury

– Alterations in vascular caliber

– Structural changes in microvasculature

– Emigration and activation of leukocytes

Components of Inflammation

Triggers

• Infections bacterial, viral, parasitic and microbial toxins

• Trauma• Physical and Chemical agents– Thermal Injury-Burns/ frostbite– Irradiation – Environmental chemicals

• Tissue necrosis• Foreign bodies- splinters, dirt, sutures• Immune reactions – Hypersensitivity reactions

Vasodialtion

• Earliest • Histamine,N

O

↑ Vascular permeability

• Exudate• Histamine,

Leukotrienes• IL-1, TNF

Stasis

Leukocyte AdhesionTransmigrationChemotaxisPhagocytosis

Termination

• Selectins • Integrins• Chemokines• Complement

VASCULAR CHANGES

Major role in acute infl ammati on


Termination

Stasis


Vasodialtion

Vasodilation

• Earliest manifestation• First involves arterioles• Important mediators- Histamine and NO

Stimuli For Degranulation

• Physical injury• Immune reactions• Complement (C3a,C5a)• Cytokines (IL-1, IL-8)

• Histamine– Dilation of arterioles and – Increases the permeability of the venules– Principal mediator of the immediate transient

phase of increased vascular permeability, causing venular gaps

Increased vascular permeability

Dilation of blood vessels

Pain

• Mobilization of P-selectin• Production of chemokines• Expression of endothelial

adhesion molecules• Induction of cyclooxygenase-

2• Prostaglandins, NO, PAF

Vasoactive kinins

Thrombin and fibrinopeptides

Plasmin

Anaphylatoxins

Lipid mediators

CytokinesLeukotriene C4

Leukotriene D4

Prostaglandin D2

Platelet Activating Factor

• Bioactive phospholipid derived mediator• Chemically – acetyl-glyceryl-ether-phosphoryl

choline (AGEPC)• Mediates its effects via a single G-protein-

coupled receptor• Variety of cell types- Neutrophils,

monocytes/macrophages, basophils and mast cells, endothelial cells

Vasoconstriction and Bronchoconstriction

Vasodilation and Increased vascular permeability

100 to 10000 times potent than histamine

• Increased leukocyte adhesion to endothelium

• Chemotaxis• Degranulation and oxidative burst

Histamine

Proteases

Lipid mediators

Cytokines

Chemotactic factors

PAFFactor XII

Kinin Cascade

Vasoactive kinins

Clotting cascadeThrombin

Fibrinolytic systemPlasmin

Complement cascade

Anaphylotoxins

EndotoxinMicrobial productsImmune complexesPhysical injuryTNF/IL-1

Systemic effects

Endothelial effects

↑PGI synthesis

↑Leukocyte adherence

↑IL-1, IL-8, IL-6, PDGF

↑Procoagulant activity↓Anticoagulant activity Fibroblast effects

↑Collagen synthesis

↑PGE synthesis

↑ Protease, collagenase

↑ProliferationFever

↑Sleep

↓Appetite

↑Acute-Phase proteins

Neutrophilia

Hemodynamic effects (shock)

PYREXIA

• Pyrogens – exogenous (LPS), endogenous(IL-1, TNF)

• PGE2 is the ultimate mediator of the febrile response.

• PGE2 acts on neurons in the preoptic area (POA) through the prostaglandin E receptor3 (EP3)and elevates set-point temperature

"Positive" acute-phase proteins

Protein Immune system function

C-reactive protein Opsonin on microbes

D-dimer protein Fibrin degradation product

Mannose-binding protein Mannan-binding lectin pathway

Alpha 1-antitrypsin Serpin, downregulates inflammation

Alpha 1-antichymotrypsin Serpin, downregulates inflammation

Alpha 2-macroglobulin

•Inhibitor of coagulation by inhibiting thrombin •Inhibitor of fibrinolysis by inhibiting plasmin

Fibrinogen, prothrombin, factor VIII, von Willebrand factor, plasminogen

Coagulation factors

Complement factors Complement systemFerritin Binding iron, inhibiting microbe iron uptakeSerum amyloid Pcomponent Opsonin

Serum amyloid A Recruitment of immune cells to inflammatory sitesInduction of enzymes that degrade extracellular matrix

Orosomucoid (Alpha-1-acid glycoprotein, AGP) Steroids carrier

Ceruloplasmin Oxidizes iron, facilitating for ferritin, inhibiting microbe iron uptake

Haptoglobin Binds hemoglobin, inhibiting microbe iron uptake

"Negative" acute-phase proteins

Protein Immune system function of decrease

AlbuminTransferrinTransthyretin

Transcortin Decreased binding of cortisol, upregulation of inflammation

Retinol-binding protein

• Leukocytosis • Leukemoid reactions• Accelerated release of cells from the bone

marrow postmitotic pool• Neutrophilia / lymphocytosis/eosinophilia• Leukopenia

TNF/IL-1

Complement system


Termination

Stasis


Vasodialtion

The hallmark of acute inflammation is

increased vascular permeability

• Immediate transient response• Delayed response• Prolonged response


Termination

Stasis


Vasodialtion

CELLULAR EVENTS

Endothelial/Leukocyte Adhesion molecules

C-X-C (α)– IL-8 – act primarily on Neutrophils

C-C (β)-Mcp-1, Eotaxin, MIP-1α , RANTES

C(ϒ)- Lymphocytes

CX3C-Fractalkaline- monocytes , Tcells

PHAGOCYTOSIS

Elimination of Injurious agents

Phagocytosis

• Three distinct and interrelated steps– Recognition and attachment– Engulfment– Killing or degradation

• Oxygen independent mechanisms– BPI– Lysozyme– Lactoferrin– Major basic protein– Defensins

• Regulated secretion of lysosomal proteins is a peculiarity of leukocytes and hematopoietic cells.

AcuteAcute respiratory distress syndrome

Acute transplant rejection

Glomerulonephritis

Reperfusion injury

Septic shock

Vasculitis

ChronicArthritis

Asthma

Atherosclerosis

Chronic lung disease

Chronic rejection

• Release of leukocyte products and leukocyte-induced tissue injury

– Lysosomal enzymes– ROI– Prostaglandins, leukotrienes

Regurgitation during feeding

Frustrated phagocytosis

Cytotoxic release


Termination

Stasis


Vasodialtion

TERMINATION

Minimizing damage to host

Short half life of mediators

Produced as long as the stimulus persists

Anti-Inflammatory mediatorsTGF-β-Macrophage

Neural Impulses inhibit TNF

OUT COMES OF INFLAMMATION

Usual and Unusual

CONCLUSION

SUMMARY

REFERENCES

1.Mitchell RN(Ed). Hemodynamic Disorders, Thromboembolic Disease, and Shock. In Robbins and Cotran Pathologic Basis Of Disease, Elsevier, Philadelphia,2004; 7th Edn,p139-143

Acute and chronic inflammation In Robbins and Cotran Pathologic Basis Of Disease, Elsevier, Philadelphia,2004; 7th Edn,p47-78

acute inflammation

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