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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
Leukocyte AdhesionTransmigrationChemotaxisPhagocytosis
Termination
Stasis
↑ Vascular permeability
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
Leukocyte AdhesionTransmigrationChemotaxisPhagocytosis
Termination
Stasis
↑ Vascular permeability
Vasodialtion
The hallmark of acute inflammation is
increased vascular permeability
• Immediate transient response• Delayed response• Prolonged response
Leukocyte AdhesionTransmigrationChemotaxisPhagocytosis
Termination
Stasis
↑ Vascular permeability
Vasodialtion
Leukocyte AdhesionTransmigrationChemotaxisPhagocytosis
Termination
Stasis
↑ Vascular permeability
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
Leukocyte AdhesionTransmigrationChemotaxisPhagocytosis
Termination
Stasis
↑ Vascular permeability
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