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Chemical Mediators of Inflammation

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Outline of Lecture

Leukocyte cellular events

Leukocytes leave the vasculature routinely through the following sequence of events:

Margination and rolling

Adhesion and transmigration

Chemotaxis and activation

They are then free to participate in:

Phagocytosis and degranulation

Leukocyte-induced tissue injury

Phagocytosis

1. Recognition & attachment

Opsonins (IgG and C3) coat target

2. Engulfment

Pseudopods flow around the particle to be

engulfed. Particle is engulfed and fuses with lysosome

3. Killing/degradation

O2 dep: Reactive O2 species in lysosomes

O2 indep: Bactericidal permeability agents, lysozyme, MBP, lactoferrin

 

Recognition and Binding

Opsonized by serum complement, immunoglobulin (C3b, Fc portion of IgG)

Corresponding receptors on leukocytes (FcR, CR1, 2, 3) leads to binding

 

Phagocytosis and Degranulation

Triggers oxidative burst, engulfment and formation of vacuole which fuses with lysosomal granule membrane (phagolysosome)

Granules discharge within phagolysosome and extracellularly (degranulation)

 

Oxidative Burst

Reactive oxygen species formed through oxidative burst that includes:

increased oxygen consumption

glycogenolysis

increased glucose oxidation

formation of superoxide ion

2O2 +  NADPH  ® 2O2-rad  +  NADP+  +  H+                                   (NADPH oxidase)

O2-rad  +  2H   H2O2  (dismutase)

Reactive Oxygen Species

Hydrogen peroxide alone insufficient

MPO (azurophilic granules) converts hydrogen peroxide to HOCl , an oxidant/antimicrobial agent (“bleach”)

Degradation and Clean-up

Reactive end-products only active within phagolysosome

Hydrogen peroxide broken down to water and oxygen by catalase

Dead microorganisms degraded by lysosomal acid hydrolases

Leukocyte-induced Tissue Injury

There is a cost, destructive enzymes may enter extracellular space when:

premature degranulation

frustrated phagocytosis (large, flat)

membranolytic substances (urate crystals)

persistent leukocyte activation (RA, emphysema)

 

Defects of Leukocyte Function

Defects of adhesion:

LFA-1 and Mac-1 (integrins) subunit defects lead to impaired adhesion (LAD-1)

recurrent bacterial infections with impaired wound healing

 

Defects of Leukocyte Function

Defects of adhesion:

absence of sialyl-Lewis X, and defect in E- and P-selectin sugar epitopes (LAD-2)

clinically milder than LAD-1, but recurrent bacterial infections

 

Defects of Leukocyte Function

Defects of chemotaxis/phagocytosis:

microtubule assembly defect leads to impaired locomotion and lysosomal degranulation

neutropenia, defective neutrophil degranulation, delayed microbial killing, recurrent bacterial infections

Defects of Leukocyte Function

Defects of microbicidal activity:

deficiency of NADPH oxidase that generates superoxide, therefore no oxygen-dependent killing mechanism (Chronic Granulomatous Disease)

recurrent bacterial infections

Chemical Mediators Of Inflammation

Chemical mediators

Plasma-derived:

Complement, kinins, coagulation factors

Many in “pro-form” requiring activation (enzymatic cleavage)

Cell-derived:

Preformed, sequestered and released (mast cell histamine)

Synthesized as needed (prostaglandin)

Mediators are tightly regulated, too many or too few cause many different diseases

 

Chemical mediators

May or may not utilize a specific cell surface receptor for activity

May also signal target cells to release other effector molecules that either amplify or inhibit initial response (regulation)

Are tightly regulated:

Quickly decay (AA metabolites), are inactivated enzymatically (kininase), or are scavenged (antioxidants)

Specific mediators

Vasoactive amines

Histamine: vasodilation and venular endothelial cell contraction, junctional widening; released by mast cells, basophils, platelets in response to injury (trauma, heat), immune reactions (IgE-mast cell FcR), anaphylatoxins (C3a, C5a fragments), cytokines (IL-1, IL-8), neuropeptides, leukocyte-derived histamine-releasing peptides

Specific mediators

Serotonin: vasodilatory effects similar to those of histamine; platelet dense-body granules; release triggered by platelet aggregation

Plasma proteases

Clotting system

Complement

Kinins

Fibrinolytic system

 

Clotting cascade

Cascade of plasma proteases

Hageman factor (factor XII)

Collagen, basement membrane, activated platelets converts XII to XIIa (active form)

Ultimately converts soluble fibrinogen to insoluble fibrin clot

Factor XIIa simultaneously activates the “brakes” through the fibrinolytic system to prevent continuous clot propagation

 

Kinin system

Leads to formation of bradykinin from cleavage of precursor (HMWK)

Vascular permeability

Arteriolar dilation

Non-vascular smooth muscle contraction (e.g., bronchial smooth muscle)

Causes pain

Rapidly inactivated (kininases)

 

Complement system

Components C1-C9 present in inactive form

Activated via classic (C1) or alternative (C3) pathways to generate MAC (C5 – C9) that punch holes in microbe membranes

In acute inflammation

Vasodilation, vascular permeability, mast cell degranulation (C3a, C5a)

Leukocyte chemotaxin, increases integrin avidity (C5a)

As an opsonin, increases phagocytosis (C3b, C3bi) 

Complement system

Role in immunity

Membrane Attack Complex (MAC C5-9)

Punches a hole in bacterial membrane

 

If you have deficiencies in the MAC

you are predisposed to infections that are encapsulated

Neisseria, Strept, Hemoph, Listeria

Specific Mediators

Arachidonic acid metabolites (eicosanoids)

Prostaglandins and thromboxane: via cyclooxygenase pathway; cause vasodilation and prolong edema; but also protective (gastric mucosa); COX blocked by aspirin and NSAIDS

Specific Mediators

Leukotrienes: via lipoxygenase pathway;  are chemotaxins, vasoconstrictors, cause increased vascular permeability, and bronchospasm

PAF (platelet activating factor)

Derived also from cell membrane phospholipid, causes vasodilation, increased vascular permeability, increases leukocyte adhesion (integrin conformation)

Specific Mediators

Cytokines and Chemokines

Protein cell products that act as a message to other cells, telling them how to behave.

IL-1, TNF-a and -, IFN- are especially important in inflammation.

Increase endothelial cell adhesion molecule expression, activation and aggregation of PMNs, etc., etc., etc.

Specific mediators

Nitric Oxide

short-acting soluble free-radical gas with many functions

Produced by endothelial cells, macrophages, causes:

Vascular smooth muscle relaxation and vasodilation

Kills microbes in activated macrophages

Counteracts platelet adhesion, aggregation, and degranulation

 Specific mediators

Lysosomal components

Leak from PMNs and macrophages after demise, attempts at phagocytosis, etc.

Acid proteases (only active within lysosomes).

Neutral proteases such as elastase and collagenase are destructive in ECM.

Counteracted by serum and ECM anti-proteases.

 

More specific mediators

Oxygen derived free radicals

Released extracellularly from leucocytes

Dependent on NADPH oxydative system  e.g Super oxide ,Hydrogen per oxide & OH ion important in inflammation.

Endothelial cell adhesion molecule expression, activation and aggregation of PMNs, etc., etc., etc.

More specific mediators

Neuropeptides

Similar to vasoactive amines/ecosanoids

play role in initiation and propagation of inflammation.

1. Substance P

2. Neurokinine A

Other Mediators

Response to hypoxia

Hypoxia induced factor  1 a

 

Response to necrotic cells

Uric acid

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