Inflammation (4 of 5)

What will we discuss today?

• Plasma protein–derived mediators

• Anti-inflammatory mediators

• Morphologic patterns of acute inflammation

Plasma protein–derived mediators

… 3 systems:

-Complement system

-Kinin system

-Coagulation system

Complement 3 pathways

Robbins basic pathology 9th edition

Each complement component needs to be cleaved (activated) by proteolysis to be able to act as enzyme that can cleave another component and so on…cascade of reactions

Each large fragment takes the name C#b

Each small fragment takes the name C#a

Large fragment is the fragment that can act as enzyme and cleave the next component in the cascade

Complement, functions

• Opsonization of particles such as microbes for phagocytosis…C3b

• Chemotaxis…C5a and to a lesser degree: C3a and C4a

• Anaphylatoxins…C3a and C5a which affect mast cells to release histamine

(vasodilation + increased vascular permeability)

• Arachidonic acid metabolism in WBCs …induced by C5a

• Formation of membrane attack complex (MAC)

A hole formed by multiple copies of C9 in the membrane of the cell we want to destroy

Binds to complement receptor on phagocyte

Especially against Neisseria

The classical pathway of complement

• Steps:

1- Immune complexes (Ag-Ab) are formed

2- C1 is activated by binding to these complexes

3- A C3 convertase is formed

4- C3 is cleaved to C3a and C3b

The alternative pathway of complement

*In this pathway, we need: - Bacterial polysaccharides (e.g., endotoxin) and other microbial cell wall components - Properdin (a complement component)

- Factor B (a complement component) - Factor D (a complement component)

also… C3 convertase is formed

The lectin pathway of complement

A plasma lectin binds to mannose residues on microbes (in the absence of antibodies)

Few steps

C3 is cleaved

Inhibitors of complement system

• C1 inhibitor

…inherited deficiency of C1 inhibitor: hereditary angioedema

• Decay-accelerating factor (DAF)

…its deficiency: paroxysmal nocturnal

hemoglobinuria (complement-mediated

lysis of RBCs)

• Factor H

…its deficiency: -hemolytic uremic syndrome

-macular degeneration of the eye

Activation of complement

Kinins

Edema in tissues including

larynx

Coagulation and kinin systems

• Some molecules activated in clotting will activate multiple inflammatory responses

Of these molecules: Hageman factor (also known as factor XII of the intrinsic coagulation cascade)

- Produced by the liver - Produced inactive then

become activated at sites of endothelial injury

How will Hageman factor contribute in inflammation? …see next slide

How will Hageman factor contribute in inflammation?

**Activated Hageman factor (factor XIIa) initiates four systems that may contribute to the inflammatory response:

• The kinin system…produces vasoactive kinins

• The clotting system… -thrombin

-fibrinopeptides

-factor X

• Fibrinolytic system…activation of plasmin

• Complement system

Have inflammatory properties

Kinin system

• High molecular-weight kininogen (HMWK)… = circulating precursor of bradykinin

Bradykinin

Kallikrein

-arteriolar dilation -increased vascular permeability -bronchial smooth muscle contraction -pain Short-acting…rapidly

degraded by kininases in plasma and tissues

The clotting system • Factor Xa… -increased vascular permeability

-chemotaxis

• Thrombin…- Binds to “protease-activated receptors” on many cell

types…on endothelial cell: more adhesion to WBCs

- Generates fibrinopeptides: -increased vascular permeability

-chemotaxis

- Cleaves C5 (complement activation)

• Fibrinolytic system: …this system is activated concurrently whenever clotting is initiated

-fibrin degradation products…vascular permeability -Plasmin…-cleaves C3 -also activates Hageman…augmentation of responses

Anti-inflammatory molecules

• Degradative enzymes

• Lipoxins

• Complement regulatory proteins (mentioned in slide #10)

• IL-10…inhibits macrophages

• TGF-beta (transforming growth factor beta)… a mediator of fibrosis

• Tyrosine phosphatases…intracellular proteins

Morphologic patterns of acute inflammation

• Serous inflammation:

…outpouring of watery, relatively

protein-poor fluid

…examples: skin blisters in -burns

-viral

infections

Robbins basic pathology 9th edition

Morphologic patterns of acute inflammation, cont’d

• Fibrinous inflammation:

…more severe injury with more

severe vascular permeability

so large molecules like fibrinogen

will get out from the vessel

Robbins basic pathology 9th edition

Morphologic patterns of acute inflammation, cont’d

• Suppurative (purulent) inflammation and abscess formation:

…large amounts of purulent exudate (pus), which is…

…some microbes are more likely to induce such “suppuration”…so called: pyogenic (= pus-forming), e.g. Staphylococcus aureus

…localized collection of pus = abscess

…here the necrosis in tissue is severe…so the usual outcome of abscess is repair by scarring

Robbins basic pathology 9th edition