1. Inflammation (4 of 5) Ali Al Khader, M.D. Faculty of Medicine
Al-Balqa’ Applied University

2. What will we discuss today?
Plasma protein–derived mediators
Anti-inflammatory mediators
Morphologic patterns of acute inflammation

3. Plasma protein–derived mediators
… 3 systems:
-Complement system
-Kinin system
-Coagulation system

4. Complement
3 pathways
Robbins basic pathology 9th edition

5. 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

6. Complement, functions
Binds to complement receptor on phagocyte
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
Especially against Neisseria

7. 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

8. 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

9. The lectin pathway of complement
A plasma lectin binds to mannose residues on microbes (in the absence of antibodies)
Few steps
C3 is cleaved

10. 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

11. 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

12. 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

13. 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

14. 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
- 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

15. 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

16. 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

17. 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

18. 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

19. Thank You