INFLAMMATION AND REPAIR
Lecture 3
Dr. Maha Arafah
Dr. Maha Arafah
Assistant Professor
Department of Pathology
King Khalid University Hospital
and King Saud University
Email: marafah@ksu.edu.sa
marafah @hotmail.com
Monday, October 25, 2010
11:00-12:00 am
1
Upon completion of this lecture, the student should:
1.
2.
3.
4.
5.
Define the chemical mediators of inflammation.
Know the general principles for chemical mediators.
Know the cellular sources and major effects of the
mediators.
List the most likely mediators of each of the steps of
inflammation.
List and describe the outcome of acute inflammation.
What are mediators?
• Chemical mediators of inflammation
are substances produced during
inflammation inducing a specific
events in acute inflammation.
-
The production of active mediators is triggered by:
microbial products
2. host proteins, such as the proteins of the
complement, kinin and coagulation systems
1.
 ( these are themselves activated by microbes
and damaged tissues)
-

-

1)
2)
3)
Most mediators have the potential to cause harmful
effects.
Therefore, there should be a mechanism to checks
and balances their action.
Mediator function is tightly regulated by:
decay (e.g. AA metabolites)
inactivated by enzymes (kininase inactivates
bradykinin)
eliminated ( antioxidants scavenge toxic oxygen
metabolites)

Plasma-derived:
1.
2.
3.
Complement
kinins
coagulation factors

Cell-derived:
1.
2.

Many in “pro-form”
requiring activation
(enzymatic cleavage)
Synthesized as
needed
(prostaglandin)
Preformed,
sequestered and
released (mast cell
histamine)
Chemical Mediators of Inflammation
Cell-Derived
Plasma-Protein-Derived
Vasoactive Amines
Eicosanoids
PAF
Cytokines
Chemokines
ROS
NO
Lysosomal Enzymes of Leukocytes
Neuropeptides
Chemical Mediators
of Inflammation
Cell-Derived
Plasma-ProteinDerived
Complement
Coagulation and Kinin
Systems
Producing cells:
Tissue macrophages
Mast cells
Endothelial cells
Leukocytes
Among first mediators in acute inflammatory reactions
 Preformed mediators in secretory granules
Source:
many cell types, esp. mast cells, circulating
basophils, and platelets
Stimuli of Release:
Physical injury
Immune reactions
C3a and C5a fragments
Leukocyte-derived histaminereleasing proteins
Neuropeptides
Cytokines (e.g. IL-1 and IL-8)
Actions:
1.
2.
3.
ARTERIOLAR DILATION
INCREASED VASCULAR
PERMEABILITY (venular gaps)
ENDOTHELIAL ACTIVATION
Inactivated by:
Histaminase
Source:
Platelets
Action:
Similar to histamine
Stimulus:
Platelet aggregation
Source:
Leukocytes
Mast cells
Plasma-Protein-Derived
Endothelial cells
Platelets
Chemical Mediators of Inflammation
Cell-Derived
Vasoactive Amines
Eicosanoids
PAF
Cytokines
Chemokines
ROS
NO
Lysosomal Enzymes of Leukocytes
Neuropeptides
Chemical Mediators of Inflammation
Cell-Derived
Plasma-Protein-Derived
Vasoactive Amines
Eicosanoids
PAF
Cytokines
Chemokines
ROS
NO
Lysosomal Enzymes of Leukocytes
Neuropeptides
Chemical Mediators of Inflammation
Cell-Derived
Plasma-Protein-Derived
Vasoactive Amines
Cytokines
Polypeptides
Eicosanoids
Actions:
PAF
Involved in early immune and inflammatory
Cytokines
reactions
Chemokines
Some stimulate bone marrow
precursors to produce
more leukocytes
ROS
NO
Lysosomal Enzymes of Leukocytes
Neuropeptides
Cytokine of
Acute inflammation:
Interleukin (IL-1) & TNF
Chronic Inflammation:
Interferon-γ INF- γ & Interleukin ( IL-12)
Activated lymphocytes and macrophages influence each other and also
release inflammatory mediators that affect other cells.
Chemical Mediators of Inflammation
Cell-Derived
Plasma-Protein-Derived
Vasoactive Amines
Chemokines
Small proteins Eicosanoids
They are chemoattractants
for leukocytes
PAF
Main functions:
Cytokines
Leukocyte recruitment & activation in
inflammationChemokines
Normal anatomic organization
of cells in
ROS
lymphoid and other tissues
NO
Lysosomal Enzymes of Leukocytes
Neuropeptides
Chemical Mediators of Inflammation
Cell-Derived
Plasma-Protein-Derived
Reactive Oxygen Species
Vasoactive Amines
Synthesized via Eicosanoids
NADPH oxidase pathway
PAF
Source:
Cytokines
Neutrophils and Macrophages
Stimuli of release:Chemokines
Microbes
ROS
Immune complexes
NO
Cytokines
Action: Lysosomal Enzymes of Leukocytes
Microbicidial (cytotoxic)
agent
Neuropeptides
Chemical Mediators of Inflammation
Cell-Derived
Plasma-Protein-Derived
Vasoactive
Amines
Nitric Oxide
( NO)
Short-lived
Eicosanoids
Soluble free-radical gas
PAF
Functions:
Vasodilation Cytokines
Antagonism Chemokines
of platelet activation
(adhesion, aggregation, &
degranulation)ROS
Reduction of leukocyte
recruitment
NO
Microbicidial
(cytotoxic) agent (with or
Lysosomal Enzymes of Leukocytes
without ROS) in activated
Neuropeptides
macrophages
Chemical Mediators of Inflammation
Cell-Derived
Plasma-Protein-Derived
Lysosomal Enzymes Vasoactive
of Leukocytes
Amines
Neutrophils & Monocytes
Eicosanoids
Enzymes:
PAF
Acid proteases
Neutral proteases (e.g. elastase,
Cytokines collagenase, &
cathepsin)
Chemokines
Their action is checked by:ROS
Serum antiproteases (e.g. α1-antitrypsin)
NO
Lysosomal Enzymes of Leukocytes
Neuropeptides
Chemical Mediators of Inflammation
Cell-Derived
Plasma-Protein-Derived
Vasoactive Amines
Neuropeptides
Eicosanoids
Small proteins
PAF
Secreted by nerve fibers
mainly in lung & GIT
Initiate inflammatoryCytokines
response
e.g. Substance P : Chemokines
Transmits pain signals
ROS
Regulates vessel tone
NO
Modulates vascular permeability
Lysosomal Enzymes of Leukocytes
Neuropeptides
Neuropeptides
Small proteins
Secreted by nerve fibers mainly in lung & GIT
Initiate inflammatory response
e.g. Substance P :
Transmits pain signals
Regulates vessel tone
Modulates vascular permeability
Chemical Mediators
of Inflammation
Cell-Derived
Plasma-ProteinDerived
Complement
Coagulation and Kinin
Systems

A variety of phenomena in the inflammatory response
are mediated by plasma proteins that belong to three
interrelated systems
1. Kinin
2. the complement
3. clotting systems
Kinin & clotting systems
enhanced
leukocyte
adhesion &
activation
increases vascular
permeability, pain
increases vascular
permeability,
Chemotaxis
Complement System
C3a & C5a  Increase vascular permeability (^ histamine)
anaphylatoxins
C5a 
Chemotaxis
C3b 
Opsonization
C5-9 
membrane attack complex
Role of Mediators in
Different Reactions of
Inflammation
Vasodilation
Prostaglandins
Histamine
Nitric oxide
Increased vascular
permeability
Vasoactive amines
Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
Chemotaxis, leukocyte
recruitment and
activation
C5a
Leukotriene B4
Chemokines
IL-1, TNF
Bacterial products
Fever
IL-1, TNF
Prostaglandins
Pain
Prostaglandins
Bradykinin
Tissue damage
Neutrophil and macrophage
lysosomal enzymes
Oxygen metabolites
Nitric oxide
Acute inflammation may have one of the four
outcomes:





Complete resolution
Healing by connective tissue replacement (fibrosis)
Progression of the tissue response to chronic
inflammation
Abcess formation
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Events in the resolution of
inflammation
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