Lecture 12:

Morphologic Patterns of Acute

Inflammation
 Morphology of acute inflammation
• Characteristically, the acute inflammatory
response involves production of exudates.
• Several types of inflammation vary in their
morphology and clinical correlates. Why?
– The severity of the reaction
– specific cause
– the particular tissue
– site involved
 Morphologic types of acute
inflammation
1 Serous inflammation

2 Fibrinous inflammation

3 Suppurative inflammation

4 Ulcers
1. Serous inflammation
• Characterized by the
outpouring of a thin
fluid / watery poor
protein fluid.
– Blood serum
– Secretion of mesothelial
cells lining the cavities.
• Fluid in a serous cavity is
called an effusion.
• Example:
• Skin blister resulting from
– burn
– viral infection
2. Fibrinous inflammation
• Consequence of more severe injuries.
• Resulting in greater vascular permeability.
– Allows large molecules (such as fibrinogen) to pass
the endothelial barrier.
• A fibrinous exudate is
characteristic of inflammation
in the lining of body cavities
Degraded by fibrinolysis.
Definitions …
• Resolution :
» Accumulated debris that removed by
macrophages, resulting in restoration of the
normal tissue structure.

• Organization :
» Extensive fibrin-rich exudates may not be
completely removed, and are replaced by an
ingrowth of fibroblasts and blood vessels,
leading ultimately to scarring that may have
significant clinical consequences.
3. Suppurative inflammation
• Purulent inflammation
• It is characterized by the production of a large
amount of pus.
• Pus: is a thick creamy liquid, yellowish or blood
stained in colour and composed of;
– A large number of living or dead leukocytes (pus cells)
– Necrotic tissue debris
– Living and dead bacteria
– Edema fluid
4. Ulcers
• An ulcer is a local defect of the surface of an
organ or tissue that is produced by the sloughing
(shedding) of inflammatory necrotic tissue

Epithelial Defect

Necrotic base
Fibrinopurulent exudates

9
What are mediators?

• Chemical mediators of inflammation are

substances produced during inflammation inducing
a specific events in acute inflammation.
• Chemical mediators that are responsible for
vascular and cellular events in acute inflammation.
General principles for mediators…
 The production of active mediators is
triggered by:

1) Microbial products
2) Host proteins
– proteins of the complement
– kinin
– coagulation systems

 Mediators produced locally by cells or from

plasma protein derived.
General principles for
mediators…
Most mediators act by binding to specific
receptors on different target cells.
– Such mediators may act on only one or a very few
cell types
– Other mediators (e.g., lysosomal proteases, ROS)
have direct enzymatic and/or toxic activities that
do not require binding to specific receptors.
General principles for
mediators…

Most mediators have the potential to cause

harmful effects.
– Therefore, there should be a mechanism to
checks and balances their action.
General principles for
mediators…
Mediator function is tightly regulated by:
• Decay
– (e.g. Arachidonic acid metabolites)
• Inactivated by enzymes
– (kininase inactivates bradykinin)
• Eliminated
– ( antioxidants scavenge toxic oxygen metabolites)
• Inhibited
– (e.g., Complement regulatory proteins block complement
activation).
 Source of mediators

Cell-derived: Plasma-derived:
1. Synthesized as needed 1. Complement
(prostaglandin) 2. kinins
2. Preformed, 3. coagulation factors
sequestered and
released (mast cell – Many in “pro-form”
histamine) requiring activation
(enzymatic cleavage)
 Chemical Mediators of Inflammation

Cell-Derived Plasma-Protein-Derived
Vasoactive Amines
Complements
Eicosanoids

PAF Coagulation and

Kinin Systems
Cytokines

Chemokines

ROS

NO

Lysosomal Enzymes of Leukocytes

Neuropeptides
 Cell- Derived Mediators
• Producing cells:
– Tissue macrophages
– Mast cells
– Endothelial cells
– Leukocytes
Cell-Derived Mediators
 1. Vasoactive Amines

• Histamine & Serotonin

• Among first mediators in acute inflammatory reactions
• stored as pre- formed molecules in mast cells and
other cells.
Vasoactive Amines
 Histamine
• Source:
– Mast cells
– Circulating basophils
– Platelets
• Stimuli of Release:
1. Physical injury
– Heat, Trauma
2. Immune reactions
– IgE antibodies bind to Fc receptors on mast cells
3. C3a and C5a fragments
4. Leukocyte-derived histamine- releasing proteins
5. Neuropeptides
6. Cytokines (e.g. IL-1 and IL-8)
 Histamine…
• Actions:
1. Arteriolar dilation
2. Increased vascular permeability (venular gaps)
• Inactivated by:
• Histaminase
 Serotonin (5- HT)

• 5-hydroxytryptamine
• It is produced mainly in some neurons
• It is a neurotransmitter
• Source:
– Platelets
• Action:
– It induces vasoconstriction during clotting.
• Stimulus:
– Platelet aggregation
 2. Arachidonic Acid Metabolites
• Prostaglandins, Leukotrienes, and Lipoxins
• Known as eicosanoids  Greek  eicosa  twenty.
– derived from 20-carbon fatty acids
• Source:
• Component of cell membrane phospholipids.
• Leukocytes, mast cells, endothelial cells, and platelets
• Stimuli/ Activated by:
• Their synthesis is increased at sites of inflammatory response.
• Mechanical, chemical, or physical stimuli.
• Inflammatory mediators such as C5a.
• Phospholipases.

• Two enzymatic pathways:

1. Cyclooxygenase
• Prostaglandins and Thromboxanes
2. Lipoxygenase
• Leukotrienes and Lipoxins
• Functions:
 Anti-inflammatory Drugs That Block
Prostaglandin Production
• Nonsteroidal anti-inflammatory drugs
(NSAIDs)
• Inhibit cyclooxygenase activity
– By blocking all prostaglandin synthesis
– Their ability in treating pain and fever.
• Examples of NSAIDs
– aspirin
– ibuprofen
3. Platelet – Activating Factor
• Source:
• Membrane phospholipids of neutrophils, monocytes,
basophils, endothelial cells, and platelets (and other cells)
• Stimuli:
• Phospholipase A2.
• Function:
• Induce vasodilation
• Induce increased vascular permeability.
• Stimulates the synthesis of other mediators
– Eicosanoids
– Cytokines
• Enhance leukocyte adhesion and chemotaxis
 4. Cytokines
• Polypeptides
• Molecularly characterized cytokines are
called interleukins
• Functions:
• Involved in early immune and inflammatory
reactions
• Some stimulate bone marrow precursors to
produce more leukocytes
 TNF and IL- 1
• Tumor Necrosis Factor and Interleukin-1
• Source:
• Activated macrophages, mast cells, and
endothelial cells.
• Stimuli:
• Bacterial endotoxin
• Immune complexes
• Inflammasome activation
 TNF and IL- 1 …
• Function:
• The expression of adhesion molecules on
endothelial cells
• Enhance the production of additional
cytokines and eicosanoids.
• TNF  increases the thrombogenicity of
endothelium.
 5. Chemokines
• Small proteins  8 to 10 kDa
• They are chemoattractants for leukocytes

• Functions:
• Leukocyte recruitment to the site of
inflammation.
 Chemokines …
• Chemokines binds to specific G protein-coupled
receptors on target cells.
• Two chemokine receptors:
• CXCR4 and CCR5
• Important co- receptors for the binding and
entry of the human immunodeficiency virus
into lymphocytes
 Chemokines …
• Chemokines are classified into four groups
based on the arrangement of conserved
cysteine residues.
• The two major groups of chemokines.
– CXC chemokines
– CC chemokines
 6. Reactive Oxygen Species
(ROS)
• Synthesized via
• NADPH oxidase pathway
• Nicotinamide adenine dinucleotide phosphate oxidase
• Source:
• Neutrophils and Macrophages
• Stimuli of release:
• Microbes
• Immune complexes
• Cytokines
• Function:
• Microbicidial (cytotoxic) agent
 Reactive Oxygen Species …
• At low levels:
• Increase chemokine, cytokine, and adhesion molecule
expression
• At high levels:
• Responsible for tissue injury by several mechanisms
including:
– (1) endothelial damage, with thrombosis and increased
permeability
– (2) protease activation and anti- protease inactivation
– (3) direct injury to other cell types (e.g., tumor cells, red
cells, parenchymal cells).
• Antioxidant protective mechanisms
• Catalase, superoxide dismutase, and glutathione
 7. Nitric Oxide (NO)
• Short-lived
• Soluble free-radical gas
• Regulates neurotransmitter release
• Regulates blood flow.
• Functions:
• Vasodilation
• Antagonism of platelet activation
– adhesion, aggregation, & degranulation
• Reduction of leukocyte recruitment
• Microbicidial (cytotoxic) agent in activated
macrophages
 8. Lysosomal Enzymes of
Leukocytes
• Source:
• Neutrophils & Monocytes
• Enzymes:
• Acid proteases
• Neutral proteases (e.g. elastase, collagenase, &
cathepsin)

• Limited by anti – proteases present in the plasma and

tissue fluids.
• Example of anti – proteases:
– α1-antitrypsin inhibitor of neutrophil elastase.
– α2-macroglobulin.
 9. Neuropeptides
• Small proteins
• Secreted by nerve fibers mainly in lung & GIT

• Initiate inflammatory response

• e.g. Substance P

• Transmits pain signals

• Initiate inflammatory responses

• Modulates vascular permeability
Plasma – Protein Derived
 1. Complement proteins
• Complement system consists of plasma
proteins
• Play an important role in host defense
(immunity) and inflammation.
• Function:
– Opsonization
– Increase vascular permeability and
– Induce Leukocyte chemotaxis
 Complement proteins …

• C3a & C5a  Increase vascular permeability (^

histamine)
• C5a  Chemotaxis

• C3b  Opsonization

• C5-9  membrane attack complex (attack

membranes of invading microbes by making
holes)
Complement System
 2. Coagulation and Kinin
Systems
• Activated during blood clotting.
• Responsible for inflammation.
• Hageman factor
– known as factor XII of the coagulation cascade.
• Protein synthesized by the liver.
Coagulation and Kinin Systems …

• Function:
• Initiates four systems:
❶ The kinin system
– Producing vasoactive kinins
– Bradykinin  increased vascular permeability,
arteriolar dilation, Pain.
» short-lived because
» rapidly degraded by kininases
Coagulation and Kinin Systems …

❷The clotting system

– Inducing the activation of thrombin  enhanced
leukocyte adhesion.
– Activation of fibrinopeptides  increase vascular
permeability and are chemotactic for leukocytes.
– Activation of factor X Factor Xa  causes
increased vascular permeability and emigration.
Coagulation and Kinin Systems …
❸The fibrinolytic system
– Activated when clotting system is initiated by
Hageman factor.
– Limit clotting by cleaving fibrin, thereby solubilizing
the fibrin clot.

– Producing plasmin protease that

» cleaves fibrin
» Clots lysis
– Inactivating thrombin
– vasodilation and increased vascular permeability.
Coagulation and Kinin Systems …

❹The complement system

– producing the anaphylatoxins C3a and C5a.
– vasodilation and increased vascular permeability.