Inflammation

Benito K. Lim Hong III, M.D.

 Objectives

1. Understand the chain, progression, or

sequence of vascular and cellular events in the
histologic evolution of acute inflammation.
2. Learn the roles of various “chemical
mediators” of acute inflammation.
 Objectives
3. Know the three possible outcomes of acute
inflammation.
4. Visualize the morphologic patterns of acute
inflammation.
5. Understand the causes, morphologic patterns,
principle cells, minor cells, of chronic and
granulomatous inflammation.
 Sequence Of Events
• NORMAL HISTOLOGY  VASODILATATION 
INCREASED VASCULAR PERMEABILITY  LEAKAGE
OF EXUDATE  MARGINATION, ROLLING,
ADHESION  TRANSMIGRATION (DIAPEDESIS) 
CHEMOTAXIS  POLYMORPHONUCLEAR CELLS
ACTIVATION  PHAGOCYTOSIS: Recognition,
Attachment, Engulfment, Killing (degradation or
digestion)  TERMINATION  100% RESOLUTION,
SCAR, or CHRONIC INFLAMMATION are the three
possible outcomes
 Acute Inflammation
• “PROTECTIVE”
RESPONSE
•NON-specific
 Acute Inflammation
• VASCULAR EVENTS
• CELLULAR EVENTS (PMN or
PolyMorphonuclear Neutrophil,
Leukocyte?, “POLY”, Neutrophil,
Granulocyte, Neutrophilic Granulocyte
• “MEDIATORS”
Acute Inflammation
 Neutrophil
 Polymorphonuclear
Leukocyte, PMN, PML
 “Leukocyte”
 Granulocyte,
Neutrophilic granulocyte
 “Poly-”
 Polymorph
 HISTORICAL
HIGHLIGHTS
(Egypt, 3000 BC)

1. Rubor (Redness)
2. Calor (Heat)
3. Tumor (Swelling)
4. Dolor (Pain)
5. 5th (Functio laesa)
 Stimuli for Acute
Inflammation
1. Infectious
2. Physical
3. Chemical
4. Tissue Necrosis
5. Foreign Bodies (FBs)
6. Immune “responses”, or “complexes”
 Differentiation
Exudate Transudate
1. High protein 1. Low protein
concentration concentration
2. Much cellular debris 2. Ultrafiltrate of blood
3. Specific Gravity above plasma
1.020 3. Specific Gravity below
1.012
4. Result from hydrostatic
imbalance across the
vascular endothelium
 Exudation

• The escape of fluid, proteins, & blood cells

from the vascular system into the interstitial
tissue or body cavities.
 Edema

• Denotes an excess of fluid in the interstitial

tissue or serous cavities; it can either an
exudate or a transudate.
 Pus

• A purulent inflammatory exudate rich in

leukocytes & parenchymal cell debris.
 Vascular Changes

• Changes in Vascular Flow and

Caliber
• Increased Vascular
Permeability
Increased Permeability
• Dilatation
• Endothelial “gaps”
• Direct Endothelial Injury
• Leukocyte Injury
• Transocytosis (endo/exo)
• New Vessels
LEAKAGE OF PROTEINACEOUS
FLUID ( EXUDATE, NOT
TRANSUDATE)
 Extravasation of
Polymorphonuclear Cells
• MARGINATION
(PMN’s go toward
wall)
• ROLLING (tumbling
and HEAPING)
• ADHESION
• TRANSMIGRATION
(DIAPEDESIS)
 Adhesion Molecules
(glycoproteins) affecting
Adhesion and Transmigration
1. SECRETINS (from endothelial
cells)
2. INTEGRINS (from many cells)
 Chemotaxis

Polymorphonuclear cells going

to the site of “injury”
After transmigration
 Leukocyte “Activation”
• Triggered by the offending stimuli for PMNs to:
1. Produce eicosanoids (arachidonic acid
derivatives)
a. Prostaglandin (and thromboxanes)
b. Leukotrienes
c. Lipoxins
2. Undergo Degranulation
3. Secrete Cytokines
 Phagocytosis

1. Recognition
2. Engulfment
3. Killing
(Degradation/
Digestion)
 Chemical Mediators
• From plasma cells
• Have “triggering” stimuli
• Usually have specific targets
• Can cause a “cascade”
• Are short lived
 Classic Mediators
1. Histamine 8. Platelet Activating
2. Serotonin Factor (PAF)
3. Complement 9. Cytokines/Chemokine
s
4. Kinins
10.Lysosome
5. Clotting Factors
Constituents
6. Eicosanoids
11.Free Radicals
7. Nitric Oxide
12.Neuropeptides
 Histamine

• Mast Cells, Basophils

• POWERFUL Vasodilator
• Vasoactive “amine”
• IgE on Mast cell
 Serotonin
• (5HT, 5-Hydroxy-
Tryptamine)
• Platelets and
EnteroChromaffin Cells
• Also vasodilatation, but
more indirect
• Evokes N.O. synthetase
(a ligase) from arginine
 Complement System

• >20 components, in
circulating plasma
• Multiple sites of action, but
LYSIS is the underlying
theme
 Kinin System
• BRADYKININ is KEY component, 9 aa’s
• Bradykinin is a potent endothelium-
dependent vasodilator
• Also from circulating plasma
• Actions:
1. Increased vascular permeability
2. Smooth muscle contraction, NON vascular
3. Involved in the mechanism of pain
 Clotting Factors

• Also from circulating plasma

• Coagulation, i.e., production of fibrin
• Fibrinolysis
 Eicosanoids
(Arachidonic Acid Derivatives)
• Part of cell membranes
1. Prostaglandins (incl. Thromboxanes)
2. Leukotrienes
3. Lipoxins (new)
• Multiple Actions at many levels
 Prostaglandins
(Thromboxanes included)

1. Pain
2. Fever
3. Clotting
 Leukotrienes

1. Chemotaxis
2. Vasoconstriction
3. Increased Permeability
 Lipoxins

1. Inhibit chemotaxis
2. Vasodilatation
3. Counteract actions of leukotrienes
 Platelet-Activating Factor
(PAF)
• Phospholipid
• Produced in response to specific
stimuli by a variety of cell types,
including neutrophils, basophils,
platelets, and endothelial cells.
• ACTIVATE PLATELETS, powerfully
 Platelet-Activating Factor
(PAF)
• Potent phospholipid activator &
mediator of many leukocyte
functions, including
platelet aggregation and
degranulation, inflammation, &
anaphylaxis.
 Platelet-Activating Factor
(PAF)
• Also involved in changes to
vascular permeability, the
oxidative burst, chemotaxis of
leukocytes, as well as
augmentation of arachidonic
acid metabolism in phagocytes.
Cytokines/Chemokines
• CYTOKINES are PROTEINS produced by MANY
cells, but usually LYMPHOCYTES and
MACROPHAGES, numerous roles in acute and
chronic inflammation.
– TNFα, IL-1, by macrophages
• CHEMOKINES are small proteins which are
attractants for PMNs (>40), e.g., CXC, CC,
CX3C, XC families, PF-4, IL-8.
Cytokines/Chemokines

• TNFα - also called tumor necrosis factor, or

cachectin, is a substance that is destructive of
human tissues, and is a key player in
“cachexia”.
Cytokines/Chemokines

• Interleukin-1 was the first of many

interleukins discovered and generally
propagates the inflammatory response at
many levels and also has a significant effect
on T-cells.
 Nitric Oxide

• Potent vasodilator
• Produced from the action of nitric oxide
synthetase from arginine
 Lysosomal Constituents
• PRIMARY • SECONDARY
1. Also called 1. Also called SPECIFIC
AZUROPHILIC, or 2. Lactoferrin
NON-specific 3. Lysozyme
2. Myeloperoxidase 4. Alkaline
3. Lysozyme (Bact.) Phosphatase
4. Acid Hydrolases 5. Collagenase
 Lysosomal Constituents

• Myeloperoxidase
– Produces hypochlorous acid and tyrosyl
radical, are cytotoxic, so they are used by
the neutrophil to kill bacteria and
other pathogens.
– It is what makes pus look greenish yellow.
 Lysosomal Constituents

• Lactoferrin (LF)
– Also known as lactotransferrin (LTF), is
a globular multifunctional protein with
antimicrobial activity (bacteriocide,
fungicide).
 Lysosomal Constituents

• Lysozymes
– Also known as muramidase or N-
acetylmuramide glycanhydrolase, are a
family of enzymes (EC 3.2.1.17) which
damage bacterial cell walls by
causing hydrolysis.
 Free Radicals

1. O2 – (SUPEROXIDE)
2. H2O2 (PEROXIDE)
3. OH- (HYDROXYL RADICAL)

•VERY VERY DESTRUCTIVE

 Free Radicals
• Are generated through a variety of enzymatic
pathways as one of the main killing
mechanisms of microbes.
• Are just as toxic to human cells as they are
microbes.
• Ultimately, they all affect the NADPH system.
 Neuropeptides

• Produced in CNS (neurons)

1. SUBSTANCE P
2. NEUROKININ A
 Neuropeptides
• Substance P
– an 11 amino acid polypeptide tied into many
things including mood disorders, anxiety,
stress, reinforcement, respiration rate,
neurotoxicity, nausea, emesis, and pain.
 Outcomes of
Acute Inflammation

1. 100% complete RESOLUTION

2. SCAR
3. CHRONIC inflammation
Morphologic Patterns
of Acute Inflammation
(Exudate)
1. Serous (watery)
2. Fibrinous (hemorrhagic, rich in FIBRIN)
3. Suppurative (PUS)
4. Ulcerative
BLISTER, “Watery”, i.e., SEROUS
FIBRINOUS
 PUS
=
PURULENT

ABSCESS
=
POCKET
OF
PUS
=
NEUTROPHILS
PURULENT, FIBRINOPURULENT
ULCERATIVE
Chronic Inflammation
(MONOS)

“MONO”CYTE

LYMPHOCYTE MACROPHAGE
HISTIOCYTE
APC
 CAUSES of
CHRONIC INFLAMMATION

1. PERSISTENCE of Infection
2. PROLONGED EXPOSURE to insult
3. AUTO-IMMUNITY
 What does chronic
inflammation look like
microscopically?
Answer: Infiltrates of lymphs and monos
“peppering” normal histology.
Most auto-immune inflammations
are long standing, or “chronic”
clinically as well.
CHRONIC INFLAMMATION
Cellular Components

1. LYMPHOCYTES
2. MACROPHAGES (aka, HISTIOCYTES)
3. PLASMA CELLS
4. EOSINOPHILS
5. MAST CELLS
 Morphology

1. INFILTRATION
2. TISSUE DESTRUCTION
3. HEALING
Granulomatous Inflammation
• A form of chronic inflammation is characterized
by granulomas – small nodular collection of
modified macrophages. The latter when
modified acquire abundant pink cytoplasm &
are called epithelioid cells.
• Epithelioid cells may coalesce to form multi-
nucleated giant cells.
• Lymphocytes, plasma cells, neutrophils, &
central necrosis may also be present in a
granuloma.
 Granulomas in
Granulomatous Inflammation
• Know, ALWAYS, the FOUR cells of granulomatous
inflammation:
1. FIBROBLASTS
2. LYMPHOCYTES
3. HISTIOCYTES
4. “GIANT” CELLS
 Granulomas in
Granulomatous Inflammation
• The FOUR common types of granulomatous
infections:
1. TUBERCULOSIS
2. SARCOIDOSIS
3. FUNGI
4. FOREIGN BODIES
 Granulomas in
Granulomatous Inflammation
• The TWO types of granulomas:
1. Foreign body granulomas – incited by relatively
inert foreign bodies.
2. Immune granulomas – formed by immune T cell-
mediated reactions to poorly degradable antigens.
Lymphokines, principally γ-interferon from
activated T cells, cause transformation of
macrophages to epithelioid cells & multinucleate
giant cells.
GRANULOMAS
GRANULOMATOUS INFLAMMATION
 2 types of Granulomas

1. CASEATING (TB)
2. NON-CASEATING
 Lymphatic Drainage

• The drainage patters of acute or chronic

inflammation follow the same general
drainage patterns of tumor cells.
– SITE REGIONAL LYMPH NODES
Systemic Manifestations
(Non-Specific)
1. FEVER, CHILLS
2. C-Reactive Protein (CRP)
3. “Acute Phase” Reactants, i.e., α1-α2
4. Erythrocyte Sedimentation Rate (ESR)
increases
5. Leukocytosis
6. Pulse, Blood Pressure
7. Cytokine Effects, e.g., TNF(α), IL-1
C-Reactive Protein (CRP)
 A member of the class of acute phase
reactants as its levels rise dramatically during
inflammatory processes occurring in the body.
It is thought to assist in complement binding
to foreign and damaged cells and affect the
humoral response to disease. It is also
believed to play an important role in innate
immunity, as an early defense system against
infections.