Acute and Chronic

Inflammation
Dr. Pedrito Tagayuna
Department
Diagnosis

of

Pathology

and

Laboratory

HISTORY
Celsus 4 cardinal signs of inflammation
Virchow 5th cardinal sign
John Hunter inflammation is not a disease
but a response.
Julius Cohnheim 1st noted an inflamed
blood vessel
Elie Metchnikoff phagocytosis
Paul Erlich humoral immunity
Sir Tomas Lewis concept of chemical
substanceAA
INFLAMMATION
Complex reaction in the vascularized
connective tissue brought about
by exogenous and endogenous stimuli.
Fundamentally a protective response the
ultimate goal of which is to get
rid of the organism
STRUCTURES INVOLVED IN
INFLAMMATORY RESPONSE
Connective tissue cells
Circulating cells
Connective tissue matrix
CONNECTIVE TISSUE CELLS
Mast cells
Fibroblasts
Macrophage
CIRCULATING CELLS
Neutrophils
Monocytes
Eosinophils
Lymphocytes
Basophils
Platelets
CONNECTIVE TISSUE MATRIX
Endothelium
Basement membrane

Type IV collagen
Laminin
Finronectin
Proteoglycans
Elastic fibers
Collagen fibers
Proteoglycans
PATTERNS OF INFLAMMATION
Acute
Short duration
Exudation of fluid and plasma protein
Emigration of leukocyte (neutrophils)
Chronic
Mononuclears
Proliferation of blood vessels
Fibrosis
Tissue necrosis

ACUTE INFLAMMATION
3 MAJOR COMPONENTS OF ACUTE
INFLAMMATION
Alteration in vascular caliber that lead to an
increase in blood flow.
Structural changes in microvasculature that
permit the plasma proteins
and leukocytes to leave the circulation.
Emigration
of
leukocyte
from
the
microcirculation and their
accumulation in the focus of injury.
STIMULI FOR ACUTE INFLAMMATION
Infections
Bacterial, viral, fungal, parasitic
Microbial toxins
Tissue necrosis
Ischemia, trauma, physical
chemical injuries
Foreign bodies
Spinsters, dirt, sutures
Immune reactions
Hypersensitivity reactions
Autoimmune disease

and

VASCULAR CHANGES
Changes in vascular flow and caliber
Inconstant
and
transient
vasoconstriction,
followed
by
vasodilation.
Slowing of the circulation - stasis
Leukocyte
margination,
rolling,
migration

Increased vascular permeability

Formation of endothelial gaps in
venules
15 to 30 minutes, immediate
transient response
Delayed prolonged leakage, 2
to 12 hours
Mild injury, ei.gi after
burns, X-radiation, UV
radiation)
Cytoskeletal
reorganization
(endothelial retraction)
Increased transcytosis
Direct endothelial injury
Delayed prolonged leakage
Leukocyte mediated endothelial injury
Leakage from new blood vessels

INTEGRINS
ICAM 1 - integrins , LFA-1, MAC 1
VCAM 1 a4B1 (VLA -4) & a4B7
MECHANISM
Redistribution of adhesion molecules to the
cell surface.
Induction of the adhesion molecules on
endothelium
Increase avidity of binding
STEPS OF NEUTROPHIL ADHESION
Endothelial activation
Rolling
Firm Adhesion
Transmigration

CELLULAR EVENTS
Leukocyte extravasation and Phagocytosis
Adhesion and transmigration
Chemotaxis
Leukocyte activation
Phagocytosis
SEQUENCE OF EVENTS IN
EXTRAVASATION
Lumen: margination, rolling & adhesion.
Diapedesis
Migration in interstitial tissues towards a
chemotactic stimulus.
ADHESION & TRANSMIGRATION
Four
molecular
families
of
molecules:
Selectins
Immunoglobulins
Integrins
Mucin-like glycoproteins

adhesion

SELECTINS:
Characterized by an extracellular N terminal
domain related to sugar
binding mammalian lectins
E selectin- ELAM 1- endothelium
P selectin GMP140 or PADGEM
endothelium & platelets
L selectin LAM 1 most leukocytes
IMMUNOGLOBULINS:
Intercellular adhesion molecule 1 (ICAM 1)
Vascular cell adhesion molecule 1 (VCAM 1)

ADHESION MOLECULE DEFICIENCY

Leukocyte adhesion deficiency 1 defect in
the biosynthesis of the Beta
2 chain shared by LFA1 & MAC 1
Leukocyte adhesion deficiency 2- absence of
sialyl-Lewis X, ligand for Eselectin,
generalized defect in fucose metabolism
LEUKOCYTE DIAPEDESIS
Occurs predominantly in the venules except in
the lungs where it also
occurs in the capillaries.
CHEMOTAXIS
Locomotion along a chemical gradient
Exogenous
bacterial products
Endogenous
Complement C5a

Lipooxygenase pathway, LTB4

Cytokines, IL8
PHAGOCYTOSIS
Recognition and attachment of the particle to
be ingested by the
leukocyte.
Engulfment with subsequent formation of the
phagocytic vacoule.
Killing and degradation of the ingested
material.
RECOGNITION OF MICROBES AND DEAD
TISSUES
Events in the Response of leukocytes:
Recognition of the offending agents
Activation of leukocytes to ingest and
destroy
Receptors for microbial products

Toll-like receptors (TLRs)
G protein-coupled receptors
Found on neutrophils, macrophages
Receptors for opsonins
Receptors for cytokines
Interferon gamma secreted by natural
killer cells
RECOGNITION AND ATTACHMENT
Opsonins
naturally occurring factors that coats
the microorganisms to be recognized
Enhance
the
efficiency
of
phagocytosis.
MAJOR OPSONINS
Fc fragment of IgG
C3b opsonic fragment of C3
Mannan-binding lectin (Carbohydrate binding
protein)
RECEPTORS ON LEUKOCYTES
FcyR recognize the Fc fragment of IgG
Complement receptors 1,2 & 3 interact with
C3b & C3bi
C1Q R binds to collectins
CR3 recognizes C3bi
Identical with the Beta2 integrin
(MAC1/CD11b) involved in the adhesion of
Endothelium
ENGULFMENT
Binding of the opsonized particle to the FcyR
triggers engulfment

Complement Receptors markedly enhance

engulfment
STEPS IN PHAGOCYTOSIS

1. Recognition and attachment

2. Engulfment
3. Killing and degradation of the ingested
material
KILLING AND DEGRADATION
O2 dependent mechanisms
Burst in O2 consumption, glycogenolysis,
increase glucose oxidation via
the HMP shunt and production of reactive
oxygen metabolites
GENERATION OF O2 METABOLITES
Oxidase
Superoxide
KILLING AND DEGRADATION
Reactive oxygen species (ROS)
NADPH
oxidized
by
NADPH
oxidase(a.k.a. phagocytic oxidase)
In the process reduces O2 to
superoxide anion
Respiratory burst
Reactive nitrogen species
Derived from NO
NO reacts with superoxide =
peroxynitrite
Attacks and damage lipids,
proteins and nucleic acids of
microbes

H2O2 MPO Halide System

H2O2
(lysozomes)
+
Myeloperoxidase
(azurophilic granules of
neutrophils) in the presence of Cl- =
hypochlorite
Most
efficient
bactericidal
system
in
neutrophils
H2O2 may also be converted to hydroxyl
radical
Fungi,viruses, protozoa and helminths
BACTERICIDAL KILLING DUE TO
NEUTROPHIL GRANULES
Bactericidal permeability increasing protein
Lysozyme
Lactoferrin
Major Basic Protein
Defensins

DEFECTS IN LEUKOCYTE FUNCTION

Defects in leukocyte adhesions.
Defects in Phagocytosis.
Defects in microbicidal activity
DEFECTS IN LEUKOCYTE ADHESIONS
Genetic deficiencies in leukocyte adhesion
molecules (LAD 1 & 2).
LAD 1

DEFECTS IN PHAGOCYTOSIS
Chediak-Higashi Syndrome
Defective fusion of phagosomes and
lysosomes
Neutrophils have giant granules
Reduced
transfer
of
lysosomal
enzymes to phagocytic vacuoles
Affects melanocytes, cells of
the nervous system and platelets.
DEFECTS IN MICROBICIDAL ACTIVITY
Chronic Granulomatous Disease
Congenital / inherited defects in
genes encoding several components of NADPH
oxidase which generates superoxide.

LEUKOCYTE-MEDIATED TISSUE INJURY

Lysosomal enzymes, ROS and NO
collateral damage
Autoimmune disease
Allergic diseases
CLINICAL
EXAMPLES
LEUKOCYTEINDUCED
INJURY
Acute
ARDS
Acute Transplant Rejection
Asthma
Glomerulonephritis
Reperfusion injury
Septic Shock
Vasculitis
Chronic
Arthritis
Asthma
Atherosclerosis
Chronic Lung Disease
Chronic rejection

recurrent
bacterial
infection
&
impaired wound healing.
Deficiency in Beta2 integrins (CD 18)
LAD 2
Absence of Sialyl- Lewis X
clinically milder than LAD 1
Recurrent bacterial infection

OF

ACQUIRED DEFICIENCIES
Bone Marrow suppression
Decreased function of leukocytes
following radiation and chemotherapy, leukemia
and bone metastases of tumors
CHEMICAL
MEDIATORS
OF
INFLAMMATION
originate either from plasma or from cells.
Major
cell
types:
platelets,
neutrophils,
monocyte/macrophages, mast cells
Mesenchymal
cells
(endothelium,
smooth muscle,
fibroblasts) can also be induced to produce
Plasma-derived
(complements,
protein, kinins)
Precursors are inactive in
plasma
CHEMICAL
MEDIATORS
OF
INFLAMMATION
can stimulate the release of mediators by
target
cells themselves.
Once activated and released from the cells,
most of
these are short-lived.

Most have the potential to cause harmful

effects.
Sequestered in intracellular granules that
need to
be secreted e.g. Histamine in mast cells
Synthesized de novo e.g. Prostaglandins &
Cytokines
CHEMICAL MEDIATORS
Vasoactive Amines
Plasma Proteases
Arachidonic Acid Metabolites
Platelet activating factors
Cytokines & Chemokines
Nitric Oxide
VASOACTIVE AMINES
Histamine
Present in mast cells near connective
tissues adjacent to blood vessels
Stimuli for Release:
Physical injury,
binding of antibodies to mast
cells
Fragments of complements
C3a & C5a
Histamine releasing proteins
derived from leukocytes
Neuropeptides Substance P
Cytokines- IL1 & IL 8
Dilation of arterioles and increase vascular
permeability mediated by binding to H1
receptors of microvascular endothelial cells
SEROTONIN
5- hydroxytryptamine
Platelets and neuroendocrine cells
Preformed vasoactive mediator
actions similar to histamine
PLASMA PROTEASES
Complement System
Kinin system
Clotting system

BIOLOGIC EFFECT OF COMPLEMENT

FRAGMENTS:
C3 & C5 most important inflammatory
mediators
Vascular phenomena (release of histamine,
increased vascular
permeability&vasodilation) C3a, C5a, C4a
(anaphylotoxins)
Leukocyte adhesion, chemotaxis & activation
C5a
Phagocytosis C3b & C3bi(inactive)
Cell lysis
MAC

THE KININ SYSTEM

Generate vasoactive peptides from plasma
proteins
called Kininogens by kallikriens.
Bradykinins
vasoactive nonapeptide
Increased vascular permeability
Contraction of smooth muscle,
dilatation of blood
vessels & pain
Activation of Hageman factor of the
Intrinsic clotting
Pathway

KALLIKRIENS
Potent activator of Hageman factor
Chemotactic activity: direct conversion of C5
to C5a

FIBRINOLYTIC SYSTEM
Counter balances clotting by cleaving fibrin
solubilizing the fibrin clot
Plasmin
important in lyzing clot
Cleaves C3 to produce C3 fragments,
and it degrades fibrin to form fibrin split
products, which may have permeabilityinducing properties
ARACHIDONIC ACID METABOLITES

20 carbon polyunsaturated fatty acid

ANTI-INFLAMMATORY THERAPY
Aspirin & NSAIDS (indomethacin or ibuprofen)
inhibit cyclooxygenase
Glucocorticoids
down-regulating
the
expression of specific target
agents including COX2
Fish Oil poor substrate for conversion to
active metabolites of the
cyclooxygenase & lipooxygenase series

PLATELET ACTIVATING FACTORS

Phospholipid derived mediator
Cells that elaborate PAF
Platelets
Basophils (Mast cells)
Neutrophils
Monocyte/Macrophage
Endothelial cells
PLATELET ACTIVATING FACTOR
Vasoconstriction
Bronchoconstriction
Vasodilation
Increased vascular permeability
Increase leukocyte adhesion to endothelium
Chemotaxis
Degranulation
Oxidative burst

CYTOKINES & CHEMOKINES

Cytokines proteins produced by many cell
types, endothelium &
connective tissues that modulate the function of
other cell types.
Chemokines cytokines that share the ability
to stimulate leukocyte
movement ( chemokinesis) and directed
movement (chemotaxis)
Monokines monocyte
Lymphokines activated lymphocytes
Interleukins broad family of cytokines that
are
produced by hematopoeitic cells & act primarily
on
leukocytes
Growth factors growth promoting properties
GENERAL PROPERTIES &
FUNCTIONAL CLASSES OF
CYTOKINES:
Secretion is transient & closely regulated
Many cells produce multiple cytokines
Proteins are pleotrophic
Redundant effects
Produce +/- regulatory effects
5 CLASSES OF CYTOKINES
Cytokines that regulate lymphocyte growth
Cytokines that are involved in Natural
Immunity
Cytokines that activate inflammatory response
Chemokines
Cytokines that stimulate hematopoiesis
REGULATE LYMPHOCYTE FUNCTIONS:
IL2 & IL 4 promotes lymphocyte growth
IL10 & TGF Beta Negative regulators of
Immune Response

NATURAL IMMUNITY
TNF alpha
IL 1 B
Type I interferons (IFNa & IFN b)
IL6
ACTIVATE INFLAMMATORY RESPONSE:
IFN gamma
TNF alpha
TNF beta
IL5
IL10
IL12
STIMULATE HEMATOPOEISIS
IL3, IL7
c kit ligand
GSF
MSF
Stem cell factors
ACUTE PHASE REACTANTS
Fever
Increased sleep
Decreased appetite
Increased acute phase proteins
Hemodynamic effects
Neutrophilia
SYSTEMIC EFFECTS OF INFLAMMATION
(ACUTE-PHASE RESPONSE)
Fever
Acute-phase proteins
Leukocytosis
Other manifestations
Sepsis, in severe large amount or in
debilitated patientsnts of organisms
and LPS in the blood
SYSTEMIC EFFECTS OF INFLAMMATION
(ACUTE-PHASE RESPONSE)
Fever
Elevation 1 to 4 C
Most prominent
Caused by pyrogens resulting to the
resetting of the temperature set point
SYSTEMIC EFFECTS OF INFLAMMATION
(ACUTE-PHASE RESPONSE)
Acute-phase proteins
CRP, fibrinogen, Serum Amyloid A
(SAA) protein
Acts as opsonins

SYSTEMIC EFFECTS OF INFLAMMATION

(ACUTE-PHASE RESPONSE)
Leukocytosis
15,000 to 20,000 cells/uL
40,000 - 100,000 cells/uL Leukemoid
reaction
Accelerated release
Shift to the left
Neutrophilia,
generally
bacterial
Lymphocytosis, generally viral
Eiosinophilia, allergic reaction,
asthma parasitic infections
Leukopenia in some infections
like typhoid fever
Other manifestations
Increased pulse and blood pressure
Decreased sweating
Rigors (shivering)
Chills
Anorexia
Somnolence
malaise
Sepsis, in severe large volume of infectious
agent or in debilitated
patients and LPS in the blood
ENDOTHELIAL EFFECTS
Increased leukocyte adherence
Increased PGI synthesis
Increased procoagulant activity
Decreased anticoagulant activity
Increased IL1, IL6, PDGF
FIBROBLAST EFFECTS
Increased proliferation
Increase collagen synthesis
Increased collagenase
Increased proteases
Increase PGE synthesis
LEUKOCYTE EFFECTS
Increase cytokine secretion
Priming
CHEMOKINES
Superfamily of small (8-10kD) proteins that
act primarily as activators &
chemoattractants for specific types of leukocytes

4 MAJOR CLASSES OF CHEMOKINES

C-X-C or alpha chemokines
acts primarily on neutrophils
IL8 typical of this group
IL1 & TNF a - inducers
C-C or beta chemokines
attract
mononytes,
eosinophils,
basophils and lymphocytes
C or Gamma chemokines relatively specific
for lymphocytes
CX3C chemokines
NITRIC OXIDE
Pleiotrophic mediator of inflammation
Released by endothelial cells causing
Vasodilation (EDRF)
Soluble gas produced by macrophage &
neurons of the brain
3 TYPES OF NO SYNTHASE
Endothelial (eNOS)
Neuronal (nNOS)
Cytokine inducible (iNOS)
MORPHOLOGIC PATTERNS OF
INFLAMMATION
 Morphologic hallmarks of all acute
inflammatory reactions:
 Dilation of small blood vessels,
slowing of blood flow, accumulation of
leukocytes and fluid
in the extravascular tissue
 Serous inflammation
 Fibrinous inflammation
 Suppurative or Purulent inflammation
 Ulcers
SEROUS INFLAMMATION
 Marked by outpouring of a thin fluid from the
plasma or secreted by
mesothelial cells
 Effusion, accumulation of fluid in cavities
 Skin blisters from burns
FIBRINOUS INFLAMMATION
 Fibrin is formed and deposited in the
extravascular space
 Fibrinous exudate is formed if the vascular
leak is large or if there is
procoagulant stimulus (cancer cells)
 Characteristic inflammation in the lining
cavities: meninges, pericardium
and pleura

 Removed by fibrinolysis
 May undergo organization to form scar tissue
SUPPURATIVE/PURULENT
INFLAMMATION
 Production of large amount of pus or purulent
exudate consisting of
neutrophils, liquefactive necrosis and edema
fluid.
 Acute appendicitis, common example
 Abscess localized collection of purulent
inflammatory tissue
 Produced by deep seeding of a
pyogenic bacteria into a tissue
 In time abscess may be walled off
and replaced by connective tissue
ULCERS
 Local defect or excavation of the surface of
an organ or tissue that is
produced by the sloughing/shedding of inflamed
necrotic tissue
 Occur only when tissue necrosis and
inflammation exist on or near a
surface
 Best exemplified by peptic ulcer
OUTCOMES OF ACUTE INFLAMMATION:
 Complete resolution
 Fibrosis
 When there is substantial tissue
destruction, incapable of regeneration
fibrin
exudation that cannot be adequately
cleared
 Connective tissue grow into the area
of damage
 Progression to Chronic Inflammation

CHRONIC INFLAMMATION
Causes:
1. Persistent infections
Mycobacteria, fungi, parasites
2. Immune-mediated inflammatory diseases
Autoimmune diseases
Ex. RA & MS
3. Prolonged exposure to toxic agents, either
exogenous or endogenous
Exogenous: silica
Endogenous: atherosclerosis

Histologic
features
of
Chronic
Inflammation
 Infiltration with Mononuclear cells
(Chronic Inflammatory Cells)
 Macrophages, lymphocytes &
plasma cells
 Tissue Destruction
 Destruction of Parenchyma
induced by persistent offending agent or
by inflammatory cells
 Replacement by Connective tissue

Accomplished
by
angiogenesis and fibrosis
MACROPHAGE
 Predominant cell in chronic inflammation
 Derived from blood monocyte
 Life span:
 Monocyte 1 day
 Macrophage several weeks

 Microscopic aggregation of macrophages that

are transformed into
epithelium like cells surrounded by collar of
mononuclear leukocytes,
lymphocytes and occasionally plasma cells.
 Rim of fibroblasts & connective tissue
 Giant cells
TYPES OF GRANULOMA
 Foreign body granuloma
 Incited by inert foreign body
 Immune granulomas
 Cell-mediated immune response
 Inciting agent is poorly degradable,
HALLMARK OF CHRONIC INFLAMMATION
 Tissue destruction

----------------------

F.R.2011
MECHANISM OF MACROPHAGE
ACCUMULATION:
 Continued recruitment of monocyte from the
circulation
 Local proliferation of macrophage
 Immobilization of macrophage
OTHER CELLS IN CHRONIC
INFLAMMATION
 Lymphocytes Types:
 T & B lymphocytes
 States: Activated or Memory
 Plasma cells
 Mast cells
 Eosinophils
GRANULOMATOUS INFLAMMATION
 Distinct pattern of chronic inflammatory
reaction in which the
predominant cell type is an activated
macrophage with a modified
epithelial appearance
 Cellular attempt to contain an offending
agent
 Often there is strong activation of T
lymphocytes leading to macrophage
activation
 TB is the prototype
GRANULOMA
 Focal area of a granulomatous inflammation

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