ACUTE and CHRONIC INFLAMMATION
GENERAL FEATURES of INFLAMMATION:
INFLAMMATION: - Complex reaction to injurious agents
(microbes , damaged & necrotic cells)
- Consists of Vascular responses (unique
feature of inflammation leading to
accumulation of fluid and leukocytes in
extravascular tissues),migration and
activation of leukocytes and systemic
reactions
- Mechanisms to get rid of these injurious
agents include ENTRAPMENT and
PHAGOCYTOSIS of offending agents by
Hemacytes and neutralization of noxious
stimuli through hypertrophy of the host
cell or its organelles.
- Inflammatory response is closely
intertwined with process of REPAIR
- Serves to destroy, dilute, or wall off
injurious agents and triggers series of
events that try to heal and reconstitute
damaged tissue (repair begins during
early phases of inflammation and reaches
completion after injurious influence has
been neutralized).
- a protective response (goal of which is
to rid organism of initial cause (toxins and
microbes) and consequences (necrotic
cells and tissues) of injury
1
- Absence of Inflammation would let
infections go unchecked and never heal
– might remain permanent lesions, though
inflammation and repair maybe
potentially harmful
- underlie common chronic diseases
(rheumatoid arthritis, atherosclerosis, lung
fibrosis, hypersensitivity reactions to insect
bites, drugs, and toxins)
- Repair by fibrosis – leads to disfiguring
scars or fibrous bands that may cause
intestinal obstruction or limit mobility of
joints
- ANTI-INFLAMMATORY DRUGS are
significant that would control the harmful
sequelae of inflammation but not interfere
with its beneficial effects
- consists of two main components:
1. Vascular Reaction
2. Cellular Reaction
Tissues and cells involved includes
* Fluids
* Plasma Proteins
* Circulating cells (neutrophils,
monocytes, eosinophils,
lymphocytes, basophils,
platelets)
* Blood Vessels,
2
* Cellular (mast cells, fibroblasts,
resident macrophage,
lymphocytes)
* Extracellular constituents of
connective tissue(collagen,
elastin, fibronectin, laminin ,
non-fibrillar collagen,
proteoglycans).
- divided in ACUTE and CHRONIC
INFLAMMATION
ACUTE INFLAMMATION:
- rapid in onset
- relatively of short duration(lasting for minutes, hours or
few days)
- main characteristic : exudation of fluid and plasma
proteins(edema)
- emigration of leukocytes (predominantly neutrophils).
- Rapid response to injurious agents that serves to deliver
mediators of host defense – LEUKOCYTES and
PLASMA PROTEINS
- 3 MAJOR COMPONENTS :
1. Vascular Caliber Alterations (leading to increase
blood flow)
3
2. Structural Changes in Microvasculature (permit
plasma proteins and leukocytes to leave
circulation)
3. Emigration of Leukocytes, their accumulation in
the site of injury and its activation to eliminate
offending agent.
EXUDATION: Escape of fluid, proteins and blood
cells from vascular system to interstitial tissue
and body cavities.
EXUDATE : Anti-inflammatory extravascular
fluid with
High protein concentration
Cellular debris
Sp. Gr - > 1.020
- Implies significant alteration n the
normal permeability of small vessels in the
area of injury
TRANSUDATE : Fluid with low protein content
(albumin)
Sp.Gr - <1.020
- essentially an ultrafiltrate of blood
plasma resulting from osmotic or
hydrostatic imbalance across vessel
wall without increase in vascular
permeability.
EDEMA :
Excess of fluid in the interstitial or
serous cavities (exudate or
transudate)
PUS : a purulent exudates/inflammatory
exudates filled with leukocytes
4
(neutrophils), dead cell, debris, microbes
STIMULI for ACUTE INFLAMMATION:
- INFECTIONS (bacterial, viral, parasitic) &
microbial toxins
- TRAUMA (blunt and penetrating)
- PHYSICAL & CHEMICAL AGENTS (thermal injury
/ frostbite, irradiation, environmental
chemicals)
- TISSUE NECROSIS
- FOREIGN BODIES (splinters, dirt, sutures)
- IMMUNE REACTIONS (hypersensitivity
reactions)
CHARACTERISTIC REACTIONS of ACUTE INFLAMMATION:
VASCULAR CHANGES
A. Changes in Vascular Flow and Caliber
1. Vasodilation:
- Earliest manifestation
- Follows transient constriction of
arterioles
- Initially involves arterioles then
opening of new capillary beds
- Increase blood flow causing heat
and redness
- induce by action of several
mediators (histamine, nitric
oxide)
- Increase permeability of
microvasculature –
outpouring of protein rich fluid into the extravascular
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tissues- Loss of fluid results in red cell concentration in small
vessels – increased viscocity of blood - slower blood flow
(STASIS) - with STASIS , leukocytes (neutrophils) accumulate
and stick along vascular endothelium – migrate through
vascular wall – interstitial tissue
2. Increased Vascular Permeability
(Vascular Leakage)
- Hallmark of Acute Inflammation
- Escape of protein-rich fluid
(exudate) into extravascular tissue
- Loss of protein from the plasma
reduces intravascular osmotic
pressure of interstitial fluid. Increase
hydrostatic pressure due to increase
blood flow through vessels leads to
outflow of fluid and accumulation in
the interstitial tissue – INCREASE of
EXTRAVASCULAR FLUID ---EDEMA
Mechanisms through which endothelium
become LEAKY in inflammation :
 Formation of Endothelial Gaps in
venules :
- most common mechanism of vascular
leakage (elicited by histamine,
bradykinin , leukotrienes, neuropeptide
substance P)
6
- occurs rapidly after exposure to
mediator and is reversible and short
lived
- known as IMMEDIATE TRANSIENT
RESPONSE
- affects venules 20-60 um diameter
(leaving capillaries and arterioles
unaffected).
- Gaps in venular endothelium are
largely intracellular
- Cytokines (Interleukin-1, Tumor Necrosis
Factor, Interferon-y) also increase
vascular permeability – inducing
structural reorganization of
cytoskeleton where endothelial cells
retract from one another.
 Direct Endothelial Injury resulting
in Endothelial Cell Necrosis and
detachment
- usually encountered in necrotizing
injuries due to endothelial damage
- Adherent endothelial neutrophils also
injure endothelial cells
- Leakage starts immediately after injury
and sustained at high level until
damaged vessels are thrombosed or
repaired (IMMEDIATE SUSTAINED
RESPONSE)
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- All levels of the microcirculation are
affected includes venules, capillaries,
arterioles.
- Endothelial detachment associated
with platelet adhesion and thrombosis.
 Delayed Prolonged Leakage
- Begins after a delay of 2-12 hours, lasts
for several hours or days and involves
venules and capillaries
- Leakage is caused by mild to
moderate thermal injury, x-radiation, UV
radiation, certain bacterial toxin
- Late-appearing sunburn is a delayed
reaction
- Result from direct effect of the injurious
agent leading to delayed endothelial
cell damage or the effect of cytokines
causing endothelial retraction
 Leukocyte-Mediated Endothelial
Injury
- Leukocytes adhere to endothelium and
activated in the process, releasing
toxic oxygen species and
proteolytic enzymes causing
endothelial injury or
detachment resulting in increase
permeability.
8
- This injury is largely restricted to vascular
sites (venules, pulmonary and
glomerular capillaries)
 Increase Transcytosis Across
Endothelial Cytoplasm
- Transcytosis occurs across channels
consisting of clusters of
interconnected, uncoated vesicles and
vacuoles – VESICULOVACOULAR
ORGANELLE
- VEGF (Vascular Endothelial Growth
Factor) cause vascular leakage by
increasing number and size of channels
- Increase permeability is induce y
histamine and most chemical
mediators
 Leakage from New Blood vessels
- During repair, endothelial cells
proliferate and form
new blood
vessels (ANGIOGENESIS)
- New vessel sprouts remain leaky till
endothelial cells mature & form
intercellular junctions
- VEGF also increase vascular
permeability
- Endothelial cells in foci of angiogenesis
have increase density of receptors for
vasoactive mediators (histamine,
9
substance P, & VEGF) – these account
for the EDEMA characteristic of healing
following inflammation
In Summary , Acute Inflammation’s fluid
loss from vessels with increased permeability occurs
in distinct phases :
1. Immediate Transient Response –
lasting 30 minutes or less,
mediated by Histamines and
Leukotrienes
2. Delayed response starting 2 hours
lasting for 8 hours mediated by
kinins, & complement products
3. Prolonged response is most
noticeable after direct injury (e.g
Burns).
CELLULAR EVENTS : Leukocyte Extravasation &
Phagocytosis
(Critical Function of inflammation is the delivery
of leukocytes in the site of injury & its activation
for their functions in host defense)
(leukocytes ingest offending agents, kill
bacteria, microbes, rid of necrotic tissues and
foreign substances)
(Leukocytes may also induce tissue damage
and in prolonged inflammation it can also
destroy normal host tissues aside from
microbes and necrotic debris)
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SEQUENCE of EVENTS of LEUKOCYTIC JOURNEY
to INTERSTITIAL TISSUE (EXTRAVASATION)
A. (Lumen) Margination, Rolling, Adhesion
to Endothelium In inflammation, Vascular
endothelium is activated permitting
leukocytes exit form the blood vessels
B. Transmigration across
endothelium(DIAPEDESIS)
C. Migration in interstitial Tissues toward a
chemotactic stimulus
I. LEUKOCYTE ADHESION &
TRANSMIGRATION
- Regulated largely by binding of
complementary adhesion molecules
on the leukocyte & endothelial surfaces
and chemical mediatorschemoattractants and cytokines
- Adhesion Receptors include :
(SELECTINS, IMMUNOGLOBULINS,
INTEGRINS , MUCIN-LIKE
GLYCOPROTEINS)
 SELECTINS : Extracellular N-terminal
domain related to lectins :
E-selectin – CD62E also known
as ELAM-1 confined to
endothelium,
11
P-selectin – CD62P also known
GMP140 or PAGDEM present in
endothelium & platelets
L-selectin – CD621 expressed
on most leukocyte types
 IMMUNOGLOBULIN FAMILY
MOLECULES
Includes 2 endothelial
adhesion molecules:
ICAM – Intercellular Adhesion
Molecule
VCAM – Vascular Cell Adhesion
Molecule
Both serve as Ligands for
integrins found on Leukocytes
 INTEGRINS
Transmembrane heterodimeric
glycoproteins made up of a & B
chains, binds to ligands on
endothelial cells, leukocytes
and extracellular matrix
 MUCIN-LIKE GLYCOPROTEINS
Heparan Sulfate serves as
ligands for Leukocyte adhesion
molecules (CD44)found in the
extracellular matrix cell surface
Multistep process of Leukocytic
recruitment to sites of injury and infection
12
Induction of Adhesion Molecules on
Endothelial Cells
- Mediators include histamine,
thrombin, platelet activating factor –
stimulates redistribution of P-selectins from
normal intracellular stores in granules
(weibel-palades bodies) to the cell
surface.
- Tissue macrophages, mast cells,
endothelial cells respond to injurious
agents by secreting the cytokines TNF, IL-1
& Chemokines.
- TNF and IL-1 act on endothelial
cells of postcapillary venules adjacent to
the infection
- TNF & IL-1 also induce endothelial
expression of ligands for integrins mainly
VCAM & ICAM-1
- Chemokines produced at the site
of injury enter blood vessels bind to
endothelial cell heparin sulfate
glycosaminoglycans (proteoglycans) in
high concentrations on the endothelial
surface.
- Chemokines act on rolling
leukocytes and activates it
Migration of the Leukocytes through the
Endothelium(Transmigration or Diapedesis)
13
- Chemokines act on the adherent
leukocytes and stimulate cells to migrate
on interendothelial spaces towards the
site of injury or infection
- Leukocyte diapedesis(similar to
increased vascular permeability) occurs
predominantly in the venules (except in
lungs).
- Leukocytes are retarded in their
journey by the continuous venular
basement membrane then eventually
pierces the BM by secreting collagenases,
then leucocytes rapidly accumulate
where they are needed.
- Once leukocytes enter the
extravascular connective tissue, they
adhere to the extracellular matrix by B1
integrins and CD44 binding to matrix
proteins where they are now retained at
the site till needed.
Clinical Genetic Deficiencies in
Leukocyte Adhesion Proteins
Characterized by :
- impaired leukocyte adhesion
- recurrent bacterial infection
 Leukocyte adhesion deficiency
type 1(LAD1)
- Patients have defect in
biosynthesis of B2 chain shared by
the LFA-1 and Mac-1 integrins
14
 Leucocyte adhesion deficiency
type 2 (LAD2)
- caused by the absence of
Sialyl-Lewis X, fucose-containing
ligand for E selectin due to a
defect in fucosyl transferase-enzyme
that attaches fucose moieties to
protein backbones.
Type of emigrating leukocyte varies
with age of inflammatory response
and type of stimulus.
In most of acute inflammation,
neutrophils predominate in the
inflammatory infiltrate during the 1st
6-24 hours then replaced by
monocytes in 24-48 hours
- neutrophils are more numerous
in the blood
- they respond rapidly to
chemokines,
- attached firmly to adhesion
molecules that rapidly induced on
endothelial cells such as P & E
selectins).
- after entering tissues, neutrophils
are short-lived and undergo
apoptosis, disappear in 24-48 hours
(monocytes survived longer)
- exception noted in Pseudomonas
infection where neutrophils
predominate over 2-4 days,
15
- viral infections, lymphocytes are 1st cells
to arrive
- hypersensisitivity reactions,
eosinophilic granulocytes are the
main cell type
II . CHEMOTAXIS
- Leukocytes emigrate in tissues toward
site of injury
- Locomotion oriented along a chemical
gradient
- Granulocytes, monocytes, and
lymphocytes respond ot chemotactic
stimuli with varying rates of speed
- Both exogenous and endogenous
substance act as chemoattractants
-
-
EXOGENOUS AGENTS (bacterial
products, peptides with N-formylmethionine terminal amino acid)
ENDOGENOUS CHEMOATTRACTANTS
(chemical mediators such as
1. Components of
complement system
(particularly C5a)
2. Products of the
lipooxygenase pathway
(mainly leukotriene B4LTB4)
3. Cytokines (particularly
chemokine family e.g IL-8)
16
How does leukocyte sense chemotactic
agents and how do these substances
induce directed cell movement :
- All chemotactic agents mentioned
bind to specific 7 transmembrane Gprotein-coupled receptors (GCPRs) on the
surface of leukocytes
- Signals initiated from these
receptors result in recruitment of Gproteins and activation of effector
molecules including PHOSPHOLIPASE C
(PLCy), PHOSPHOINOSITOL-3 KINASE
PROTEIN TYROSINE KINASES
- GTPases include Polymerization of
actin resulting in increased amounts of
polymerized actin at leading edge of cell
- Leukocyte moves by extending
filopodia in the direction of extension
- Actin reorganization occur at
trailing edge of cell
- Actin-regulating proteins (filamin,
gelsolin,profiling, calmodulin) interact with
actin and myosin in the filopodium to
produce contraction
III. LEUKOCYTE ACTIVATION
- Microbes, necrotic cell products,
antigen-antibody complexes, cytokines
17
induces leukocyte response (leukocyte
defense function)
- Functional Responses induce on
leukocyte activation :
 Production of arachidonic Acid
metabolites from phospholipids as
a result of Phospholipase A2 by
increased intracellular calcium
 Degranulation & Secretion of
lysozomal enzymes & activation of
the oxidative burst
 Secretion of Cytokines – amplify &
regulate inflammatory reactions.
Activated macrophages-chief
source of cytokines involved in
inflammation (includes also mast
cells and other leukocytes)
 Modulation of Leukocyte
Adhesion Molecules – diff
cytokines cause increased
enbdothelial expression of
adhesion molecules & increased
avidity of leukocyte integrinsallowing firm adhesion of
activated neutrophils to
endothelium
 Leukocyte surface receptors
involved in their activation:
- Toll-like receptors function to
activate leukocyte in response to
18
different types and components of
microbes
- play essential roles in cellular
responses to bacterial
lipolysaccharides (LPS, endotoxin),
bacterial proteoglycans,
unmethylated CpG nucleotides (all
found in bacteria), double-stranded
RNA(produced by viruses)
- Different 7-transmembrane
G-protein- coupled receptor
- recognized microbes
and mediators produced in response
to infections and tissue injury
- have a conserved structure
with 7 transmembrane a-helical
domains, found in neutrophils,
macrophages, & are specific for
diverse ligand
- recognized short peptides
containing N-formylmethionyl
residues, chemokines, chemotactic
breakdown products (C5a & lipid
mediators of inflammation, platelet
activating factor, prostaglandin E,
and LTB).
- N-formylmethionine allows
neutrophils to detect & respond to
bacterial proteins
- Binding of ligands such as
microbial products & chemokines,
19
to the G-proteins-coupled receptors
induces migration of cells from
blood through the endothelium &
production of microbicidal
substances by activation of
respiratory burst.
- Receptor associated Gproteins in resting cell from stable
inactive complex containing
Guanosine Diphosphate (GDP)
bound to Ga subunits.
- Receptor occupied by
ligand results in exchange of GTP for
GDP.
- GTP bound form of G-protein
activated cellular enzymes that
includes Isoform of
Phosphatidylinositol-specific
phospholipase C – functioning to
degrade inositol phospholipids to
increase Intracellular Calcium &
activate protein kinase C.
- The G-proteins stimulate
cytoskeletal changes resulting in
increase cell motility
- Phagocytes express
Receptors for Cytokines Produced
during Immune Responses
- INTERFERON-Y (most important
of & major macrophage
20
activating cytokines) secreted by
Natural Killer cells during innate
immune responses & by antigenactivated T lymphocytes during
adaptive immune responses
- Receptors for Opsonins
promote phagocytosis of microbes
coated with various proteins and
deliver signals that activate
phagocytes
OPSONIZATION- coating a
particle such as microbe for
phagocytosis , OPSONINS are
substances that do this & include
Antibodies, Complement Proteins &
Lectins
- IgG Antibodies – most efficient
opsonizing particle (specific
opsonins) & recognized by high
affinity Fcy receptor of
phagocytes
- Complement system
(complement protein 3) are also
potent opsonins that bind to
microbes & phagocytes expressing a
receptor-Complement Receptor 1.
These complement fragments are
produced when it is activated by the
Classical (antibody dependent) or
the alternative (antibody
independent) pathway.
21
- Plasma proteins, fibronectin,
Mannose binding lectins, fibrinogens
and C-reactive proteins can coat
microbes recongnized by
phagocytic receptors.
IV. PHAGOCYTOSIS
- Responsible for eliminating injurious
elements
- STEPS involved in phagocytosis:
1. Recognition & Attachment of
Particle to be Ingested by
Neutrophils
2. Engulfment, with Formation of
Phagocytic Vacoule
3. Killing or Degradation of ingested
material
 Recognition & Attachment:
Mannose & Scavenger receptors
function to bind & ingest microbes
MANNOSE Receptor – macrophage
lectin that binds terminal mannose &
fucose residues of glycoproteins &
glycolipids
- these sugars are part of the
molecules found in microbial cell
22
walls & therefore it recognizes
microbes and not host cells
SCAVENGER Receptor – bind and
mediate endocytosis of oxidized or
acetylated low-density lipoprotein
particles. Macrophage SR binds
variety of microbes for
phagocytosis
 Engulfment :
- during engulfment , extensions of
the cytoplasm (pseudopods) flow
around the particle to be engulfed
resulting to complete enclosure of
the particle within a phagosome
- Membrane of this phagocytic
vacuole fuses with limiting
membrane of lysosomal granule
discharging contents into
phagolysosome. Neutrophils and
monocytes then become
progressively degranulated
 Killing and Degradation:
- ultimate step in the elimination of
infectious and necrotic elements
thru degradation within the
neutrophils and macrophages
- microbial killing is accomplished by
oxygen-dependent mechanisms
23
- Phagocytosis stimulates burst in
oxygen consumption,
glycogenolysis, increase
glucose oxidation thru hexose
monophosphate shunt & production
of Reactive Oxygen Intermediates
(ROI).
- ROI are produced within the
lysosome where ingested substance
are segregated & cell’s own
organelle’s are protected from the
harmful effect of the ROI’s.
- Bacterial killing occurring by
Oxygen-independent mechanism
through action of leukocytes
substances that includes :
* bactericidal permeability
increasing protein, a cationic
granule-associated protein causing
phospholipase activation,
phospholipids degradation, &
increase permeability in the outer
membrane of microorganisms ;
* lysozyme – hydrolyzes muramic
acid N-acetyl-glucosamine bond
found in glycopeptide coat of all
bacteria
* lactoferrin – iron-binding protein in
specific granules
major basic protein – cationic
protein of eosinophils cytotoxic to
many parasites
24
* defensins – cationic arginine-rich
granule peptide cytotoxic to
microbes.
V. RELEASE of LEUKOCYTE PRODUCTS
& LEUKOCYTE-INDUCE TISSUE INJURY
- during activation and
phagocytosis, leukocytes release
microbicidal products within
phagolysosome & extracellular
space.
- Lysosomal enzymes – most
important substance in neutrophils &
macrophages present in the
granules of ROI’s & products of
arachidonic acid
metabolism(includes prostaglandins
& leukotrienes)
- these products are capable
of endothelial injury & tissue
damage amplifying effects of
initial injurious agent
- products of monocytes /macrophages
may have additional potentially harmful
products & if persistent & unchecked,
leukocyte infiltrate itself becomes injurious
and leukocyte-dependent tissue injury
underlies acute & chronic human
diseases.
25
- Regulated secretion of lysosomal
proteins is a peculiarity of leukocytes and
other hemopoietic cells considering that
most secretory cells, proteins are secreted
and not stored within lysosomes
- Lysosomal granules are secreted by
leukocytes into the extracellular area &
release may occur if phagocytic vacuole
remains open to the outside prior to
complete closure of the phagolysosome
- If cells are exposed to potentially
ingestible materials (immune complexes
deposited on immovable flat surface, e.g
glomerular BM), attachment of leukocytes
to the immune complexes cannot be
phagocytosed & these enzymes are
released into the medium (frustrated
phagocytosis)
( see Table 2-2: Clinical Examples of
Leukocyte-induced injury)
- Cytotoxic release occur after
phagocytosis of potentially membranolytic
substance (urate crystals) damaging
phagolysosomal membrane
- Proteins in certain granules particularly
that of neutrophils may be directly
secreted by exocytosis
- After phagocytosis , neutrophils rapidly
undergo apoptotic cell death and are
ingested by macrophages.
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VI. DEFECTS in LEUKOCYTE FUNCTION
(see table 2-3 for examples of
diseases)
- Leukocytes play a central role in
host defense
- Defects in leukocyte functions, both
genetic & acquired, lead to
increase vulnerability to
Infections
- Impairment of leukocyte functionfrom adherence to vascular
endothelium to microbicidal
activity, existence of clinical
genetic deficiencies are all
identified.
 Defects in Leukocyte Adhesion
- Genetic deficiencies in
Leukocyte Adhesion Molecules
(LAD types 1 & 2) is
characterized by recurrent
infections, impaired would
healing.
 Defects in Phagolysosome
Function
Chediak-Higashi Syndrome:
- Autosomal recessive condition
characterized by neutropenia,
defective degranulation &
delayed microbial killing
27
- There is reduced transfer of
lysosomal enzymes to
phagocytic vacuole in
phagocytes(causing
susceptibility to infections) &
abnormalities in melanocytes
(causing albinism), cells of the
nervous system (nerve defects)
& platelets(bleeding disorders)
- Secretion of granule proteins
by cytotoxic T cells is also
affected accounting for part of
the immunodeficiency seen in
this disorder.
 Defects in Microbicidal Activity
Chronic Granulomatous Disease –
render patients susceptible to
recurrent bacterial infection
- results from inherited defects
in the genes encoding several
NADPH oxidase generating
superoxide.
- Most common variants are Xlinked defect in one of the plasma
membrane-bound components
(gp91phox) & autosomal recessive
defects in the genes encoding 2 of
the cytoplasmic components
(p47phox & p67phox)
28
 Bone Marrow Depression:
- Most frequent cause of leukocyte
defect leading to reduced
production of leukocytes
- Seen following cancer
chemotherapies & marrow space
compromised by bone tumor
metastases
- Resident cells in tissues serving
important functions in initiating
acute inflammation.
Mast cells - react to physical
trauma, breakdown products
of complement, microbial
products, & neuropeptides.
- cells release histamine,
leukotrienes, enzymes and
cytokines(TNF, IL-1)
Tissue Macrophages –
recognized microbial products
& secrete most of cytokines in
acute inflammation
- cells are stationed in
tissues to rapidly recognized
potentially injurious stimuli &
initiate host defense reaction
29
TERMINATION of the ACUTE INFLAMMATORY
RESPONSE
- Acute inflammatory response needs to
be tightly controlled to minimized
damage
- Inflammation declines because its
mediators have short half lives,
degraded after their release, produced
in quick bursts only as long as the
stimulus persists
- Process also triggers stop signals serve
to actively terminate the reaction
which includes:
 switch in the production of proinflammatory leukotrienes to antiinflammatory lipoxins from
arachidonic acid
 liberation of anti-inflammatory
cytokine transforming growth
factor-B (TGF-B), from
macrophages * other cells
 neural impulses (cholinergic
discharge) that inhibit TNF
production in macrophages
CHEMICAL MEDIATORS of INFLAMMATION
1. Vasoactive Amines (Histamine/Serotonin)
2. Plasma Proteins (Complement system, kinin
system, clotting system)
30
3. Arachidonic Acid Metabolites
(prostaglandins, leukotrienes, lipocins)
4. Platelet-Activating Factor
5. Cytokines & Chemokines
6. Nitric Oxide
7. Lysosomal Constituents of leukocytes
8. Oxygen-derived free radicals
9. Neuropeptides
Principles & Highlights of Major Chemical
Mediators
- Mediators originate either from plasma
or cells
 Plasma-derive mediators
(complement proteins, kinins)
 Cell-derived mediators (histamine
in mast cell granules) or
synthesized de novo
(prostaglandins, cytokines) in
response to a stimulus
 Major cellular sources (platelets,
enturophils,
monocytes/macrophages, mast
cells) & mesenchymal cells
(endothelium, smooth muscle,
fibroblasts)
- Production of active mediators is
triggered by microbial products or by
host proteins (proteins of the
complement, kinin, coagulation
systems activated by microbes &
damaged tissues)
31
- Most mediators initially bind to specific
receptors on target cells. Some have
direct enzymatic activity (lysosomal
proteases), or mediate oxidative
damage (reactive oxygen & nitrogen
intermediates).
- One mediator can stimulate release of
other mediators by target cells
themselves. They provide amplifying
mechanisms.
- Mediators can act on one or few target
cell type
- Once activated & released from the
cell, most mediators are:
short-lived, quickly decay (arachidonic
acid metabolites)
inactivated by enzymes (kininase
inactivates bradykinin),
scavenged (antioxidants scavenged toxic
oxygen metabolites),
inhibited (complement regulatory proteins
break & degrade activated
complement components)
- Most mediators have potential to
cause harmful effects
I. VASOACTIVE AMINES
32
- Histamine & Serotonin : preformed
stores in cells & first mediators to be
released during inflammation
Histamine:
- widely distributed in tissues
- richest source being the mast cells
present in connective tissue and blood
vessels
- found also in blood basophils &
platelets
- released by mast cells in response to
variety of stimuli such as
1. Physical injury (trauma, cold, heat)
2. Immune reactions involving
binding of antibodies to mast
cells
3. Fragments of complement called
Anaphylatoxins (C3a & C5a)
4. histamine-releasing proteins
derived from leukocytes
5. Neuropeptides (substance P)
6. Cytokines (IL-1 & IL-8)
- causes dilation of arterioles & increase
permeability of venules (constricts large
arteries)
- principal mediator of immediate
transient phase of increased vascular
permeability causing venular gaps
33
- acts on microcirculation binding to H1
receptors on endothelial cells
Serotonin :
- 5-hydroxytryptamine
- preformed vasoactive mediator similar
to histamine
- present in platelets & enterochromaffin
cells
- its released from platelets is stimulated
when platelets aggregate after in
contact with collagen, thrombin,
adenosine diphosphate(ADP), antigenantibody complexes
II. PLASMA PROTEINS
A. Complement System
- Consists of 20 component proteins
found in greatest concentration in
plasma
- Functions in both innate & adaptive
immunity for microbial defense
- A number of complement component
are detailed that cause increase
vascular permeability, chemotaxis &
opsonization
34
- Complement protein are present as
inactive forms in plasma & numbered
from C1 to C9, C3(most abundant
component)
- Many are activated to become
proteolytic enzymes degrading other
complement proteins
- Cleavage of C3 occur in one of three
ways:
 Classical Pathway – triggered by
fixation of C1 to antibody (IgM of
IgG) combined with antigen
 Alternative Pathway –triggered by
microbial surface molecules
(endotoxin or LPS), complex
polysaccharides , cobra venom,
in the absence of antibody
 Lectin Pathway – plasma
mannose-binding lectin binds to
carbohydrates on microbes and
activates C1
- Whichever pathway is involved in the
early steps of complement pathway, it
all leads to the formation of an active
enzyme – C3 CONVERTASE ---split into
C3a (released) & C3b covalently
attached to cell or molecule where
complement is being activated & binds
to previously generated fragments
forming C5 convertase - cleaved to
release C5a. Remaining C5b bonds the
35
late components (C6-C9) ---- forming
MEMBRANE ATTACK COMPLEX (MAC).
- Functional Categories of complement
system :
1. Cell Lysis by MAC
2. Effects of proteolytic
complement fragments
 Vascular Phenomena
- C3a, C5a & C4a – split products of
complement components
stimulating release of HISTAMINE from
MAST CELLS – increasing vascular
permeability & cause
vasodilation. They are then called
ANAPHYLATOXINS – similar to
mediators involved in anaphylactic
reactions
 Leukocyte adhesion, chemotaxis,
& activation
- C5a – powerful chemotactic agent
for neutrophils, monocytes,
eosinophils, and basophils
 Phagocytosis
- C3b & cleavage product
iC3b (inactive C3b) when fixed to
bacterial cell wall, acts as OPSONINS
& favor phagocytosis by neutrophils
and macrophage bearing cell
surface receptors for C3b
36
- C3 & C5 – most important inflammatory
mediators
- can be activated by several proteolytic
enzymes present within the
inflammatory exudates that includes
plasmin & lysosomal enzymes released
from neutrophils
- Activation of complement is tightly
controlled by Cell-associated &
Circulating regulatory proteins.
- Presence of these inhibitors in host cell
membrane protects host from
inappropriate damage during
protective reactions against microbes
B. Kinin System
- Generates vasoactive peptides from
plasma proteins called Kininogens by
proteases known as Kallikreins.
- Activation of KS results in release of
Bradykinin – increases vascular
permeability cause contraction of
smooth muscle, vascular dilation, pain
when injected into the skin
* Effects similar to that of Histamine
- Triggered by activation of Factor 12
(Hageman factor) upon contact with
collagen and BM
37
- Prekallikrein (fragment of factor 12a) is
produced & converts plasma
prekallikrein into active formKALLIKREIN – cleaves a plasmaglycoprotein
precursor HMW kininogens
– to produce Bradykinin (HMW kininogen
that acts as cofactor or catalyst in the
activation of Hageman factor).
- Potent activator of Hageman
Factor allowing autocatalytic
amplification of initial stimulus
- Has Chemotactic activity &
directly converts C5 to
chemoattractant product C5a.
- Bradykinin – short-lived & quickly
inactivated by Kininase
C. Clotting System
- Interrelated with inflammation
- Divided into two(2) pathways that
culminates in the activation of
THROMBIN
- Intrinsic clotting pathway is a series of
plasma proteins activated by
Hageman Factor (protein synthesized
by the liver circulating in inactive form
until it encounters collagen or BM or
38
activated platelets-as occurs at the site
of endothelial injury)
- Protease thrombin provides main link
between coagulation system &
inflammation
- Activation of clotting system results in
activation of THOMBIN (factor 2a) from
precursor PROTHROMBIN (factor 2)
- THROMBIN – enzyme that cleaves
circulating soluble fibrinogen to
generate an insoluble fibrin clot and is
the major coagulation protease.
- binds with receptors called
Protease-activated receptors (PAF) since
they bind multiple trypsin-like serine
proteases in addition to thrombin
- PAF (7 transmembrane G proteincoupled receptors) expressed on
platelets, endothelial & smooth mucles
cells.
- Engagement of these
receptors by proteases, particularly
thrombin, triggers responses that induce
inflammation that includes :
1. Mobilization of P selectin
2. Production of chemokines
3. Endothelial adhesion molecules for
leukocyte integrins
4. Induction of cyclooxygenase-2,
39
5. Production of prostaglandins,
production of PAF & nitric oxide
6. Changes in endothelial shape
- These promote recruitment of
leukocytes & many other inflammatory
reactions
- At the same time that factor 12a is
inducing clotting, it can also activate
fibrinolytic system. I counter- balance
clotting by cleaving fibrin, solubilizing
fibrin clot
- Fibrinolytic system contributes to the
vascular phenomena of inflammation
- Plasminogen activator (released from
endothelium & leukocytes) cleaves
plasminogen (plasma protein that
binds to evolving fibrin clot to generate
Plasmin which is important in :
* Lysing fibrin clots also cleaves C3 to
produce C3 fragments.
* It also degrades fibrin to fibrin split
products having permeability-inducing
properties.
* It also activate Hageman factor
that trigger multiple cascades amplifying
the response
How Plasma proteases are activated by kinin,
complement, & clotting systems :
40
 Most important are the
Bradykinin, C3a & C5a (mediators
of increased vascularity), C5a
(mediator of chemotaxis),
Thrombin (has effects on
endothelial cells)
 C3a & C5a generated by
1. Immunologic Reactions
involving antibodies(classical
pathway)
2. Activation of alternative or
lectin complement
pathways by microbes in
the absence of antibodies
3. Agents not directly related
to immune responses such as
plasma, kallikrein, and serine
proteases found in tissues
 Activated Hageman Factor (factor
12a) initiates 4 systems involved
inflammatory response:
1. Kinin system –producing
vasoactive kinins
2. Clotting system – induces
formation of thrombin,
fibrinopeptides & factor 10
3. Fibrinolytic system –
producing plasmin &
degrades fibrin
41
4. Complement system –
produces anaphylatoxins
Coagulation & Inflammation are tightly
linked. Acute inflammation, by activating
or damaging the endothelium, can
trigger coagulation & induce thrombus
formation
III. ARACHIDONIC ACID METABOLITES:
PROSTAGLANDINS, LEUKOTRIENES & LIPOXINS
- Lipid mediators known as Autocoids or
local short-ranged hormones, formed
rapidly, exert their effects locally, and
either decay spontaneously or destroyed
enzymatically
- AA- 20-carbon polyunsaturated fatty
acid derived from dietary sources or by
conversion from the essential fatty acid
linoleic acid.
- Normally esterified in membrane
phospholipids and released through
the action of cellular phospholipases,
activated by mechanical, chemical &
physical stimuli.
- AA metabolites – also called
EICOSANOIDS – synthesized by two
major classes of enzymes
42
1. Cyclooxygenases (prostaglandins
& thromboxanes)
2. Lipooxygenases (leukotrienes &
lipoxins)
EICOSANOIDS - can mediate
every step of inflammation & can be
found in inflammatory exudates
- Its synthesis is increased at sites of
inflammation.
CYCLOOXYGENASE PATHWAY
- Initiated by 2 different enzymes (COX-1
& COX-2) leading to generation of
Prostaglandins (divided into series
based on structural features – PGD,
PGE, PGF, PGG, & PGH)
- Most important ones in inflammation
are PGE2, PGD2, PGF2a, PGI2
(prostacyclin), TxA (thromboxane)
- Some of these enzymes have restricted
tissue distribution like platelets
containing enzyme thromboxane
synthetase & hence TxA is the major
product in these cells.
- TxA2 – potent platelet aggregating
agent & vasoconstrictor is itself
unstable & rapidly converted to its
inactive form TxB2
43
- Vascular endothelium lacks
thromboxane synthetase leading to
formation of Prostacyclin-PGI2
- Prostacyclin – vasodilator
- potent inhibitor of platelet
aggregation
- potentiates permeabilityincreasing & chemotactic
effects of other mediators
- Thromboxane-prostacyclin imbalance
has been implicated as an early event
in thrombus formation in coronary &
cerebral blood vessels
- Prostaglandins – involved in the
pathogenesis of pain & fever in
inflammation
PGE2 – Hyperalgesic that makes skin
hypersensitive to painful
stimuli
Causes marked increased in pain
produced by intradermal injection of
suboptimal concentrations of histamine
& bradykinin involved in cytokineinduce fever during infections
PGD2 – Major metabolite of
cyclooxygenase pathway in mast cells
and along with
PGE2 & PGF2a, causes vasodilation,
increase postcapillary venule
permeability
potentiating edema formation
COX-1 - responsible for the
production of prostaglandins that are
44
involved in inflammation but also serve a
homeostatic function ( fluid & electrolye
balance in the kidneys, cytoprotection in
the GIT).
COX-2 - stimulated the production
of the prostaglandins involved in
inflammatory reactions.
LIPOOXYGENASE PATHWAY
- initial products generated by 3 different
lipooxygenases present in only few cell
types.
- 5-lipoxygenase (5-LO) is the
predominant enzyme in neutrophils.
- 5-HETE the main product is
chemotactic for neutrophils &
convereted to LEUKOTRIENES (LTB)potent chemotactic agent & activator
of neutrophilic functional responses
(aggregation & adhesion of leukocytes
to venular endothelium, generation of
oxygen free radicals & release of
lysosomal enzymes).
- Cysteinyl-containing leukotrienes C4,
D4 & E4 (LTC4, LTD4, & LTE4) causes
Bronchoconstriction
Bronchospasm
Increase Vascular Permeability
 LIPOXINS
45
- Bioactive products generated from AA
& transcellular biosynthetic
mechanisms
- Leukocytes(neutrophils) produce
intermediates in lipoxin synthesis &
converted to lipoxins by platelets
interacting with leukocytes.
- Lipoxin A4 & B4(LXA4, LXB4) – are
generated by the action of platelet 12
lipooxygenase on neutrophil derived
LTA4
- Cell-cell contact enhances
transcellular metabolism & blocking
adhesion inhibits lipoxin production
- Principal action of lipoxins are to inhibit
leukocyte recruitment & cellular
components of inflammation
- They inhibit neutrophil chemotaxis &
adhesion to endothelium
 RESOLVINS
- AA-derived mediators that inhibit
leukocyte recruitment & activation, in
part by inhibiting production of
cytokines
- Thus the anti-inflammatory activity of
aspirin is due to its ability to inhibit
46
cyclooxygenases & to stimulate the
production of resolvins
 CYCLOOXYGENASE INHIBITORS
- include aspirin & NSAIDS
(indomethacin)
- inhibits prostaglandin synthesis
 BROAD SPECTRUM INHIBITORS
- include glucocorticoids
- anti-inflammatory agents acts by
downregulating expression of specific
target genes-including genes encoding
COX-2, Phospholipases A2,
proinflammatory cytokines(IL-1 & TNF),
& Nitric Oxide synthase
IV. PLATELET-ACTIVATING FACTOR (PAF)
- Bioactive phospholipid-derived
mediator
- Factor derived from antigen-stimulated,
IgE-sensitized basophils causing platelet
aggregation
- Platelets, basophils, mast cells,
neutrophils, monocytes/macrophage &
endothelial cells elaborate PAF
47
- In addition to platelet stimulation, it
causes vasoconstriction &
bronchoconstriction & at low
concentrations, it induces vasodilation
& increased venular permeability
- Also causes increased leukocyte
adhesion to endothelium, chemotaxis,
degranulation, & oxidative burst
- Can elicit most of the cardinal features
of inflammation
- Boosts the synthesis of other mediators
particularly eicosanoids, by leukocytes
& other cells
V. CYTOKINES & CHEMOKINES
- Proteins produced principally by
activated lymphocytes &
macrophages, but also endothelium,
epithelium & connective tissue cells
- Long known to be involved in cellular
immune responses, & play important
roles in acute & chronic inflammation
 Tumor Necrosis Factor &
Interleukin-1
- Two major cytokines that mediate
inflammation
- Produced mainly by activated
macrophages
48
- Cytokine resembling TNF (lymphotoxin)
is produced by activated T
lymphocytes.
- Secretion of both is stimulated by
endotoxin & microbial products,
immune complexes, physical injury &
other inflammatory stimuli.
- Their most important action in
inflammation are their effects in the
endothelium, leukocytes & fibroblasts
- They induce synthesis of endothelial
adhesion molecules & chemical
mediators (includes cytokines,
chemokines, growth factors,
eicosanoids & nitric oxide
- TNF induces priming of neutrophils
leading to augmented responses of
cells to other mediators
- Induce systemic acute phase reactants
associated with infection or injury
Features of the systemic responses
include
Fever
Loss of apetite
Slow-wave sleep
Release of neutrophils into
circulation
Release of corticotropins &
corticosteroids
49
With regard to TNF, hemodynamic
effects of septic shock:
Hypotension
Decreased vascular resistance
Increased heart rate
Decreased blood pH
- TNF also regulates body mass by
promoting lipid & protein mobilization &
by suppressing appetite
- Sustained production of TNF contributes
to Cachexia (weight loss & anorexia
that accompanies infections &
neoplastic diseases)
 Chemokines
- proteins that act primarily as
chemoattractants for specific types of
leukocytes
- Classified into four (4) major groups
accdg to cysteine residue
arrangement
1. C-X-C chemokines (alpha
chemokine)
- act primarily on neutrophil
- IL-8 is common in this group
- It is secreted by activated
macrophages, endothelial cells
- causes activation &
chemotaxis of neutrophils
- most important inducers are
microbial products & IL-1 & TNF
50
2. C-C chemokines (Beta
Chemokines)
- include monocyte
chemoattractant protein,
eotaxin, macrophage inflammatory
protein-1a and RANTES
- attracts monocytes,
eosinophils, basophils & lymphocytes
3. C Chemokines (gamma
chemokine)
- relatively specific for
lymphocytes
4. CX3C Chemokine
- contains 3 aminoi acid
between cysteines.
- exist in two(2) forms –
a.Cell surface-bound protein
induced on endothelial cells by
inflammatory cytokines & promote
adhesion of monocyte & T cells
b. Soluble form- derived by
proteolysis of the membrane bound
protein that has potent chemoattractant
activity for same cells
- Chemokines stimulate leukocyte
recruitment in inflammation & control
the normal migration of cells through
tissues
- Chemokines are transiently produced n
response to inflammatory stimuli &
promote the recruitment of leukocytes
to the sites of inflammation
51
 NITRIC OXIDE
- Pleiotropic mediator of inflammation
released from endothelial cells causing
vasodilation by relaxing smooth muscle
cell
- Known as Endothelium-derived relaxing
factor
- Soluble gas produced by endothelial
cells & macrophage & some neurons of
the brain
- Plays important role in vascular &
cellular components of inflammatory
responses
- Potent vasodilator by virtue of its
actions on the vascular smooth muscle
- Reduces platelet aggregation &
adhesion
- Inhibits mast cell-induced inflammation
- Serves as endogenous regulator of
leukocyte recruitment
- Production of NO is an endogenous
compensatory mechanism reducing
inflammatory responses.
- Its derivatives are microbicidal &
mediator of host defense against
infection
52
 Lysosomal Constituents of
Leukocytes
- Neutrophils & Monocytes contain
lysosomal granules that contribute to
inflammatory response
- Two (2) Main Types of granules
1. Specific (Secondary) Granules: Smaller granules
that contain Lysozyme, collagenase, gelatinase,
lactoferrin,plasminogen activator, histaminase &
alkaline phosphatase.
2. Large Azurophil (Primary) granules: contain
myeloperoxidase, bactericidal factors (lysozymes,
defensins), acid hydrolases, neutral
proteases(elastase, cathepsin G, non-specific
collagenases, proteinases)
- Both types of granules empty into phagocyttic
vacuoles that formed around engulfed
material
- Granule contents released into the extracellular
space
- Specific granules secreted extracellularly & with
lower concentration of agonists
- More destructive azurophil granules release their
contents within the phagosome & require high
levels of agonists for release extracellularly
53
Functions of different granule enzymes:
Acid Proteases – degrade bacteria & debris within
the phagolysosomes
Neutral Proteases – capable of degrading various
extracelular components. Can attack
collagen, BM, fibrin, elastin & cartilage, resulting
in tissue destruction that accompanies
inflammation
Neutrophil elastase – degrade virulence factors of
bacteria combating bacteria infection
Acid hydrolases, collagenases, elastase,
phospholipase & plasminogen activator –
Active enzymes in chronic inflammatory
reactions
With the destructive effects of lysosomal enzymes, if
initial effects of leukocytic infiltration left unchecked,
it can further potentiate increase vascular
permeability & tissue damage
Antiproteases in serum & fluid serves to check
harmful effects of proteases
Alpha-1 Antitrypsin
- major inhibitor of neutrophil elastase
- Deficiency may lead to sustained action
of leukocyte proteases
Macroglobulin – another antiprotease found in
serum & fluids
54
 Oxygen-Derived Free Radicals
- released extracellularly from leukocytes
after exposure to microbes,
chemokines, immune complexes or
after phagocytic challenge.
- Produced by activation of the NADPH
oxidative system
- Major species produced within the cells
1. Superoxide anion (O2)
2. Hydrogen peroxide (H202)
3. Hydroxyl radical (OH)
- Extracellular release of these mediators
increase expression of chemokines,
cytokines, & endothelial leukocyte
adhesion molecule eliciting cascade of
inflammatory response
- Physiologic function of these reactive
oxygen intermediates is to destroy
phagocytosed microbes
Release of these potent mediators can be
damaging to host cells causing:
1. Endothelial cell damage with
increase vascular permeability
2. Inactivation of antiproteases (a1antitrypsin)leading to unopposed
protease activity resulting to
increase ECM destruction.
55
3. Injury to other cell types
(parenchymal cells, RBC’s).
- Antioxidant mechanisms produced by serum
& tissue fluids serve to protect against
potentially harmful oxygen-derived radicals:
Includes:
1. Ceruloplasmin (copper containing
serum protein)
2. Transferrin (iron free fraction of serum)
3. Superoxide Dismutase
4. Catalase (detoxifies H2O2)
5. Glutathione Peroxidase (powerful H2O2
detoxifier)
 Neuropeptides
- similar to vasoactive amines &
eicosanoids
- play a role in the initiation &
propagation of inflammatory
reponse
- Peptides Substance P & Neurokinin
produced in the CNS & PNS
Substance P :
Prominent in Lung & GIT
Functions:
- Transmission of pain signals,
- Regulation of Blood Pressure,
- Stimulation of secretion of
endocrine cells
- Increase Vascular Permeability
56
OUTCOMES of ACUTE INFLAMMATION
1. Complete Resolution
- all inflammatory reaction, after
neutralizing & eliminating injurious
stimulus , end with restoration of site of
inflammation to normal (known as
resolution)
- Resolution involves:
- neutralization or spontaneous
decay of chemical mediators
- return to normal vascular
permeability
- cessation of leukocytic infiltration
- death (by apoptosis) of neutrophils
- removal of edema fluid and
protein, leukocytes, foreign agents &
necrotic debris form site
2. Healing by Connective Tissue Replacement
(Fibrosis)
- occurs after substantial tissue destruction
 when inflammatory injury involves
tissues incapable o regeneration
 when there is abundant fibrin
exudation
 when fibrinous exudates in tissue
or serous cavities (pleura &
57
peritoneum) cannot be cleared,
connective tissue grows into the
area of exudates—converting to
mass of fibrous tissue
(organization)
3. Progression of the tissue response to Chronic
Inflammation
MORPHOLOGIC PATTERNS of ACUTE INFLAMMATION
- All acute inflammatory reactions are characterized
by Vascular changes & leukocyte infiltration,
severity of its reaction & its specific cause, particular
tissue & site involved introduced morphologic
variations in basic patterns
SEROUS INFLAMMATION
- Marked by the outpouring of thin fluid
derived from either the plasma or
secretions of mesothelial cells lining the
peritoneal, pleural & pericardial
cavities (effusion).
- Skin blister form burn or viral infection
represents large accumulation of
serous fluid within or beneath the skin
epidermis
FIBRINOUS INFLAMMATION
- with severe injuries & greater vascular
permeability, larger molecules
(fibrinogen) pass vascular barrier &
58
form fibrin deposited in extracellular
space
- Fibrinous exudates develops when
vascular leaks are large enough
- Fibrinous exudate is characteristic of
inflammation in the lining of body
cavities (meninges, pericardium &
pleura).
- Histologically fibrin appears as
eosinophilic meshwork of threads as an
amorphous coagulum
- Fibrinous exudates may be removed by
fibrinolysis & clearing of other ddebris
by macrophages
- Process of resolution may restore
normal tissue structure but if fibrin is not
removed, may stimulate growth of
fibroblasts & blood vessels---Scarring
- Conversion of fibrinous exudates to scar
tissue (organization) within the
pericardial sac leads to fibrous
thickening of the pericardium &
epicardium & development of fibrous
strands reducing and obliterating
pericardial space.
59
SUPPURATIVE or PURULENT INFLAMMATION
- Characterized by production of large
amount of pus or purulent exudates
consisting of neutrophils, necrotic cells
& edema fluid
- Bacteria (staphylococci) produce
localized suppuration referred to as
pyogenic/pus-forming bacteria
- Common example is Acute
Appendicitis
- Abscess – localized collections of
purulent inflammatory tissue caused by
suppuration buried in a tissue, an organ
or confined space
- Produced by deep seeding of
pyogenic bacteria into a tissue
- Have a central region
appearing as mass of necrotic
leukocytes & tissue cells
- there usually is a zone of
neutrophils around this necrotic
focus & vascular dilation with
parenchymal & fibroblastic
proliferation occur (beginning of
repair)
- abscess maybe walled off &
ultimately replaced by connective
tissue
60
ULCERS
- local defect, or excavation , of the
surface of an organ produced by
sloughing (shedding) of inflammatory
necrotic tissue
- can occur when tissue necrosis &
resultant inflammation exist on or near
a surface
- commonly encountered in
1. Inflammatory necrosis on the
mucosa of mouthn stomach,
intestines or GUT
2. Subcutaneous inflammation of
the lower extremities (older
persons) having circulatory
disturbances predisposing to
extensive necrosis
- Best exemplified by peptic ulcer of the
stomach & duodenum where acute &
chronic inflammation coexist
- In acute stage, intense neutrophilic
infiltration & vascular dilatation in the
margins of defect noted
- With chronicity – margins and base of
ulcer develops fibroblastic proliferation,
scarring & accumulation of
lymphocytes, macrophages and
plasma cells
61
SUMMARY of ACUTE INFLAMMATION
1. Host encounter injurious agent (infectious
microbe/dead cells)
2. Phagocytes from tissues get rid of these agents
3. Phagocytes / host cells react to presence of
foreign substance by liberating cytokines & other
inflammatory mediators
4. These mediators act on endothelial cells &
promote efflux of plasma & recruits circulating
leukocytes to the site of injury
5. Activated leukocytes removed offending agent
by phagocytosis
6. If agent is eliminated & anti-inflammatory
mechanisms become active – process subsides
7. If agent not immendiately eliminated ---CHRONIC
INFLAMMATION
62
CHRONIC INFLAMMATION:
- inflammation of prolonged duration
(weeks or months)
- active inflammation , tissue destruction
and attempts at repair are proceeding
spontaneously
- frequently begins insidiously as low
grade, smoldering, often asymptomatic
response (cause of tissue damage in
most common disabling human
diseases – rheumatoid arthritis,
atherosclerosis, TB and chronic lung
diseases).
CAUSES of CHRONIC INFLAMMATION :
- Arises in the following settings :
 Persistent infections by
microorganisms (TB bacilli,
treponema pallidum, viruses,
fungi, parasites) of low toxicity &
could evoke immune reaction
called Delayed Type
Hypersensitivity & sometimes take
a specific pattern called
Granulomatous Reaction
 Prolonged exposure to potentially
toxic agents-Exogenous (e.g.
nondegradable particulate, silica,
when inhaled for prolonged
63
periods results in inflammatory
lung disease – silicosis)
Endogenous (Atherosclerosis –
chronic inflammatory process of the
arterial wall induced by endogenous
toxic plasma lipid components)
 Autoimmunity : immune reactions
developing gainst individual’s
own tissues – autoimmune
disorders.
- autoantigens evoke self
perpetuating immune reaction
resulting in chronic tissue damage &
inflammation
MORPHOLOGIC FEATURES:
- Infiltration of mononuclear cells
(macrophages, lymphocytes, plasma
cells)
- Tissue destruction – induced by
persistent offending agent or
inflammatory cells
- Attempts at healing by connective
tissue replacement of damaged tissue
(accomplished by small vessel
proliferation-angiogenesis, and fibrosis).
MONONUCLEAR CELL INFILTATION
- Macrophage is the dominant cellular
player & one component of the
64
mononuclear phagocyte system
(reticuloendothelial system)
Consists of closely related cells of
Bone marrow origin – includes blood
monocytes and tissuemacrophages
Diffusely scattered in connective
tissue or in the liver (kuppfer cells), spleen
& lymph nodes(sinus histiocytes) and
lungs (alveolar macrophages).
Arise from common precursor in the
bone marrow - -- blood monocytes –
migrate in tissues – differentiates into
Macrophages.
Monocytes (half life of 1 day)
Tissue macrophages (half life of
several months to years)
- Monocytes emigrate early into
exytravascular tissues early in acute
inflammation & its extravasation is
similarly governed by factors in
neutrophil emigration (adhesion
molecules & chemical mediators with
chemotactic and activating
properties)
- When it reach the tissue, transformed
into a larger phagocytic cell –
MACROPHAGE, activated by several
stimuli (cytokines-IFN-y), secreted by Tlymphocytes & NK cells, & bacterial
endotoxins.
65
- Activation results in increased cell size,
levels of lysosomal enzymes, more
active metabolism, greater ability to
phagocytose, & kill ingested microbes
- Activated macrophages secrete
variety of biologically active products &
if unchecked result in tissue injury &
fibrosis (characteristic of chronic
inflammation).
- Short lived inflammation, if irritant is
eliminated, macrophages eventually
disappear through either dying off or
lymphatics & lymph nodes)
Mechanisms by which macrophage
accumulation persists in Chronic Inflammation:
1. Recruitment of monocytes from the
circulation
-resulting from adhesion molecules
and chemotactic factors
- similar to recruitment of neutrophils
- Chemotactic stimuli includes
chemokines produced by activated
macrophages, lymphocytes & other
cell types.
2. Local proliferation of Macrophages
after emigration from the bloodstream
66
3. Immobilization of Macrophage within
the site of inflammation caused by
certain cytokines and oxidized lipids
Products of activated macrophages serve
to eliminate injurious agents (microbes) to
initiate process of repair & responsible for
much of the tissue injury.
Some of these products are
 toxic to microbes and host cells
(reactive
oxygen & nitrogen
intermediates)
 extracellular matrix (proteases)
 cause influx of other cell types
(cytokines
chemotactic
factors)
 cause fibroblast proliferation,
collagen deposition &
angiogenesis
 These mediators makes
macrophages powerful allies in
the body’s defenses against
unwanted debris but similar
arsenals are used to induce
considerable tissue destruction
when inappropriately activated
making tissue destruction as one
of the hallmarks of Chronic
Inflammation
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 Variety of substances may also
contribute to tissue damage
- Necrotic tissue perpetuate
inflammatory cascade through
activation of kinin, coagulation,
complement, & fibrinolytic systems,
release of mediators from leukocytes
responding to necrotic tissue
- Other cells in Chronic Inflammation :
 Lymphocytes
- mobilized in both antibody mediated &
cell mediated immune reactions
- Antigen stimulated lymphocytes (T & B)
use adhesion molecule pairs (integrins &
their ligands) & chemokines to migrate to
inflammatory site
- Cytokines from activated macrophages
mainly TNF, IL-1 & chemokines promote
leukocyte recruitment
- Lymphocytes & Macrophages interact
bidirectionally for chronic inflammatory
response
- Macrophage display antigens to T-cells
& produce
membrane molecules &
cytokines (IL-12) that stimulate T-cell
responses
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- Activated T lymphocyte produce
cytokines (IFN-y)-major activator of
macrophage
 Plasma Cells
- Develop from B Lymphocytes &
produce antibody-directed either
against persistent antigen in the
inflammatory site or altered tissue
components
- May assume morphologic features of
lymphoid organs (lymph nodes) .
 Eosinophils
- Abundant in immune reactions
mediated by IgE & in parasitic
infections
- Eotaxin – chemokine important for
eosinophilic recruitment
- Have granules that contain major basic
protein toxic to parasites but also cause
lysis of epithelial cells (can control
parasitic infection but contribute also
to tissue damage in immune reaction)
 Mast Cells
- widely distributed in connective tissues
- participate in both acute & persistent
inflammatory reactions
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- express in their surface the receptors
binding the Fc portion of IgE antibody.
- In acute reactions, IgE antibodies
bound to cells Fc receptors specifically
to recognize antigen & cells
degranulate & release mediators
(histamine & products of arachidonic
acid oxidation).
- This type of response occur during
anaphylactic reactions to foods,
venom, drugs, frequently with
catastrophic results
- Present in chronic inflammatory
reaction producing cytokines that
contribute to fibrosis
GRANULOMATOUS INFLAMMATION :
- pattern of chronic inflammatory
reaction characterized by focal
accumulation of activated
macrophages,
developing an
epithelioid appearance.
- Encountered in immunologically
mediated infectious 7 non-infectious
conditions
- Tuberculosis is the prototype of
Granulomatous diseases
sarcoidosis
cat-scratch
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lymphogranuloma inguinale
leprosy
syphilis
mycotic infections
reaction to irritant lipids
- Granuloma – focus of chronic
inflammation consisting of aggregation of
macrophages, transformed into epitheliallike cells surrounded by mononuclear
leukocytes( lymphocytes & occasional
plasma cells)
- Frequently epithelioid cells fused to
form Giant Cells in the granuloma –
containing several nuclei, 20 or more,
(Langhan’s-type Giant Cell).
- Two types of granuloma :
 Foreign Body Granulomas incited
by inert foreign bodies but do not
incite specific inflammatory or
immune response
 Immune Granulomas caused by
insoluble particles (microbes)
capable of inducing cellmediated immune response
- produce granulomas when
inciting agent is poorly degradable
or particulate
- macrophages then engulfed
the foreign material & present to T
lymphocytes for their activation
- The T cells then produce
cytokines (IL-2) activating other T
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cells, & IFN-y important in activating
macrophages transforming them to
epithelioid cells & multinucleated
giant cells.
- The prototype of Immune
granuloma is that caused by bacillus
of TB
The granuloma is referred to as
Tubercle characterized by presence
of central caseous necrosis.
LYMPHATICS in INFLAMMATION
- System of lymphatics & lymph nodes
filters & polices extravascular fluid
- With mononuclear phagocyte system,
it represents secondary line of defense
when local inflammatory reaction fails
to contain & neutralize microbes.
- (Lymphatics) are delicate channels
lined by continuous thin endothelium
with loose overlapping cell junctions,
scant basement membrane with no
muscular support
- Lymph flow is increased & helps drain
the edema fluid from extravascular
space.
- Leukocytes and cell debris also find
their way to lymphs
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- Severe injuries, drainage may also
transport offending agent (chemical or
microbial).
- Lymphangitis - lymphatics secondarily
inflamed as Lymphadenitis inflammed draining lymph nodes
- Nodal enlargement – caused by
hyperplasia of the phagocytic cells
lining the sinuses of LN’s
(reactive/inflammatory lymphadenitis).
- Bacteremia – severe infections that
gain access to the vascular circulation
where liver, spleen & bone marrow
constitute next line of defense.
SYSTEMIC EFFECTS of INFLAMMATION
-
Acute Phase Response / Systemic
Inflammatory Response Syndrome
- Systemic changes associated with
inflammation in patients with infections
- Reactions to cytokines stimulated
by bacterial products such as LPS & other
inflammatory stimuli
 FEVER
- Most prominent manifestation when
inflammation is associated with
infection
- Produced in response to substances (
PYROGENS) that act by stimulating
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prostaglandins synthesis in the vascular
& perivascular cells of hypothalamus
- Bacterial products- LPS (exogenous
pyrogens) stimulates leukocytes to
release cytokines (IL-1 & TNF endogenous pyrogens) that increase
enzymes (cyclooxygenases) converting
AA to prostaglandins
- Hypothalamus : Prostaglandins-PGE2
stimulate production of
neutrotransmitters (cyclic AMP)
functions to reset temperature set point
at higher level
- NSAIDS & aspirin reduced fever by
inhibiting cyclooxygenase blocking
prostaglandin synthesis
 ACUTE-PHASE PROTEINS
- Plasma proteins synthesized in the liver
whre its concentration increased
hundred-fold in response to
inflammatory stimuli
- Three proteins known are
C-reactive protein (CRP)
Fibrinogen,
Serum Amyloid A protein (SAA)
- CRP & SAA bind to bacterial cell walls,
act as opsonins & fix complement
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- Bind also to chromatin aiding in
clearing necrotic cell nuclei
- Rise in fibrinogen causes erythrocytes to
form stacks (rouleaux) that sediment
rapidly at unit gravity that individual
erythrocytes thus the basis for ESR
(erythrocyte sedimentation rate) test for
systemic inflammatory response
- Elevated levels of CRP used as marker
for increased risk of myocardial
infarction in patients with Coronary
Artery Diseases
- Inflammation involving atherosclerotic
plaques in the coronary arteries
predisposes to thrombosis & infarction
and thus CRP is produced during
inflammation.
 LEUKOCYTOSIS
- Common feature of inflammatory
reaction especially those induced by
bacterial infection
- Leukocyte count may reach 15 to 20T
cells/ul.
- Extreme elevations referred to as
leukemoid reactions (similar to counts
obtained in leukemia)
- Occurs due to accelerated release of
cells from the bone marrow postmitotic
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reserve pool(caused by cytokines IL-1 &
TNF), associated with rise of more
immature neutrophils in blood (shift to
the left)
- Prolonged infection induces
proliferation of precursors in bone
marrow cause by increase production
of colony stimulating factors (CSF)
- Neutrophilia – increased in blood
neutrophil count (bacterial infection)
- Lymphocytosis – absolute increase in
numbers of lymphocytes (viral
infections-infectious mononucleosis,,
mumps, german measles)
- Eosinophilia – absolute increase in the
number of eosinophils (bronchial
asthma, parasitic infections).
- Leukopenia encountered in infections
overwhelmed patients with
disseminated cancers or rampant TB,
also with certain infections (typhoid
fever).
 Other manifestations of acute
phase response
- increase pulse & blood pressure
- decrease sweating
- rigors (shivering), chills, anorexia,
somnolence, malaise
 Severe Bacterial infections (sepsis)
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- large amounts of organisms & LPS in the
blood stimulate production of
enormous quantities of several
cytokines-TNF & IL-1
- High levels of TNF may cause DIC
(disseminated Intravascular
Coagulation
- Thrombosis results from 2 simultaneous
reactions
- LPS & TNF induce tissue factor
expression on endothelial cells initiating
coagulation
- same agents inhibit natural
anticoagulation mechanisms by
decreasing expression of tissue factor
pathway inhibitor & endothelial cell
thrombomodulin
- Cytokines cause liver injury & impaired
liver function resulting in failure to
maintain normal glucose levels-lack of
gluconeogenesis from stored glycogen
- Overproduction of NO by cytokineactivated cardiac myocytes & vascular
smooth muscle cells lead to heart
failure & loss of perfusion pressure
resulting in hemodynamic shock
- Clinical Triad of DIC, hypoglycemia &
CV failure
leads to Septic Shock.
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CONSEQUENCES of DEFECTIVE or EXCESSIVE
INFLAMMATION
 Defective Inflammation
- results in susceptibility to infections &
delayed healing of wounds & tissue
damage
 Excessive Inflammation
- basis of many categories of human
diseases
- well established in allergies &
autoimmune diseases – where immune
responses develop against normally
tolerated self-antigens
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