Imelda D.

Rivera, MD, DPSP

College of Dentistry
UE Manila

INFLAMMATION
INFLAMMATION
a complex reaction in tissues that
consists mainly of responses of bld
vessels & leukocytes
 Types:
• ACUTE
• CHRONIC
5 CARDINAL SIGNS:
 Rubor (redness)
 Calor (warmth)

 Tumor (swelling)

 Dolor (pain)

 Functio laesa (loss of function)

Figure 2-1 The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (causing erythema and warmth); (2)
extravasation and extravascular deposition of plasma fluid and proteins (edema); (3) leukocyte emigration and accumulation in the site of injury.

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STIMULI FOR INFLAMMATION:
 Infectious

 Tissue necrosis
 Foreign bodies

 Immune reactions
ACUTE INFLAMMATION
 rapid host response that serves to
deliver WBCs & plasma CHONs to the
site of infection/tissue injury
 Events:
o Reactions of vessels
o Reactions of WBCs

o Termination
REACTIONS OF VESSELS:
 Changes in vascular flow & caliber
 Vascular leakage / Increased vascular
permeability
 Responses of lymphatic vessels
 Figure 2-2 Formation of transudates and exudates. A, Normal hydrostatic pressure (blue arrows) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg
at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure. Therefore, the
net flow of fluid across the vascular bed is almost nil. B, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic
pressure. C, An exudate is formed in inflammation, because vascular permeability increases as a result of increased interendothelial spaces.

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CHANGES IN VASCULAR FLOW & CALIBER:

 Vasodilation
 Increased permeability of the
microvasculature
 Stasis

 Activation of endothelial cells

MECHANISMS OF VASCULAR LEAKAGE:

 Contraction of endothelial cells

• Immediate transient response
• Delayed prolonged leakage
 Endothelial injury
 Increased transcytosis
Figure 2-3 Principal mechanisms of increased vascular permeability in inflammation, and their features and underlying causes. NO, nitric oxide; VEGF, vascular
endothelial growth factor.

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RESPONSES OF LYMPHATIC VESSELS:

 Increased lymph flow

 Proliferation

 Lymphangitis (2ndary)

 Reactive lymphadenitis
REACTIONS OF WBCs:
 Recruitment of WBCs to Sites of Infection & Injury
(Extravasation)
 Recognition of Microbes & Dead Tissues
 Removal of the Offending Agents (Phagocytosis)
 Other Fxnal Responses of Activated WBCs
 Release of WBC Products & WBC-Mediated Tissue
Injury
 Defects in WBC Fxn
Extravasation:

 In the lumen:
• Margination
• Rolling
• Adhesion
 Migration
• Transmigration/diapedesis
• Emigration/chemotaxis
Figure 2-4 The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to
endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury.
Different molecules play predominant roles in different steps of this process-selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the
neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. Neutrophils express low levels of L-selectin; they bind to
endothelial cells predom in antly via P- and E-selectins. ICAM-1, intercellular adhesion molecule 1; TNF, tumor necrosis factor.

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Figure 2-5 Regulation of expression of endothelial and leukocyte adhesion molecules. A, Redistribution of P-selectin from intracellular stores to the cell surface. B,
Increased surface expression of selectins and ligands for integrins upon cytokine activation of endothelium. C, Increased binding avidity of integrins induced by
chemokines. Clustering of integrins contributes to their increased binding avidity (not shown). IL-1, interleukin-1; TNF, tumor necrosis factor.

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Figure 2-6 Scanning electron micrograph of a moving leukocyte in culture showing a filopodium (upper left) and a trailing tail. (Courtesy of Dr. Morris J. Karnovsky,
Harvard Medical School, Boston, MA.)

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 Figure 2-7 Nature of leukocyte infiltrates in inflammatory reactions. The photomicrographs are representative of the early (neutrophilic) (A) and later (mononuclear)
cellular infiltrates (B) seen in an inflammatory reaction in the myocardium following ischemic necrosis (infarction). The kinetics of edema and cellular infiltration (C) are
approximations.

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Recognition of Microbes & Dead Tissues
(Events):
 Recognition of the offending agents
 Activate the WBCs to ingest & destroy the
offending agents & amplifying the
inflammatory rxn
Figure 2-8 Leukocyte receptors and responses. Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors initiate responses that
mediate the functions of the leukocytes. Only some receptors are depicted (see text for details). IFN-γ, interferon-γ; LPS, lipopolysaccharide(s).

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Phagocytosis (steps):

 Recognition & attachment

 Engulfment

 Killing & degradation

Recognition & attachment (receptors):

 Mannose receptor (lectin)↔ terminal mannose

& fructose residues of glycoCHONs & glycolipids
 Scavenger receptor↔modified LDL, microbes
 Receptors for opsonins (IgG Abs, C3b
breakdown product, plasma lectins)
Engulfment:

 Pseudopods
 Phagosome

 Phagolysosome
Killing & degradation:

 H2O2-MPO-halide  Cathelicidins
system:  Lysozyme (hydrolysis)
• OCl ˙
 Lactoferrin
(halogenation/oxidat
ion)  MBP

• ˙OH  Bactericidal/permeab

• NO ility increasing
protein
 OONO˙

 Defensins
Figure 2-9 Phagocytosis and intracellular destruction of microbes. Phagocytosis of a particle (e.g., bacterium) involves binding to receptors on the leukocyte membrane,
engulfment, and fusion of lysosomes with phagocytic vacuoles. This is followed by destruction of ingested particles within the phagolysosomes by lysosomal enzymes
and by reactive oxygen and nitrogen species. The microbicidal products generated from superoxide () are hypochlorite (HOCl•) and hydroxyl radical
(•OH), and from nitric oxide (NO) it is peroxynitrite (OONO•). During phagocytosis, granule contents may be released into extracellular tissues (not
shown). MPO, myeloperoxidase; iNOS, inducible NO synthase.

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Other fxnal responses of leukocytes:
 production of GFs
 “classically activated” macrophages – trigger
inflammation
 “alternatively activated” macrophages – limit
inflammation
Figure 2-10 Subsets of activated macrophages. Different stimuli activate monocytes/macrophages to develop into functionally distinct populations. Classically activated
macrophages are induced by microbial products and cytokines, particularly IFN-γ, and are microbicidal and involved in potentially harmful inflammation.
Alternatively activated macrophages are induced by other cytokines and in response to helminths (not shown), and are important in tissue repair and the resolution of
inflammation (and may play a role in defense against helminthic parasites, also not shown).

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Release of leukocyte products & leukocyte-
mediated tissue injury:
 “collateral damage”
 autoimmune d’ses
 host reacts x’ssively against usually harmless
environmental substances
 lysosomal enzymes & reactive O2 & N2 sp.
 frustrated phagocytosis
 phagocytosis of membrane-damaging substances
Defects in wbc fxn:

 Inherited defects in adhesion - integrin &

selectin
 Inherited defects in phagolysosome fxn
(Chédiak-Higashi syndrome)
 Inherited defects in microbicidal activity
(chronic granulomatous dse)
 Acquired deficiencies – BM suppression
TERMINATION OF ACUTE
INFLAMMATION
 Mediators:
• Stimulus does not persists
• Short half-lives
• Degraded after release
 Stop signals:
• Switch in the arachidonic acid metabolite produced , from
proinflammatory leukotrienes to anti-inflammatory lipoxins
• Liberation of anti-inflammatory cytokines (TGF-ß, IL-10)
• Production of anti-inflammatory lipid mediators (resolvins, protectins)
• Neutral impulses that inhibit the prod’n of TNF (cholinergic
discharge)
OUTCOMES OF ACUTE INFLAMMATION:

 Complete resolution – removal of cellular debris &

microbes, resorption of edema

 Fibrosis (organization) – connective tissue grows in

the area of damage

 Progression to chronic inflammation

Figure 2-16 Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation. The components of the various reactions and their functional
outcomes are listed.

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MORPHOLOGIC  Dilatation of sm. bld vessels
HALLMARKS OF  Slowing of bld flow
ACUTE  Accumulation of leukocytes & fluid
INFLAMMATION: in the extravascular tissue

Figure 2-17 The characteristic histopathology of acute inflammation. A, Normal lung shows thin (virtually invisible) blood vessels in the alveolar walls and no cells in the
alveoli. B, The vascular component of acute inflammation is manifested by congested blood vessels (packed with erythrocytes), resulting from stasis. C, The cellular
component of the response is manifested by large numbers of leukocytes (neutrophils) in the alveoli.

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MORPHOLOGIC PATTERNS OF ACUTE
INFLAMMATION
 SEROUS
 FIBRINOUS

 SUPPURATIVE/PURULENT; ABSCESS

 ULCERS
MORPHOLOGIC
PATTERNS OF
ACUTE
INFLAMMATION

SEROUS -
effusion

Figure 2-18 Serous inflammation. Low-power view of a cross-section of a skin blister showing the epidermis separated from the dermis by a focal collection of serous
effusion.

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MORPHOLOGIC  FIBRINOUS – fibrinous
PATTERNS OF exudate
ACUTE
INFLAMMATION

Figure 2-19 Fibrinous pericarditis. A, Deposits of fibrin on the pericardium. B, A pink meshwork of fibrin exudate (F) overlies the pericardial surface (P).

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MORPHOLOGIC
PATTERNS OF ACUTE
 SUPPURATIVE/PURULENT;
INFLAMMATION ABSCESS – purulent exudate

Figure 2-20 Purulent inflammation. A, Multiple bacterial abscesses in the lung, in a case of bronchopneumonia. B, The abscess contains neutrophils and cellular debris,
and is surrounded by congested blood vessels.

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MORPHOLOGIC  ULCERS
PATTERNS OF
ACUTE
INFLAMMATION

Figure 2-21 The morphology of an ulcer. A, A chronic duodenal ulcer. B, Low-power cross-section of a duodenal ulcer crater with an acute inflammatory exudate in the
base.

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CHRONIC INFLAMMATION
 prolonged duration (wks/months) in w/c
inflammation, tissue injury, attempts of repair
coexist, in varying combinations
CAUSES OF CHRONIC INFLAMMATION

 Persistent infections (delayed-type hypersensitivity –

granulomatous rxn)
 Immune-mediated inflammatory d’ses
(autoimmune d’ses, allergic d’ses)
 Prolonged exposure to potentially toxic
agents (silicosis, atherosclerosis)
MORPHOLOGIC FEATURES OF CHRONIC
INFLAMMATION:
 Infiltration of mononuclear cells
 Tissue destruction
 Attempts at healing: angiogenesis, fibrosis

Figure 2-22 A, Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells (*), (2) destruction of
parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows). B, By
contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested.

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CELLS IN CHRONIC INFLAMMATION

 Macrophage
 Lymphocyte

 Plasma cell

 Eosinophil

 Mast cell
MACROPHAGE

Figure 2-23 Maturation of mononuclear phagocytes. (From Abbas AK et al: Cellular and Molecular Immunology, 5th ed. Philadelphia, WB Saunders, 2003.)

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MACROPHAGE

Figure 2-24 The roles of activated macrophages in chronic inflammation. Macrophages are activated by nonimmunologic stimuli such as endotoxin or by cytokines from
immune-activated T cells (particularly IFN-γ). The products made by activated macrophages that cause tissue injury and fibrosis are indicated. AA, arachidonic
acid; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; TGFβ, transforming growth factor β.

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LYMPHOCYTE

Figure 2-25 Macrophage-lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines that recruit macrophages (TNF, IL-17, chemokines) and
others that activate macrophages (IFNγ). Different subsets of T cells (called TH1 and TH17) may produce different sets of cytokines; these are described in
Chapter 6. Activated macrophages in turn stimulate T cells by presenting antigens and via cytokines (such as IL-12).

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Eotaxin –
chemokine impt for
recuitment of
eosinophil

MBP – toxic to
parasites

EOSINOPHILS
Figure 2-26 A focus of inflammation showing numerous eosinophils.

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GRANULOMATOUS INFLAMMATION

Granuloma – cellular attempt to contain the

offending agent that is difficult to eradicate;
focus of chronic inflammation consisting of a
microscopic aggregation of macrophages
that are transformed into epith.-like cells
(epithelioid cells), surrounded by a collar of
mononuclear leukocyte, principally
lymphocytes & occasional plasma cells
TYPES OF GRANULOMA

 Foreign body – incited by inert foreign bodies

foreign body-type giant cell
e.g. talc, suture

 Immune – caused by agents capable of

inducing a cell-mediated immune response;
Langhans-type giant cell
e.g. TB, leprosy, syphilis, cat-scratch dse
Figure 2-27 Typical tuberculous granuloma showing an area of central necrosis surrounded by multiple Langhans-type giant cells, epithelioid cells, and lymphocytes.

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MEDIATORS OF INFLAMMATION
 Properties & Gen. Principles of Their
Prod’n:
 Mediators are generated either from cells /
from plasma CHONs.
 Active mediators are produced in response
to various stimuli.
MEDIATORS OF INFLAMMATION
 Properties & Gen. Principles of Their
Prod’n:
 One mediator can stimulate the release of
other mediators.
 Mediators vary in their range of cellular
targets
 Once activated & released from the cell,
most of these mediators are short-lived.
MEDIATORS OF INFLAMMATION
 Cell-derived  Plasma CHON-derived
 Vasoactive amines  Complement system
 AA metabolites  Coagulation & Kinin
 PAF systems
 ROS
 NO
 Cytokines & Chemokines
 Lysosomal constituents
of Leukocytes
 Neuropeptides
Vasoactive amines
 Histamine
 dilationof arterioles
 increases permeability of venules (immediate
transient ph. of vascular permeability)
 Serotonin
 increased vascular permeability
AA metabolites
 PGs - vasodilators
 PGI2

 PGD2

 PGE2

 TxA2 – vasoconstrictor
 Leukotrienes
 LTB4 – potent chemotactic agent
 C4, D4, E4 – intense vasoconstriction,
bronchospasm, increased vascular permeability
Figure 2-11 Generation of arachidonic acid metabolites and their roles in inflammation. The molecular targets of action of some anti-inflammatory drugs are indicated by a
red X. Not shown are agents that inhibit leukotriene production by inhibition of 5-lipoxygenase (e.g., Zileuton) or block leukotriene receptors (e.g., Monteleukast). COX,
cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid.

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PAF
 plt aggregation
 vasoconstrictor
 bronchoconstriction
 vasodilation & increased venular permeability (in very low
conc’n)
 increased leukocyte adhesion to endothelium
 chemotaxis
 degranulation
 oxidative burst
 boost synthesis of eicosanoids
ROS
 Superoxide anion
 H2O2

 Hydroxyl radical

 increase
expression of chemokines, cytokines,
ELAMs (in low levels)
NO
 eNOS
 nNOS
 iNOS

 relaxes vascular smooth m.

 reduced plt aggregation & adhesion
 inhibits mast cell-induced inflammation
 inhibits leukocyte recruitment
 microbicidal
Figure 2-12 Functions of nitric oxide (NO) in blood vessels and macrophages. NO is produced by two NO synthase (NOS) enzymes. It causes vasodilation, and NO-
derived free radicals are toxic to microbial and mammalian cells.

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Cytokines

 TNF & IL-1

 endothelialactivation
 induce systemic acute-ph responses

 IL-6
 loc. & systemic rxns
 IL-17
 promotes neutrophil recruitment
Figure 2-13 Principal local and systemic actions of tumor necrosis factor (TNF) and interleukin-1 (IL-1).

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Chemokines
 C-X-C/α (IL-8)
 Activation & chemotaxis of neutrophils
 C-C/β (MCP-1, MIP-1α, RANTES)
 Attact monocytes, eosinophils, basophils, lymphocytes
 C/ɣ (lymphotactin)
 CX3C (fractalkine)
 Cell surface CHON – promotes strong adhesion of
monocyte & T cell
 Soluble form – potent chemoattractant
Lysosomal constituents of leukocytes

 Acid proteases – degrade bact. & debris

 Neutral proteases
 degrading extracellular components
 cleave C3 & C5

 Neutrophil elastase – degrade virulence

factor of bact.
Neuropeptides

 Substance P
 transmission of pain signals
 reg’n of bld pressure

 stimulation of secretion by endocrine cells

 increasing vascular permeability

 Neurokinin A
Complement system

 Inflammation
 C3a, C5a, C4a
 stimulatehistamine release
 powerful chemotactic agent for neutrophils,
monocytes, eosinophils, basophils
 Phagocytosis
 C3b, iC3b - opsonins
 Cell lysis
 MAC – makes cells permeable to water
Figure 2-14 The activation and functions of the complement system. Activation of complement by different pathways leads to cleavage of C3. The functions of the
complement system are mediated by breakdown products of C3 and other complement proteins, and by the membrane attack complex (MAC).

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Coagulation & kinin systems

 Bradykinin – increased vascular permeability

 Activated hageman factor / factor XIIa –
initiates 4 systems:
 Kinin - vasoactive
 Clotting – form’ n of thrombin

 Fibrinolytic – produced plasmin & degrade

 Complement – produces anaphylotoxins

SYSTEMIC EFFECTS OF INFLAMMATION

 Fever (PG2)
 Acute-phase proteins:
 CRP
 Fibrinogen
 SAA
 Leukocytosis
 Increased PR, BP; decreased sweating; rigors;
chills; anorexia; somnolence; malaise
 Septic shock
Figure 2-15 Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor). Note that thrombin induces inflammation
by binding to protease-activated receptors (principally PAR-1) on platelets, endothelium, smooth muscle cells, and other cells. HMWK, high molecular weight kininogen.

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CONSEQUENCES OF DEFECTIVE/X’SSIVE
INFLAMMATION
 Defective inflammation
 Increasedsusceptibility to infections
 Delayed wound healing

 X’ssive inflammation
 Allergies
fin