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* ACUTE AND CHRONIC

INFLAMMATION
Mila Amor V. Reyes, MD, FPSP
Anatomic and Clinical Pathologist

* Inflammation is the reaction of vascularized living tissue to local


injury.

* It is evoked by microbial infections, physical agents, chemicals,


necrotic tissue, and immunologic reactions.

* The roles of inflammation are to contain and isolate injury, to destroy

invading microorganisms and inactive toxins, and to prepare the tissue


or organ for healing and repair.

* Inflammation and repair maybe potentially harmful, however, causing


life threatening hypersensitivity reactions and progressive organ
damage with chronic inflammation, and may lead to permanent
scarring.

ACUTE INFLAMMATION
MAJOR EVENTS IN ACUTE INFLAMMATION

* 3 major components:
1. Alterations in vascular caliber that lead to an increase in
blood flow.
2. Structural changes in the microvasculature that permit
plasma proteins and leukocytes to leave the circulation and
to produce inflammatory exudate.
3. Emigration of the leukocytes from the microcirculation and
their accumulation in the focus of injury.

* 5 cardinal signs of inflammation:


1.
2.
3.
4.
5.

Heat (calor)
Redness (rubor)
Edema (tumor)
Pain (dolor)
Loss of function (functio laesa)

DEFINITIONS

* Exudationthe escape of fluid, proteins, and blood cells from

the vascular system into the insterstitial tissue or body cavities.


* Exudateinflammatory extravascular fluid that has a high
protein concentration, much cellular debris, & specific gravity
above 1.020.
* Transudatefluid with low protein content and a specific gravity
of less than 1.012; ultrafiltrate of blood plasma and results from
hydrostatic imbalance across the vascular endothelium.
* Edemaexcess of fluid in the interstitial tissue or serous
cavities; can be an exudate or a transudate.
* Puspurulent inflammatory exudate rich in leukocytes and
parenchymal cell debris.

I. Changes in Vascular Flow and Caliber

* Begin immediately after injury and develop at various rate


depending on the severity of the injury

Initially, transient vasoconstriction of arterioles occur.


Vasodilation follows, causing increased flow, it accounts for
the heat and redness.
Eventually, stasis occurs as a result of increased vascular
permeability, it accounts for the edema.
With slowing, the larger white cells fall out of the axial
stream, and leukocytic margination appears.

II. Increased Vascular Permeability

* Leads to the escape of protein rich fluid into the interstitium.


* Starlings law maintains that normal fluid balance is modulated

mainly by two opposing forces:

Hydrostatic pressure causing fluid to move out of the circulation

Plasma colloid osmotic pressure causing fluid to move into


capillaries
* In inflammation, there is increased hydrostatic pressure, caused
by vasodilation, and decreased osmotic pressure, caused by
leakage of high protein fluid across a hyperpermeable
endotheliummarked net outflow of fluid and edema

6 mechanisms of increase endothelial permeability


1. Endothelial contractionformation of widened intercellular
junctions or gaps; most common form; elicited by chemical
mediators (e.g., histamine); occurs immediately after
injection of the mediator; is short lived (immediate transient
response)
2. Endothelial retractiondue to cystoskeletal and junctional
reorganization; resulting in widened interendothelial
junctions; results in delayed response that can be long-lived;
induce by cytokine mediators, such as IL-1 & TNF
3. Direct endothelial injuryresulting in endothelial cell
necrosis and detachment; caused by severe necrotizing
injuries; damage usually evokes an immediate and sustained
endothelial leakage

4. Leukocyte-mediated endothelial injuryresulting from


leukocyte aggregation, adhesion, and emigration across the
endothelium; leukocytes release toxic oxygen species and
proteolytic enzymes, which cause endothelial injury or
detachment, resulting in increased permeability
5. Increased transcytosisacross the endothelial cytoplasm via
vesicles and vacuoles; growth factors (e.g., VEGF) may cause
vascular leakage by increasing the number and size of these
channels
6. Leakage from regenerating capillariesduring healing; occurs
when new capillaries sprouts are leaky

III. Cellular Events: Leukocyte Extravasation and Phagocytosis

* A critical function of inflammation is the delivery of leukocytes


to the site of injury. The sequence of events in this journey,
called extravasation, can be divided into the following steps:

1. Margination, rolling, and adhesion of leukocytes in the


lumen
2. Transmigration across the endothelium (diapedesis)
3. Migration in the interstitial tissue toward a chemotactic
stimulus (chemotaxis)

Adhesion and Transmigration

* Occur largely as a result of interactions between complementary


adhesion molecules on the leukocytes and on the endothelium
* Major ligand-receptor pairs include:

The selectins (E,P, and L)

The immunoglobulin family (ICAM-1 and VCAM-1)

The integrins (2 integrins, LFA-1 and MAC-1, 41 and 47


integrins)

ENDOTHELIAL LEUKOCYTE ADHESION MOLECULES


Endothelial Molecule Leukocyte Receptor Major Role
P-selectin
PSGL-1

Sialyl-Lewis X
Rolling (neutrophils, monocytes,
lymphocytes)

E-selectin
Sialyl-Lewis X
Rolling, adhesion to activated
ESL-1,
PSGL-1
endothelium (neutrophils,
monocytes, T
cells)
ICAM-1
CD-11/CD18 (integrins)
Adhesion, arrest, transmigration
(LFA-1, Mac-1)
(all leukocytes)
VCAM-1
47 (LPAM-1)

41 (VLA4) (integrins)
Adhesion (eosinophils,
monocytes, lymphocytes)

GlyCam-1
CD34

L-selectin

Lymphocyte homing to high


endothelial venules
Neutrophil, monocyte rolling

Chemotaxis and Leukocyte Activation

* Adherent leukocytes emigrate through interendothelial

junctions, traverse the basement membrane, and move toward


the site of injury along a gradient of chemotactic agents
* Neutrophils emigrate first, monocytes and lymphocytes follow
* Chemotactic agents for neutrophils include bacterial products,
complements fragments (e.g., C5a), arachidonic acid
metabolites (e.g., leukotriene B4), and chemokines (e.g., IL-8)
* Chemotaxis involves binding of chemotactic agents to specific
receptors on leukocytes and production of second messengers
* Signal transduction process results in activation of
phospholipase C and protein kinase C, increased intracellular
calcium and assembly of the contractile elements responsible
for cell movement: leukocyte moves by extending a pseudopod
that pulls the remainder of the cell in the direction of extension

Phagocytosis

* Phagocytosis involves three steps:


1. Recognition and attachment of the particles by the leukocyte
microorganisms are coated with specific factors, called
opsonins, which enhance the efficiency of phagocytosis
because they are recognized by the receptors on the
leukocytes

The two major opsoninsFc fragments of the IgG and C3b

2. Engulfment by pseudopods encircling the phagocytosed


particlewith subsequent formation of phagosome

The membrane of the phagosome then fuses with the membrane


of a lysosomal granule, resulting in discharge of the granules
content into the phagolysosome

3. Killing and degradation of bacteriaphagocytosis stimulates a


burst of oxygen consumption and production of reactive
oxygen metabolites

*.

There are two types of bactericidal mechanisms:


a.

Oxygen dependent mechanismstriggered by activation of


NADPH oxidase, reducing O2 to O2- and hence to H2O2; MPO from
lysosomal granules then converts H2O2, in the presence of a
halide such as Cl-, to a highly bactericidal HOCl

b.

H2O2-MPO-halide system is the most efficient bactericidal mechanism,


the reactive O2 species produced during an oxidative burst can kill
bacteria directly

Oxygen independent mechanismsincludes bactericidal


permeability increasing protein, lysozyme, lactoferrin, MBP of
eosinophils, and arginine rich defensins; killed organisms are
then degraded by hydrolases and other enzymes in lysosomes

Release of Leukocyte Products and Leukocyte-Induced Tissue


Injury

* During phagocytosis, leukocytes release products not only within


the phagolysosome but also potentially into the extracellular
space
* These release products include:
1.
2.
3.

Lysosomal enzymes
Oxygen derived active metabolites
Products of arachidonic acid metabolism including prostaglandins
and leukotrienes

*.

These products are powerful mediators of tissue damage and


amplify the effects of the initial inflammatory stimulus
If persistent, the leukocyte dependent tissue can cause chronic
inflammation

*.

CLINICAL EXAMPLES OF LEUKOCYTE-INDUCED TISSUE INJURY

Acute

Chronic

Acute respiratory distress syndrome


Acute transplant rejection
Asthma
Glomerulonephritis
Reperfusion injury
Septic shock
Vasculitis

Arthritis
Asthma
Atherosclerosis
Chronic lung disease
Chronic rejection
Others

Defects in Leukocyte Function

* Interfere with inflammation and increase susceptibility to

infections
* Include both genetic and acquired defects, such as neutropenia
* Clinical genetic deficiencies include the following:
1.

2.

3.

Defects in leukocyte adhesion, such as leukocyte adhesion


deficiency type I and type IIresult in impaired leukocyte
adhesion and recurrent bacterial infections
Defects in phagocytosis such as Chediak-Higashi syndromePMNs
have giant granules because of abberant organelle fusion and
reduced transfer of lysosomal enzymes to phagocytic vacuoles,
causing susceptibility to infections
Defects in microbial activity such as CGDinherited defects in
NADPH oxidase, leading to a defect in the respiratory burst,
H2O2-MPO-halide bactericidal mechanism

DEFECTS IN LEUKOCYTE FUNCTIONS


DISEASE

DEFECT

Genetic
Leukocyte adhesion deficiency 1
Leukocyte adhesion deficiency 2
Neutrophil-specific granule
deficiency
Chronic granulomatous disease
X-linked
Autosomal recessive
Myeloperoxidase deficiency
Chdiak-Higashi syndrome

chain of CD11/CD18 integrins


Sialylated oligosaccharide (receptor
for selectin)
Absence of neutrophil-specific
granules
Defective chemotaxis
Decreased oxidative burst
NADPH oxidase
(membrane component)
NADPH oxidase
(cytoplasmic components)
Absent MPO-H2O2Halide system
Membrane-associated protein involved
in organelle membrane docking
and fusion

Acquired
Thermal injury, diabetes,
malignancy, sepsis,
immunodeficiency
Hemodialysis, diabetes mellitus
Leukemia, anemia, sepsis,
diabetes, neonates,
malnutrition

Chemotaxis
Adhesion
Phagocytosis and microbicidal
activity

SUMMARY

* The vascular phenomena in acute inflammation are

characterized by increased blood flow to the injured area,


resulting mainly from arteriolar dilation and opening of
capillary beds.

* Increased vascular permeability results in the accumulation of


protein-rich extavascular fluid, which forms the exudate.

* Plasma proteins leave the vessels most commonly through

widened interendothelial cell junctions of the venules or by


direct endothelial cell injury.

* The leukocytes, initially predominantly neutrophils, adhere


to the endothelium via adhesion molecules, transmigrate
across the endothelium, and migrate to the site of injury
under the influence of chemotactic agents.

* Phagocytosis of the offending agent follows, which may lead


to the death of the microorganism.

* During chemotaxis and phagocytosis, activated leukocytes

may release toxic metabolites and proteases extracellularly,


potentially causing tissue damage.

CHEMICAL MEDIATORS OF INFLAMMATION

* The vascular and white cell events described previously are

brought about by variety of chemical mediators, derived either


from plasma or from cells.
* Once activated and released, most mediators are short lived,
either quickly decaying or becoming inactivated by enzymes or
inhibited by inhibitors.

Vasoactive Amines

* Histamine and serotoninamong the first mediators to be

release during inflammation; cause vasodilation and increase


vascular permeability
* Released from mast cells is caused by:

Physical agents (e.g., trauma, heat)


Immunologic reactionsbinding of IgE antibodies to mast cells
Complement fragments C3a and C5a (anaphylatoxins)
Neuropeptides (substance P)
Cytokines (IL-1 and IL-8)
Histamine releasing factors derived from leukocytes

Released from platelets is stimulated by: contact with


collagen, thrombin, ADP, antigen-antibody complexes, and by
PAF

Plasma Proteases

* There are interrelated plasma derived mediators that play key

roles in inflammatory responses:


1. Complement system
2. Kinin sytem
3. Clotting factor system

i.

Complement system

* Activation of complement functions in host defense against

microbial agents, culminating in the assembly of the MAC and lysis


of the offending agent
* In the process, complement components are generated that caused
increased vascular permeability, chemotaxis and opsonization
* Activation of complement occurs via two general mechanisms:
1.
2.

The classic pathwayinitiated by antigen-antibody complexes


The alternate pathwayactivated by endotoxin, complex
polysaccharides, and aggregated globulins

* Complement components with inflammatory activity include:


.C3aincreases vascular permeability
.C5aincreases vascular permeability, highly chemotactic to WBCs
.C3b and C3bithe opsonins important in phagocytosis
.C5b-9MAC that lyses cells and stimulates arachidonic acid metabolism
and production of reactive oxygen metabolites by leukocytes

The complement system is closely controlled by protein


inhibitors including the following:
1. Regulation of C3 and C5 convertases, by decay accelerating
factor

Paroxysmal nocturnal hemoglobinuriacells lack the ability to


express membrane proteins, including decay accelerating factor;
characterized by recurrent bouts of intravascular hemolysis
resulting from complement-mediated lysis of red blood cells,
leading to chronic hemolytic anemia

2. Binding of active complement components by specific


proteins in the plasma, such as by C1 inhibitor

Deficiency of C1 inhibitor is associated with the syndrome of


hereditary angioneurotic edemaepisodic edema accumulation
in the skin and extremities as well as in the laryngeal and
intestinal mucosa, provoked by emotional stress or trauma

ii. Kinin System

* Generates vasoactive peptides from plasma proteins called

kininogens by specific proteases called kallikreins, ultimately


resulting in the production of bradykinin, a potent stimulator of
increase vascular permeability
* CF XIIa converts plasma prekallikrein into kallikrein
* Kallikrein in an autocatalytic loop is a potent activator of Hageman
factor, has chemotactic activity, and causes neutrophil aggregation;
resulting in profound amplification of the effects of the initial
contact

iii. Clotting System

*.The clotting system is divided into two interrelated systems,


designated as the intrinsic and extrinsic pathways, that
converged to activate a primary hemostatic mechanism.

1. The intrinsic pathwayactivated by Hageman factor


*

During this process, fibrinopeptides are formed that induce


vascular permeability and are chemotactic for leukocytes.

2. At the same time factor XIIa can also activate the fibrinolytic
system, which produces plasmin and degrades fibrin
*

Plasmin can contribute to inflammation in several ways:

Cleave C3 to produce C3 fragment


Form fibrin split products, which may increase vascular permeability
Activate Hageman factor, amplifying the response

Arachidonic Acid Metabolites


Eicosanoids are synthesized from arachidonic acids by two major
classes of enzymes:
* Cyclooxygenasesgenerate prostaglandins and thromboxanes
* Lipoxygenasesproduce leukotrienes and lipoxins
* The inflammatory prostaglandins and leukotrienes are:
Prostaglandin I2 (prostacyclin) and prostaglandin E2cause vasodilation
Prostaglandin E2 is hyperalgesicmakes the skin hypersensitive to painful
stimuli
Thromboxane A2causes vasoconstriction
Leukotrienes C4, D4, and E4cause increased vascular permeability and
vasoconstriction
Leukotriene B4powerful chemotactic agent
Lipoxins may be endogenous negative regulators of leukotriene action

Platelet-Activating Factor
* Produced by mast cells and other leukocytes
* Causes platelet aggregation and release, bonchoconstriction,
vasodilation, increased vascular permeability, increased
leukocyte adhesion, and chemotaxis

Cytokines

* Cytokines are proteins produced principally by activated


lymphocytes and macrophages.

MONOKINEScytokines generated by mononuclear phagocytes


LYMPHOKINEScytokines generated by active lymphocytes
Colony Stimulating Factors (CSF)cytokines that are produced by
monocytes and macrophages that stimulate the growth of immature
leukocytes in the bone marrow
INTERLEUKINS (IL)broad family of cytokines that are made by the
hematopoietic cells and act primarily on leukocytes
CHEMOKINEScytokines that share the ability to stimulate
leukocyte movement (chemokinesis) and directed movement
(chemotaxis), particularly important in inflammation

* General Properties and Classes of Cytokines

Cytokines are produced during immune and inflammatory


responses.
Many cell types produce multiple cytokines.
The proteins are pleiotropic in that they can act on different cell
types.
Cytokine effects are often redundant, and these proteins can
influence the synthesis or action of other cytokines.
Cytokines are multifunctional in that an individual cytokine may
have both positive and negative regulatory actions.
Cytokines mediate their effects by binding to specific receptors
on target cells.

Functions of Cytokines
*. Cytokines that regulate lymphocyte function

Regulate lymphocyte activation, growth, and differentiation (e.g., IL-2


and IL-4, which favor lymphocyte growth; IL-10 and TGF-, which are
negative regulators of immune responses)

*. Cytokines involved with natural immunity

Includes the inflammatory cytokines (e.g., TNF- and IL-1), type I IFN
(IFN- and IFN- ), and IL-6

*. Cytokines that activate inflammatory cells

Activate macrophages during cell mediated immune responses (e.g., IFN, TNF- , IL-5, IL-10, and IL-12)

*. Chemokines

Cytokines characterized by chemotactic activity for various


leukocytes (e.g., IL-8)

*. Cytokines that stimulate hematopoiesis

Mediate immature leukocyte growth and differentiation (e.g., IL-3, IL7, c-kit ligand, GM-CSF, M-CSF, G-CSF, and stem cell factor)

IL-1 and TNF-major cytokines that mediate inflammation and


are produced by activated macrophage

* Their most important actions in inflammation are their effects on

endothelium, leukocytes and induction of the systemic acutephase reactions


* Induce endothelial activationinduction of endothelial adhesion
molecules and chemical mediators, production of enzymes
associated with matrix remodeling, and increases the surface
thrombogenicity of the endothelium
* Induce the systemic acute-phase responses associated with
infection or injuryfever, loss of appetite, production of sleep,
release of neutrophils into the circulation, release of ACTH and
corticosteroids
* TNFinduce hemodynamic effects of septic shock (hypotension,
decreased vascular resistance, increased heart rate, and decreased
blood pH)

TNF- (cachectin) has a key role in the normal control of body mass

Nitric Oxide

* Also known as endothelium-derived relaxation factor


* Causes vasodilation; inhibits platelet aggregation and adhesion;
and may act as a free radical, becoming cytotoxic to certain
microbes and tumor cells
* 3 types of Nitric Oxide Synthase:
Endothelial (eNOS)
Neuronal (nNOS)
Cytokine inducible [iNOS]

* NO has many properties, including the following:


Plays an important role in vascular function during an inflammatory
response
Acts in the host response to infectioninteractions occur between NO
and reactive O2 species, leading to the formation of multiple
antimicrobial metabolites at the potential cost of inflammatory damage
to host cells and tissue

Lysosomal Constituents of Leukocytes

* Neutrophils and monocytes contain lysosomal granules, which


when released may contribute to the inflammatory response
and to tissue injury.
* Neutrophils have two main types of granules:
1.

Smaller specific (or secondary) granulescontain lysozyme,

type IV collagenase, gelatinase, lactoferrin, plasminogen


activator, histaminase, alkaline phosphatase, leukocyte
adhesion molecules, and phospholipase A2
2.

Large azurophil (or primary) granulescontain


myeloperoxidase, bactericidal factors (lysozyme defensins),
acid hydrolases, cationic proteins, phospholipase A2, and a
variety of neutral proteases (elastase, cathepsin G, nonspecific collagenases, proteinase 3)

* Lysosomal constituentscan potentiate further increases in


vascular permeability and chemotaxis and cause tissue
damage

These harmful proteases, however, are held in check by a


system of antiproteases in the serum and tissue fluid
1-antitrypsinmajor inhibitor of neutrophilic elastase
Deficiency of these inhibitor may lead to sustained action of
leukocyte proteases, as is the case in patients with
1-antitrypsin deficiency

Oxygen-Derived Free Radicals

* Include O2.-,H2O2, and OH.these metabolites can combine with

NO to form other reactive nitrogen intermediates, which cause:

Endothelial cell damage with increased vascular permeability


Inactivation of antiproteases, leading to unopposed protease
activity
Injury to a variety of cell types (e.g., tumor cells, red cells,
parenchymal cells)

* Oxygen metabolites are detoxified by:


.Antioxidantsserum proteins (ceruloplasmin and transferrin),
enzymes (superoxide dismutase, catalase, and glutathione
peroxidase)
.Net effects on tissue injury of oxygen metabolites depend on the
balance between their production and termination

Neuropeptides

* Neuropeptides play a role in the initiation of an inflammatory


response
* Substance P
Functions: transmission of pain signals, regulation of blood
pressure, and stimulation of secretion by immune and
endocrine cells
Powerful mediator of vascular permeability

SUMMARY OF MEDIATORS OF ACUTE INFLAMMATION


Mediator

Source

Vascular Leakage

Chemotaxis

Other

Histamine and serotonin

Mast cells and platelets

Bradykinin

Plasma substrate

Pain

C3a

Plasma protein via liver

Opsonic fragment (C3b)

C5a

Macrophages

Leukocyte adhesion,
activation

Prostaglandins

Mast cells, from membrane


phospholipids

Potentiate other mediators

Vasodilation, pain, fever

Leukotriene B4

Leukocytes

Leukocyte adhesion,
activation

Leukotriene C4, D4, E4

Leukocytes, mast cells

Bronchoconstriction,
vasoconstriction

Oxygen metabolites

Leukocytes

Endothelial damage, tissue

PAF

Leukocytes, mast cells

Bronchoconstriction,
leukocyte priming

IL-1 and TNF

Macrophages, other

Acute phase reactions,


endothelial activation

Chemokines

Leukocytes, other

Leukocyte activation

* During the early course of inflammation, increased vascular

permeability is mediated by histamine; the anaphylatoxins (C3a


and C5a); the kinins; leukotrienes C, D, and E; PAF; and
substance P.

* For chemotaxis, complement fragment C5a, lipoxygenase


products (leukotriene B4), other chemotactic lipids, and
chemokines are the most likely protagonist.

* Additionally, prostaglandins play an important role in

vasodilation, pain, and fever and in potentiating edema.

* IL-1 and TNF are involved with endothelial-leukocyte


interactions and with acute phase reactions.

* Lysosomal products and oxygen-derived radicals are the most


likely candidates as causes of the ensuing tissue destruction.

* Nitric oxide is involved in vasodilation and cytotoxicity.

Outcome of Acute Inflammation


1. Complete resolutionregeneration of native cells and
restoration of the site to normal
2. Abscess formationinfections by pyogenic organisms
3. Healing by connective tissue replacement (fibrosis) and
scarring occurs after substantial tissue destruction, when
the inflammation occurs in tissues that do not regenerate,
or when there is abundant fibrin exudation
4. Progression to chronic inflammation

CHRONIC INFLAMMATION
* Inflammation of prolonged duration (weeks or months) in

which active inflammation, tissue destruction, and attempts


at healing may be all proceeding simultaneously
* Arises in several ways:
1. May follow acute inflammation, because of some interference
in the process of healing
2. May results from repeated bouts of acute inflammation
3. Begins insidiously as a low grade response
Persistent infections by intracellular microbes which are of low
toxicity but evoked an immunologic reaction (e.g., tb, viral
infection)
Prolonged exposure to potentially toxic exogenous (e.g., silica,
asbestos) or endogenous substances (e.g., plasma lipid
components and atherosclerosis)
Immune reactions, perpetuated against the individuals own
tissues (e.g., SLE, RA, Sjogrens syndrome, Systemic Sclerosis)

* In contrast to acute inflammation, which is manifested by

vascular changes, edema and largely neutrophilic infiltration,


chronic inflammation is characterized by:

Infiltration with mononuclear cells (macrophages, lymphocytes,


and plasma cells)
Tissue destruction, largely induced by the inflammatory cells
Attempts at repair by connective tissue replacement (fibrosis)
and proliferation of small blood vessels (angiogenesis)

Mononuclear Infiltration: Cells and Mechanisms


MACROPHAGES
* Macrophages are the major cellular players in chronic
inflammation
Derived from peripheral blood monocytes that have been induced
to emigrate across the endothelium; when the monocytes reaches
the extravascular tissue, it transform into a large phagocytic cell,
the macrophage
Central figures in chronic inflammationgreat number of
biologically active products they can secrete
Macrophages are important host defense, some of these mediators
induce the tissue damage characteristic of chronic inflammation
Secretory products can be toxic to cells (reactive oxygen and nitric
oxide metabolites) or extracellular matrix (protease)
Other products cause fibroblast proliferation, connective tissue
production, and angiogenesis (cytokines and growth factors)

PRODUCTS RELEASED BY MACROPHAGES


1. Enzymes
2. Neutral proteases
3. Elastase
4. Collagenase
5. Plasminogen activator
6. Acid hydrolases
7. Phosphates
8. Lipases
9. Plasma proteins
10.Complement components (e.g., C1 to C5, properdin)
11.Coagulation factors (e.g., factors V, VIII, tissue factor)
12.Reactive metabolites of oxygen
13.Eicosanoids
14.Cytokinesis, chemokines (IL-1, TNF, IL-8)
15.Growth factors (PDGF, EGF, FGF TGF-)
16.Nitric oxide

Other Cells Chronic Inflammation


1. LYMPHOCYTES

*
*
*
*

Can be activated by contact with antigen and nonspecifically by


bacterial endotoxin
Activated lymphocytes produce lymphokines, and these
(particularly IFN-) are major stimulators of monocytes and
macrophages
Activated macrophages produces monokines, which, in turn,
stimulates B-cell and T-cell function (particularly IL1, TNF)
Plasma cells produce antibodies directed against either foreign
antigen or altered tissue components

2. MAST CELLSwidely distributed in connective tissues and


participate in both acute and persistent inflammatory
reactions

*
*
*
*

Express on their surface the receptor that binds the Fc portion of


the IgE antibody
In acute reactions, binding of IgE antibodies on cells Fc
receptors cause degranulation and release mediators, such as
histamine
This type of response occurs during anaphylactic reactions to
food, insect venom, or drugs
Specific types of parasite infections are also associated with
increased levels of IgE and activation of mast cells

3. EOSINOPHILScharacteristic of immune reactions mediated


by IgE and of parasitic infections

*
*
*

Recruitment depends on eotaxin, a member of chemokines


Have granules that contain MBPhighly cationic protein that is
toxic to parasites but also causes lysis of mammalian epithelial
cells
May be of benefit in parasitic infection but contribute to tissue
damage in immune reactions

Granulomatous Inflammation

* Distinctive chronic inflammatory reaction in which the

predominant cell type is an activated macrophage with a


modified epithelial-like (epithelioid cell) appearance
Encountered in chronic immune and infectious diseases, such as
tuberculosis, sarcoidosis, and syphilis
Characterized by granulomasfocal collections epithelioid
macrophages that are surrounded by a collar of fibroblasts,
mononuclear leukocytes, principally lymphocytes and occasionally
plasma cells; epithelioid cells may coalesce to form multinucleated
giant cells; central necrosis may also be present in some
granulomas

* There are two types of granulomas:


1. Foreign body granulomasincited by relatively inert foreign
bodies
2. Immune granulomasformed by immune T-cell-mediated
reactions to poorly degradable antigens
IFN- from activated T-cells, cause transformation of
macrophages to epitheloid cells and multinucleated giant
cells; e.g., M. tuberculosis bacillusthe granuloma is
referred to as a tubercle and characterized by the presence
of central caseous necrosis

EXAMPLES OF GRANULOMATOUS INFECTIONS


Disease

Cause

Tissue Reaction

Tuberculosis

Mycobactrium tuberculosis

Noncaseating tubercle
(granuloma prototype): a focus
of epithelioid cell, rimmed by
fibroblast, lymphocytes,
histiocytes, occasional Langhans
giant cell; caseating tubercle:
central amorphous granular
debris, loss of all cellular detail;
acid-fast bacilli

Leprosy

Mycobacterium leprae

Acid-fast bacilli in macrophages;


granulomas and epithelioid types

Syphillis

Treponema pallidum

Gumma: microscopic to grossly


visible lesion, enclosing wall of
histiocytes; plasma cell
infiltrate; center cells are
necrotic without loss of cellular
outline

Cat-scratch disease

Gram-negative bacillus

Rounded or stellate granuloma


containing central granular
debris and recognizable
neutrophils; giant cells
uncommon

Morphologic Patterns in Acute and Chronic Inflammation

* Inflammatory responses often have certain features that point


to their possible cause and create a distinctive morphologic
patterns:
1.

Serous inflammationimplies a modest increase in vascular


permeability; marked by an accumulation of fluid (e.g., skin
burn blisters)
when it occurs in the peritoneal, pleural, and pericardial
cavities, is called an effusion

2.

Fibrinous inflammationoccurs when the injury causes a more


marked increased in vascular permeability

exudate contains large amounts of fibrinogen, which is converted to


fibrin as a result of the coagulation system
when a serosal surface is involved, such as the pericardium, pleura,
or peitoneumfibrinous pericarditis, pleuritis, or peritonitis

3.

Suppurative or purulent inflammationcharacterized by the


production of purulent exudates or pus consisting of white blood
cells and necrotic cells
Abscesslocalized collection of purulent inflammatory tissue
that is accompanied by liquefactive necrosis

4.

Ulcerslocal defects, or excavation, of the surface of an organ


or tissue that are produced by the sloughing (shedding) of
inflammatory necrotic tissue

5.

Granulomatous inflammationa type of chronic inflammation


characterized by the presence of granulomas

Systemic Effects of Inflammation

* Endocrine and metabolicsecretion of acute-phase proteins by


the liver (including CRP, serum amyloid A, complement and
coagulation proteins)

* Autonomicredirection in blood flow from cutaneous to deep

vascular beds, to minimize heat loss through the skin; increased


pulse and blood pressure; and decrease sweating

* Behavioralrigors (shivering), chills (search for warmth),


anorexia, somnolence, and malaise

* Fever
Elevation of body temperature, usually by 1 to 4oC.
Cytokines play a key role in signaling feverIL-1, IL-6, and TNF-

*. Leukocytosis

Extreme elevationsleukemoid reactions


Leukocytosis occurs because of proliferation of precursors in
the bone marrow and the accelerated released of cells from
the bone marrow, induced by CSF

*. Most bacterial infections induced neutrophilia, but some


viral infections produce lymphocytosis

Eosinophiliaoccur in bronchial asthma, hay fever, and


parasitic infestations
Leukopeniacan be encountered in certain infections (e.g.,
typhoid fever and infections caused by viruses, rickettsiae,
and certain protozoa); also, in infections that overwhelm
patients debilitated by disseminated cancer

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