Acute and Chronic Inflammation

Dr. Dyah marianingrum, Mkes, Sp.PA

 Overview of Inflammation
• Essential to the survival of organisms is their
ability to get rid of damaged or necrotic
tissues and foreign invaders, such as
microbes.
• The host response that accomplishes these
goals is called inflammation.
• This is fundamentally a protective response,
designed to rid the organism of both the
initial cause of cell injury
• Inflammation is a complex reaction in tissues that
consists mainly of responses of blood vessels and
leukocytes.
• The body's principal defenders against foreign
invaders are plasma proteins and circulating
leukocytes (white blood cells), as well as tissue
phagocytes that are derived from circulating cells.
Acute Inflammation

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
 STIMULI FOR ACUTE INFLAMMATION

• Infections (bacterial, viral, fungal, parasitic) and microbial toxins are

among the most common and medically important causes of
inflammation
• Tissue necrosis from any cause, including ischemia (as in a
myocardial infarct), trauma, and physical and chemical injury (e.g.,
thermal injury, as in burns or frostbite; irradiation; exposure to
some environmental chemicals).
• Foreign bodies (splinters, dirt, sutures) typically elicit inflammation
because they cause traumatic tissue injury
• Foreign bodies (splinters, dirt, sutures) typically
elicit inflammation because they cause traumatic
tissue injury
• Immune reactions (also called hypersensitivity
reactions) are reactions in which the normally
protective immune system damages the
individual's own tissues
• The injurious immune responses may be directed
against self antigens, causing autoimmune
diseases
REACTIONS OF BLOOD VESSELS IN ACUTE INFLAMMATION
Increased Vascular Permeability (Vascular Leakage)
 REACTIONS OF LEUKOCYTES IN INFLAMMATION

The journey of leukocytes from the vessel lumen to the interstitial

tissue, called extravasation.
can be divided into the following steps:
• 1. In the lumen: margination, rolling, and adhesion to endothelium.
Vascular endothelium in its normal, unactivated state does not bind
circulating cells or impede their passage.
In inflammation the endothelium is activated and can bind
leukocytes, as a prelude to their exit from the blood vessels.
• 2. Migration across the endothelium and vessel wall
• 3. Migration in the tissues toward a chemotactic stimulus
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.
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).
 Phagocytosis.

• Phagocytosis involves three sequential steps

(1) recognition and attachment of the
particle to be ingested by the leukocyte;
• (2) its engulfment, with subsequent
formation of a phagocytic vacuole;
• (3) killing or degradation of the ingested
material
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.
 Other Functional Responses of Activated Leukocytes

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
 TERMINATION OF THE ACUTE INFLAMMATORY RESPONSE

• It is predictable that such a powerful system of host

defense, with its inherent capacity to cause tissue
damage, needs tight controls to minimize the
damage.
• In part, inflammation declines simply because the
mediators of inflammation are produced in rapid
bursts, only as long as the stimulus persists, have
short half-lives, and are degraded after their release.
Neutrophils also have short half-lives in tissues and
die by apoptosis within a few hours after leaving the
blood.
• These active termination mechanisms include a switch in
the type of arachidonic acid metabolite produced, from pro-
inflammatory leukotrienes to anti-inflammatory lipoxins
(described below);
• the liberation of anti-inflammatory cytokines, including
transforming growth factor-β (TGF-β) and IL-10, from
macrophages and other cells;
• the production of anti-inflammatory lipid mediators, called
resolvins and protectins, derived from polyunsaturated fatty
acids; and neural impulses (cholinergic discharge) that
inhibit the production of TNF in macrophages.
 Mediators of Inflammation

• the general principles of their production and

actions.
• Mediators are generated either from cells or from
plasma proteins.
• Cell-derived mediators are normally sequestered
in intracellular granules and can be rapidly
secreted by granule exocytosis (e.g., histamine in
mast cell granules) or are synthesized de novo
(e.g., prostaglandins, cytokines) in response to a
stimulus.
• Active mediators are produced in response to
various stimuli.
• These stimuli include microbial products,
substances released from necrotic cells, and the
proteins of the complement, kinin, and
coagulation systems, which are themselves
activated by microbes and damaged tissues.
• This requirement for microbes or dead tissues
as the initiating stimulus ensures that
inflammation is normally triggered only when
and where it is needed.
• The major cell types that produce mediators of
acute inflammation are platelets, neutrophils,
monocytes/macrophages, and mast cells, but
mesenchymal cells (endothelium, smooth
muscle, fibroblasts) and most epithelia can also
be induced to elaborate some of the mediators.
• Plasma-derived mediators (e.g., complement
proteins, kinins) are produced mainly in the liver
and present in the circulation as inactive
precursors that must be activated, usually by a
series of proteolytic cleavages, to acquire their
biologic properties.
• One mediator can stimulate the release of other
mediators.
• For instance, the cytokine TNF acts on
endothelial cells to stimulate the production of
another cytokine, IL-1, and many chemokines.
• The secondary mediators may have the same
actions as the initial mediators but may also
have different and even opposing activities.
Such cascades provide mechanisms for
amplifying—or, in certain instances,
counteracting—the initial action of a mediator.
• Mediators vary in their range of cellular
targets. They can act on one or a few target
cell types, can have diverse targets, or may
even have differing effects on different types
of cells
• Once activated and released from the cell, most
of these mediators are short-lived.
• They quickly decay (e.g., arachidonic acid
metabolites) or are inactivated by enzymes (e.g.,
kininase inactivates bradykinin), or they are
otherwise scavenged (e.g., antioxidants
scavenge toxic oxygen metabolites) or inhibited
(e.g., complement regulatory proteins break up
and degrade activated complement
components).
• There is thus a system of checks and balances
that regulates mediator actions.
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.
 PLASMA PROTEIN–DERIVED MEDIATORS
A variety of phenomena in the inflammatory response are
mediated by plasma proteins that belong to three interrelated
systems: the complement, kinin, and clotting systems.

• Complement System
• The complement system consists of more than 20 proteins, some
of which are numbered C1 through C9.
• This system functions in both innate and adaptive immunity for
defense against microbial pathogens.
• In the process of complement activation several cleavage products
of complement proteins are elaborated that cause increased
vascular permeability, chemotaxis, and opsonization
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).
 Coagulation and Kinin Systems

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.
 Outcomes of Acute Inflammation
• 1. Complete resolution.
• In a perfect world, all inflammatory reactions,
once they have succeeded in neutralizing and
eliminating the injurious stimulus, should end with
restoration of the site of acute inflammation to
normal.
• This is called resolution and is the usual outcome
when the injury is limited or short-lived or when
there has been little tissue destruction and the
damaged parenchymal cells can regenerate.
Resolution involves removal of cellular debris and
microbes by macrophages, and resorption of
edema fluid by lymphatics.
• 2. Healing by connective tissue replacement (fibrosis).
• This occurs after substantial tissue destruction, when
the inflammatory injury involves tissues that are
incapable of regeneration, or when there is abundant
fibrin exudation in tissue or serous cavities (pleura,
peritoneum) that cannot be adequately cleared.
• In all these situations, connective tissue grows into
the area of damage or exudate, converting it into a
mass of fibrous tissue—a process also called
organization.

• 3. Progression of the response to chronic

inflammation
Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation.
 Morphologic Patterns of Acute Inflammation
The morphologic hallmarks of all acute inflammatory reactions are dilation of small blood
vessels, slowing of blood flow,
and accumulation of leukocytes and fluid in the extravascular tissue .
The importance of recognizing the gross and microscopic patterns is that they often provide
valuable clues about the underlying cause.

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.
 SEROUS INFLAMMATION

Serous inflammation is marked by the outpouring of a thin fluid

that may be derived from the plasma or from the secretions of
mesothelial cells lining the peritoneal, pleural, and pericardial
cavities.
Accumulation of fluid in these cavities is called an effusion.
The skin blister resulting from a burn or viral infection
represents a large accumulation of serous fluid, either within or
immediately beneath the epidermis of the skin
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.
 SUPPURATIVE OR PURULENT INFLAMMATION; ABSCESS

• This type of inflammation is characterized by the production

of large amounts of pus or purulent exudate consisting of
neutrophils, liquefactive necrosis, and edema fluid.
• Abscesses are localized collections of purulent inflammatory
tissue caused by suppuration buried in a tissue, an organ, or
a confined space.
• They are produced by deep seeding of pyogenic bacteria
into a tissue
• Abscesses have a central region that appears as a mass of
necrotic leukocytes and tissue cells.
• There is usually a zone of preserved neutrophils around this
necrotic focus, and outside this region vascular dilation and
parenchymal and fibroblastic proliferation occur, indicating
chronic inflammation and repair
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.
 ULCERS
• An ulcer is a local defect, or excavation, of the surface
of an organ or tissue that is produced by the
sloughing (shedding) of inflamed necrotic tissue .
• Ulceration can occur only when tissue necrosis and
resultant inflammation exist on or near a surface.
• It is most commonly encountered in :
(1) the mucosa of the mouth, stomach, intestines, or
genitourinary tract;
(2) the skin and subcutaneous tissue of the lower
extremities in older persons who have circulatory
disturbances that predispose to extensive ischemic
necrosis.
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.
 Chronic Inflammation

• Chronic inflammation is inflammation of

prolonged duration (weeks or months) in which
inflammation, tissue injury, and attempts at
repair coexist, in varying combinations.
• It may follow acute inflammation, as described
earlier, or chronic inflammation may begin
insidiously, as a low-grade, smoldering
response without any manifestations of an
acute reaction.
• This latter type of chronic inflammation is the cause
of tissue damage in some of the most common and
disabling human diseases, such as rheumatoid
arthritis, atherosclerosis, tuberculosis, and
pulmonary fibrosis.
• It has also been implicated in the progression of
cancer and in diseases once thought to be purely
degenerative, such as Alzheimer disease.
Chronic inflammation arises in the following settings

• 1. Persistent infections by microorganisms that

are difficult to eradicate, such as mycobacteria,
and certain viruses, fungi, and parasites.
• These organisms often evoke an immune reaction
called delayed-type hypersensitivity
• 2. Immune-mediated inflammatory diseases.
Chronic inflammation plays an important role
in a group of diseases that are caused by
excessive and inappropriate activation of the
immune system.
• Under certain conditions immune reactions
develop against the individual's own tissues,
leading to autoimmune diseases .
• AUTOIMMUNE DISEASE, auto-antigens evoke
a self-perpetuating immune reaction that
results in chronic tissue damage and
inflammation; examples of such diseases are
rheumatoid arthritis and multiple sclerosis.
• In other cases, chronic inflammation is the
result of unregulated immune responses
against microbes, as in inflammatory bowel
disease.
• Prolonged exposure to potentially toxic agents,
either exogenous or endogenous.
• An example of an exogenous agent is
particulate silica, a nondegradable inanimate
material that, when inhaled for prolonged
periods, results in an inflammatory lung disease
called silicosis .
• Atherosclerosis is thought to be a chronic
inflammatory process of the arterial wall
induced, at least in part, by endogenous toxic
plasma lipid components
 MORPHOLOGIC FEATURES
• 1. Infiltration with mononuclear cells, which
include macrophages, lymphocytes, and plasma
cells
• 2. Tissue destruction, induced by the persistent
offending agent or by the inflammatory cells
• 3. Attempts at healing by connective tissue
replacement of damaged tissue, accomplished by
proliferation of small blood vessels (angiogenesis)
and, in particular, fibrosis
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.
 ROLE OF MACROPHAGES IN CHRONIC INFLAMMATION
• The macrophage is the dominant cellular player in chronic
inflammation, and we begin our discussion with a brief
review of its biology.
• Macrophages are one component of the mononuclear
phagocyte system
• Mononuclear phagocytes arise from a common precursor in
the bone marrow, which gives rise to blood monocytes.
• From the blood, monocytes migrate into various tissues and
differentiate into macrophages.
• The half-life of blood monocytes is about 1 day, whereas the
life span of tissue macrophages is several months or years.
The journey from bone marrow stem cell to tissue
macrophage is regulated by a variety of growth and
differentiation factors, cytokines, adhesion molecules, and
cellular interactions.
Maturation of mononuclear phagocytes.
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.
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).
 GRANULOMATOUS INFLAMMATION

• Granulomatous inflammation is a distinctive pattern of

chronic inflammation that is encountered in a limited
number of infectious and some noninfectious conditions.
Immune reactions are usually involved in the development
of granulomas,.
• Briefly, a granuloma is a cellular attempt to contain an
offending agent that is difficult to eradicate. In this attempt
there is often strong activation of T lymphocytes leading to
macrophage activation, which can cause injury to normal
tissues.
• Tuberculosis is the prototype of the granulomatous
diseases, but sarcoidosis, cat-scratch disease,
lymphogranuloma inguinale, leprosy, brucellosis, syphilis,
some mycotic infections, berylliosis, reactions of irritant
lipids, and some autoimmune diseases are also included
A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of
macrophages that are transformed into epithelium-like cells, surrounded by a collar of
mononuclear leukocytes, principally lymphocytes and occasionally plasma cells.
In the usual hematoxylin and eosin–stained tissue sections, the epithelioid cells have a pale
pink granular cytoplasm with indistinct cell boundaries, often appearing to merge into one
another.
The nucleus is less dense than that of a lymphocyte, is oval or elongate, and may show folding
of the nuclear membrane.
Older granulomas develop an enclosing rim of fibroblasts and connective tissue.
Frequently, epithelioid cells fuse to form giant cells in the periphery or sometimes in the
center of granulomas.
These giant cells may attain diameters of 40 to 50 μm.
They have a large mass of cytoplasm containing 20 or more small nuclei arranged either
peripherally (Langhans-type giant cell) or haphazardly (foreign body–type giant cell)
Typical tuberculous granuloma showing an area of central necrosis surrounded by
multiple Langhans-type giant cells, epithelioid cells, and lymphocytes.
• There are two types of granulomas, which differ in their
pathogenesis.
• Foreign body granulomas are incited by relatively inert foreign
bodies.
• Typically, foreign body granulomas form around material such as
talc (associated with intravenous drug abuse) sutures, or other
fibers that are large enough to preclude phagocytosis by a single
macrophage and do not incite any specific inflammatory or
immune response. Epithelioid cells and giant cells are apposed to
the surface of the foreign body.
• The foreign material can usually be identified in the center of the
granuloma, particularly if viewed with polarized light, in which it
appears refractile.
• Immune granulomas are caused by a variety of agents that are
capable of inducing a cell-mediated immune response .
• This type of immune response produces granulomas usually when
the inciting agent is poorly degradable or particulate.
• In such responses macrophages engulf foreign protein antigen,
process it, and present peptides to antigen-specific T lymphocytes,
causing their activation .
• The responding T cells produce cytokines, such as IL-2, which
activates other T cells, perpetuating the response, and IFN-γ,
which is important in activating macrophages and transforming
them into epithelioid cells and multinucleate giant cells.
• The prototype of the immune granuloma is that caused by
infection with Mycobacterium tuberculosis.
• In this disease the granuloma is referred to as a tubercle. It is
often characterized by the presence of central caseous necrosis.
• In contrast, caseous necrosis is rare in other granulomatous
diseases.
• The morphologic patterns in the various granulomatous diseases
may be sufficiently different to allow reasonably accurate
diagnosis by an experienced pathologist ,however, there are so
many atypical presentations that it is always necessary to identify
the specific etiologic agent by special stains for organisms (e.g.,
acid-fast stains for tubercle bacilli), by culture methods (e.g., in
tuberculosis and fungal diseases), by molecular techniques (e.g.,
the polymerase chain reaction in tuberculosis), and by serologic
studies (e.g., in syphilis).
TERIMA KASIH