ACUTE AND CHRONIC

INFLAMMATION
dr. Etty Hary Kusumastuti, Sp.
PA

OVERVIEW OF
INFLAMMATION
Inflammation is a protective
response intended to eliminate the
initial cause of cell injury as well as
the necrotic cells and tissues
resulting from the original insult.

 Inflammation accomplishes its

protective mission by diluting,
destroying, or otherwise neutralizing
harmful agents (e.g., microbes and
toxins).
Without inflammation, infections
would go unchecked and wounds
would never heal.

 The inflammatory reaction and the

subsequent repair process can cause
considerable harm. The components
of the inflammatory reaction that
destroy and eliminate microbes and
dead tissues are capable of also
injuring normal tissues.

INFLAMMATION
ACUTE INFLAMMATION
Rapid in onset and of short duration (a few
minutes - a few days), and is
characterized by fluid and plasma protein
exudation and a predominantly
neutrophilic leukocyte.
CHRONIC INFLAMMATION
Longer duration (days - years), and is
typified by influx of lymphocytes and
macrophages with associated vascular
proliferation and fibrosis (scarring).

CLINICAL FEATURE
External manifestations of
inflammation
Four cardinal sign:
Calor
Rubor
Tumor
Dolor

Virchow:
- Functio laesa

ACUTE INFLAMMATION
Acute inflammation is a rapid response
to injury or microbes and other
foreign substances that is designed
to deliver leukocytes and plasma
proteins to sites of injury.
Once there, leukocytes clear the
invaders and begin the process of
digesting and getting rid of necrotic
tissues.

STIMULI FOR ACUTE

INFLAMMATION
Infections (bacterial, viral, fungal,
parasitic)
Trauma (blunt and penetrating)
Physical & chemical agents
Tissue necrosis
Foreign bodies (splinters, dirt,
sutures)
Immune reactions

ACUTE INFLAMMATION HAS

TWO MAJOR COMPONENTS
Vascular changes
Cellular events

VASCULAR CHANGES
Alterations in vessel caliber resulting in
increased blood flow (vasodilation)
Increased vascular permeability

The major local manifestations of acute inflammation,

compared to normal. (1) Vascular dilation and increased blood
flow (causing erythema and warmth), (2) extravasation and
deposition of plasma fluid and proteins (edema), and (3)
leukocyte (mainly neutrophil) emigration and accumulation in
the site of injury.
Elsevier, Kumar et al. Robbins and Cotran Pathologic Basis of Disease, 7th ed.

Alterations in vessel caliber

resulting in increased blood
flow (vasodilation)
Vasodilation involves arterioles
opening capillary bed increased
blood flow heat & redness
Vasodilation is induced by the
action of several mediators
Histamine and Nitric oxide on
vascular smooth muscle

 Vasodilation is quick followed by

increased permeability of the
microvasculature, with outpouring
protein-rich fluid into the
extravascular tissue (ekstravasasi
cairan)
The loss fluid The red blood cells to
become more concentrated, thereby
increasing blood viscosity and
slowing the circulation.

 These changes are reflected

microscopically called stasis.
As stasis develops, leukocytes
(principally neutrophils) begin to
accumulate along the vascular
endothelial surface, a process called
margination. This is the first step in the
journey of the leukocytes through the
vascular wall into the interstitial tissue

 EXUDATE
Inflammatory extravascular fluid that
has a high protein concentrate,
cellular debris, and a specific gravity
above 1.020.
TRANSUDATE
Fluid with low protein component
(most of which is albumin) and a
specific gravity of less than 1.012.

Increased vascular
permeability in acute
inflammation
Immediate transient response
Endothelial cell contraction leading to
intercellular gaps in postcapillary venules
is the most common cause of increased
vascular permeability. It is a reversible
process elicited by histamine,
bradykinin, leukotrienes, and many
other chemical mediators.

The immediate transient

response is usually short-lived (1530 minutes).

 A slower and more prolonged

retraction of endothelial cells,
resulting from changes in the
cytoskeleton, may be induced by
cytokines such as tumor necrosis
factor (TNF) and interleukin-1 (IL1).

Immediate sustained response

Endothelial injury vascular leakage
by causing endothelial cell necrosis
and detachment after severe injury
(e.g., burns and some infections).
In most cases leakage begins
immediately after the injury and
persists for several hours (or days)
until the damaged vessels are
thrombosed or repaired.

 This reaction is known as the

immediate sustained response.
Venules, capillaries, and arterioles
can all be affected, depending on the
site of the injury.

 Delayed prolonged leakage

Direct injury to endothelial cells may also
induce a delayed prolonged leakage that
begins after a delay of 2 to 12 hours, lasts
for several hours or even days, and
involves venules and capillaries.
mild to moderate thermal injury, certain
bacterial toxins, and x- or ultraviolet
irradiation (i.e., the sunburn that appears
the evening after a day in the sun).

 Leukocyte-mediated endothelial injury

may occur as a consequence of leukocyte
accumulation along the vessel wall.
Activated leukocytes release many toxic
mediators that may cause endothelial
injury or detachment.

 Increased transcytosis of proteins via

an intracellular vesicular pathway
augments venular permeability,
especially after exposure to certain
mediators such as vascular
endothelial growth factor (VEGF).
Transcytosis occurs via channels
formed by fusion of intracellular
vesicles.

 Leakage from new blood vessels

These vessel sprouts remain leaky until
proliferating endothelial cells mature sufficiently
to form intercellular junctions. New endothelial
cells increased expression of receptors for
vasoactive mediators, and some of the factors
that induce angiogenesis (e.g., VEGF) directly
induce increased vascular permeability
via transcytosis.

Responses of Lymphatic Vessels

The small amount of interstitial fluid
formed normally is removed by
lymphatic drainage. In inflammation,
lymph flow is increased and helps
drain edema fluid from the
extravascular space.

 leukocytes and cell debris may also

find their way into lymph.
In severe inflammatory reactions,
especially to microbes, the
lymphatics may transport the
offending agent.

 The lymphatics may become

secondarily inflamed (lymphangitis),
as may the draining lymph nodes
(lymphadenitis). Inflamed lymph
nodes are often enlarged, because
of hyperplasia of the lymphoid
follicles and increased numbers of
lymphocytes and phagocytic cells
lining the sinuses of the lymph
nodes.

CELLULAR EVENTS
Leukocyte Recruitment
Leukocyte Activation

Leukocyte Recruitment
Margination, adhesion to
endothelium, and rolling along the
vessel wall
Firm adhesion to the endothelium
Transmigration between endothelial
cells
Migration in interstitial tissues toward
a chemotactic stimulus

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.

 The smaller red cells tend to move faster

than the larger white cells. As a result,
leukocytes are pushed out of the
central axial column and thus have
a better opportunity to interact with
lining endothelial cells, especially as
stasis sets in. Margination.
Leukocytes tumble on the endothelial
surface, transiently sticking along the
way Rolling.

Rolling
The weak and transient adhesions
involved in rolling are mediated by the
selectin family of adhesion molecules
E-selectin ; P-selectin; and L-selectin
Selectins bind sialylated
oligosaccharides (e.g., sialyl-Lewis X
on leukocytes)
P-selectin is distributed to the cell surface
<-- histamine or thrombin

Integrin activation by chemokines

This adhesion is mediated by
integrins expressed on leukocyte cell
surfaces interacting with their ligands
on endothelial cells .
Integrins are normally expressed on
leukocyte plasma membranes in a lowaffinity form and do not adhere to their
appropriate ligands until the leukocytes
are activated by chemokines.

Stable adhesion
Other cytokines (TNF and IL-1)
activate endothelial cells to increase
their expression of ligands for integrins.
These ligands include ICAM-1 (inter
cellular adhesion molecule 1) binds to
the integrins
stable attachment of leukocytes to
endothelial cells at sites of
inflammation.

Migration through endothelium

Leukocytes migrate through the
vessel wall primarily by squeezing
between cells at intercellular junctions
Diapedesis
Migration of leukocytes is driven by
chemokines produced in
extravascular tissues, which stimulate
movement of the leukocytes toward
their chemical gradient.

 PECAM-1 (platelet endothelial cell

adhesion molecule 1, also called
CD31), a cellular adhesion molecule
expressed on leukocytes and
endothelial cells, mediates the
binding events needed for leukocytes
to traverse the endothelium.

Tabel Endothelial and Leukocyte Adhesion

Molecules
Endothelial
Molecule

Leukocyte
Molecule

Major Role

P-selectin

Sialyl-Lewis Xmodified proteins

Rolling (neutrophils,
monocytes, lymphocytes)

E-selectin

Sialyl-Lewis Xmodified proteins

Rolling and adhesion

(neutrophils, monocytes, T
lymphocytes)

GlyCam-1, CD34

L-selectin

Rolling (neutrophils,
monocytes)*

ICAM-1
(immunoglobulin
family)

CD11/CD18
integrins (LFA-1,
Mac-1)

Adhesion, arrest,
transmigration (neutrophils,
monocytes, lymphocytes)

VCAM-1
(immunoglobulin
family)

VLA-4 integrin

Adhesion (eosinophils,
monocytes, lymphocytes)

CD31

CD31

Transmigration (all
leukocytes

Chemotaxis
Leukocytes migrate toward sites of
infection or injury along a chemical
gradient.

Chemotactic substances for

leukocytes:
Exogenous (bacterial products,
particularly peptides with Nformylmethionine termini)
Endogenous (cytokines (kemokin),
complement system (C5a),
leukotriene (LB4)).

 Chemotactic molecules bind to specific

cell surface receptors, which are
members of the seven-transmembrane
G-protein coupled receptor family.
Binding of the chemoattractants
results in G-protein-mediated signal
transduction events, increased
cytosolic calcium, which triggers the
assembly of cytoskeletal contractile
elements necessary for movement.
Pseudopods

 Leukocytes move by extending

pseudopods / filopodia that anchor to
the ECM and then pull the cell in the
direction of the extension.

Scanning
electron
micrograph of a
moving
leukocyte
in
culture showing

 The type of emigrating leukocyte

varies with the age of the
inflammatory response and with
the type of stimulus.
In most forms of acute inflammation,
neutrophils predominate in the
inflammatory infiltrate during the first
6 to 24 hours and are replaced by
monocytes in 24 to 48 hours

Leukocyte Activation
Once leukocytes have been recruited to
the site of infection or tissue necrosis,
they must be activated to perform their
functions. Stimuli for activation include
microbes, products of necrotic cells, and
several mediators.
Leukocytes express on their surface
different kinds of receptors that sense
the presence of microbes. Leukocyte
activation

 Leukocyte activation results in many

enhanced functions:
Phagocytosis of particles, an early step
in the elimination of harmful substances.
Production of substances that destroy
phagocytosed microbes and remove
dead tissues;
Leukocyte products include lysosomal
enzymes and reactive oxygen and
nitrogen

Phagocytosis
Phagocytosis consists of three distinct
but interrelated steps :
Recognition and attachment of the
particle to the ingesting leukocyte
Engulfment, with subsequent
formation of a phagocytic vacuole
Killing and degradation of the
ingested material.

Recognition
Leukocytes bind and ingest most
microorganisms and dead cells
via specific surface receptors
opsonins, that coat microbes and
target them for phagocytosis (a
process called opsonization). The
most important opsonins are
antibodies of the immunoglobulin
G (IgG) class

Engulfment
Pseudopods are extended around the
object, eventually forming a
phagocytic vacuole.

Killing
The membrane of the vacuole then
fuses with the membrane of a
lysosomal granule, resulting in
discharge of the granule's contents
into the phagolysosome.
The most important microbicidal
substances are reactive oxygen
species and lysosomal enzymes.

Leukocyte-Induced Tissue
Injury

Leukocytes are important causes

of injury to normal cells and tissues
under several circumstances
In some infections that are difficult to
eradicate, such as tuberculosis and
certain viral diseases, the host
response contributes more to the
pathology than does the microbe
itself, autoimmune, hypersensitive.

Resolution
When the injury is limited or short-lived, no
or minimal tissue damage, the tissue is
capable of replacing any irreversibly
injured cells, the usual outcome is
restoration to histologic and functional
normally.
Termination of the acute inflammatory
response involves neutralization, decay
or enzymatic degradation of the various
chemical mediators, normalization of
vascular permeability.

 Leukocytes produce mediators that

inhibit inflammation and thus limit
the reaction.
The combined efforts of lymphatic
drainage and macrophage
ingestion of necrotic debris lead to
the clearance of the edema fluid,
inflammatory cells, and detritus
from the battlefield.

Phagocytosis & clearance of necrotic tissue,

microbes

OUTCOMES OF ACUTE
INFLAMMATION
Complete resolution
Healing by connective tissue
replacement (fibrosis)
Progression to chronic inflammation

Morfologic Pattern of Acute

Inflammation
1. SEROUS INFLAMMATION
2. FIBRINOUS INFLAMMATION
3. SUPPURATIVE OR PURULENT
INFLAMMATION
4. ULCER

1. Serous Inflammation
Ditandai melubernya cairan relatif
mengandung kadar protein yg rendah.
Dibentuk dari serum atau hasil sekresi
mesothel rongga tubuh (misal:
peritoneum, ruang pleura). effusion
Misal:
Luka bakar
Infeksi virus.

2. Fibrinous Inflammation
Jejas yang lebih berat
permeabilitas vaskuler lebih
besar molekul lebih besar misal
Fibrinogen dapat melintasi barier
pembuluh darah fibrin berada di
ruang ekstraseluler.
Misal: Meningen, perikard, pleura

3. Suppurative or Purulent
Inflammation
Ditandai dengan produksi nanah
(pus) dalam jumlah banyak
neutrophil, sel-sel nekrotik, cairan
edema.
Misal: Infekfi bacteri Staphylococcus

 Abscess
Collections of pus caused by seeding
of pyogenic organisms into a tissue
or by secondary infections of necrotic
foci. Abscesses typically have a
central, largely necrotic region
rimmed by a layer of preserved
neutrophils, with a surrounding zone
of dilated vessels and fibroblastic
proliferation indicative of early repair.

4. Ulcer
Defek lokal, atau exkavasi, permukaan
organ atau jaringan yang diproduksi oleh
sloughing (shedding) jaringan
keradangan nekrotik
Misal: mukosa rongga mulut, permukaan
saluran cerna.

CHEMICAL MEDIATORS OF
INFLAMMATION
Mediators may be produced:
Locally by cells at the site of
inflammation Tissue macrophages,
mast cells end endothelial at the site
inflammation as well as leukocytes
that are recruited to the site from the
blood producing different mediator
Circulating in the plasma (typically
synthesized by the liver)

Chemical Mediators of
Inflammation

Vasoactive Amines
Histamine is released from mast cell
granules in response to a variety of
stimuli
Histamine arteriolar dilation
(immediate phase), increased vascular
permeability, inducing venular endothelial
contraction and interendothelial gaps.
Histamine is inactivated by histaminase
Serotonin platelet dense body granules

Arachidonic Acid (AA) Metabolites

Prostaglandins, Leukotrienes, and
Lipoxins
Products derived from the metabolism of
AA affect a variety of biologic processes,
including inflammation and hemostasis.
Leukocytes, mast cells, endothelial cells,
and platelets are the major sources of AA
metabolites in inflammation.

Plasma Protein Derived Mediators of

Inflammation
Complement proteins
Activation of complement system by
microbes or antibodies leads to the
generation of multiple breakdown
products responsible for leukocyte
chemotaxis, opsonization and
phagocytosis of microbes and other
particles, and cell killing
Coagulation proteins
Kinins

CHEMICAL MEDIATORS OF ACUTE

INFLAMMATION
Tabel hal 74

CHRONIC INFLAMMATION
Chronic inflammation is inflammation
of prolonged duration (weeks to
months to years)
in which active inflammation, tissue
injury, and healing proceed
simultaneously.

 Infiltration with mononuclear cells:

including macrophages, lymphocytes,
and plasma cells
Tissue destruction: largely induced by
the products of the inflammatory cells
Repair: Involving new vessel
proliferation (angiogenesis) and
fibrosis

Inflamasi kronik dapat

terjadi pada:
INFEKSI VIRUS > Hep B
Infeksi intrasel, perlu limfosit (dan makrofag)
untuk mengidentifikasi serta eradikasi

INFEKSI MIKROBA PERSISTEN

Misal: TBC, Treponema pallidum
Mengakibatkan patogenitas langsung yg
lemah, menimbulkan respos imun
hypersensitifitas lambat, menghasilkan
radang granulomatosa

 PAPARAN INFLAMASI YANG LAMA

TERHADAP AGEN YANG BERPOTENSI
TOKSIK
Misal: paparan material eksogen yang tak
dapat didegradasi, misal partikel silika
terinhalasi.

PENYAKIT AUTOIMUN
Misal: Artritis Rheumatoid

Chronic Inflammatory Cells

Macrophages, the dominant cells of
chronic inflammation, are tissue cells
derived from circulating blood
monocytes after their emigration
from the bloodstream.

Macrophage
Macrophages are normally diffusely scattered in most
connective tissues, and are also found in organs such
as the liver (where they are called Kupffer cells),
spleen and lymph nodes (called sinus histiocytes),
central nervous system (microglial cells), and lungs
(alveolar macrophages). mononuclear phagocyte
system (reticulo-endothelial system).

 In all tissues, macrophages act as

filters for particulate matter,
microbes, and senescent cells, as
well as acting as sentinels to alert
the specific components of the
adaptive immune system (T and B
lymphocytes) to injurious stimuli

Other Cells in Chronic

Inflammation
Lymphocyte
Both T and B lymphocytes migrate into
inflammatory sites using some of the
same adhesion molecule pairs and
chemokines that recruit other
leukocytes.
Lymphocytes and macrophages
interact in a bidirectional way an
important role in chronic inflammation

Macrophages produce cytokines

(notably IL-12) that stimulate T-cell
responses
Activated T lymphocytes, in turn, produce
cytokines, and one of these, IFN-, is a
activator of macrophages, promoting
more antigen presentation and cytokine
secretion.
The result is a cycle of cellular reactions that
fuel and sustain chronic inflammation.

 Plasma calls
Eosinophils : parasitic infections or
as part of immune reactions
mediated by IgE, typically associated
with allergies.
Mast cells

Granulomatous
Inflammation
Merupakan proses radang kronik yang
khas terdiri dari sel-sel macrophage
yang teraktifasi menyerupai sel
epithel (disebut epithelioid)
Misal: Tuberculosis, Lepra, Syphilis,
Cat-scratch disease

Two types of granulomas:

Foreign body granuloma
talc, suture, fiber
Immune granuloma
Disebabkan insoluble particle,
khususnya mikroba yang dapat
menginduksi respon immun.
Macrophage mencaplok partikel yang
tak dapat dihancurkan tsb
mengaktifkan T lymphosit Epithelioid
dan multinucleated giant cell

EFEK SISTEMIK INFLAMASI

Demam, malaise, anoreksi,
Laju endap darah yang meningkat
(kadar fibrinogen meningkat mudah
beraglutinasi)
Leukositosis
Other manifestation (increased pulse,
decrease sweating, chills, anorexia,
malaise, somnolence)
Severe bacterial infection (sepsis)

TERIMA KASIH