Acute & Chronic

Inflammation

Imelda Theodora, dr., SpPA

Fakultas Kedokteran
UNIKA Widya Mandala Surabaya
 Overview of Inflammation
• Inflammation:
The host response to get rid of damaged or
necrotic tissues and foreign invaders
(the cause and effects of the injuries)
• Mainly consists of responses of blood vessels,
leukocytes response, and plasma proteins.
 Overview of Inflammation

Microbes
Inflammatory Acute Chronic
Necrotic cells
mediators Inflammation Inflammation
Hypoxia
The components of acute and chronic inflammatory responses:
circulating cells and proteins, cells of blood vessels, and cells and proteins of the
extracellular matrix.
 Historical Highlights

• Four cardinal signs of inflammation by Celcus

• One other sign is added by Virchow
 Topics
• Acute Inflammation
• Mediators of Inflammation
• Outcomes of acute inflammation
• Morphologic patterns of acute inflammation
– Serous inflammation
– Fibrinous inflammation
– Suppurative or purulent inflammation; abscess
– ulcers
 Topics
• Chronic inflammation
– Causes of chronic inflammation
– Morphologic features
– Role of macrophages in chronic inflammation
– Other cells in chronic inflammation
– Granulomatous inflammation
• Systemic effects of inflammation
• Consequences of defective or excessive
inflammation
Acute Inflammation
 Acute Inflammation
• Stimuli for acute inflammation
• Reactions of blood vessels in acute
inflammation
– Changes in vascular flow and caliber
– Increased vascular permeability (vascular leakage)
– Responses of lymphatic vessels
 Acute Inflammation
• Reactions of leukocytes in inflammation
– Recruitment of leukocytes to sites of infection and injury
• Adhesion
• Migration
• Chemotaxis
– Recognition of microbes and dead tissues
• Phagocytosis
• Engulfment
• Killing and degradation
– Removal of offending agents
– Other functional responses of activated leukocytes
– Release of leukocyte products and leukocyte-mediated tissue
injury
– Defects in leukocyte function
• Termination of the acute inflammatory response
 Acute Inflammation
• : is a rapid host response that serves to deliver leukocytes and plasma
proteins, such as antibodies, to sites of infection or tissue injury
• Three major components:
(1) vasodilation that lead to an increase in blood flow
(2) structural changes in the microvasculature that permit plasma
proteins and leukocytes to leave the circulation
(3) emigration of the leukocytes accumulation activation to
eliminate the offending agent ( Fig. 2-1 ).
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
deposition of plasma fluid and
proteins (edema), and (
3) leukocyte emigration and
accumulation in the site of injury.
 Acute Inflammation
• STIMULI FOR ACUTE INFLAMMATION
-Infections (bacterial, viral, fungal, parasitic) and microbial toxins.
Toll-like receptors (TLRs). the production of various mediators.
-Tissue necrosis
-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).
-uric acid, ATP, a DNA-binding protein of unknown function called
HMGB- 1; and even DNA. HIF-1α (hypoxia-induced factor-1α).
- Foreign bodies
-Immune reactions (also called hypersensitivity reactions)
-immune-mediated inflammatory disease
 Acute Inflammation
• Reactions of blood vessels in acute inflammation
– Changes in vascular flow and caliber
•Vasodilation heat and redness (erythema) at the site of
inflammation  histamine and nitric oxide (NO), on vascular smooth
muscle.
•Increased permeability of the microvasculature, with the outpouring of
protein-rich fluid into the extravascular tissue  stasis  neutrophils
accumulate along the vascular endothelium.
Endothelial cells  increased levels of adhesion molecules 
Leukocytes adhere to the endothelium  migrate through the
vascular wall into the interstitial tissue
 Acute Inflammation
- Increased Vascular Permeability (Vascular Leakage)
• Contraction of endothelial cells  increased interendothelial spaces
histamine, bradykinin, leukotrienes, the neuropeptide substance P, and many
other chemical mediators (immediate transient response, 15-30 minutes).
• Endothelial injury, resulting in endothelial cell necrosis and detachment.
Severe injuries + neutrophils.
Leakage starts immediately after injury and is sustained for several hours until the
damaged vessels are thrombosed or repaired.
• Transcytosis: Increased transport of fluids&proteins through the endothelial cell.
Vesiculovacuolar organelle, close to intercellular junctions.
Certain factors, such as VEGF, seem to promote vascular leakage in part by
increasing the number and perhaps the size of these channels.
Figure 2-4 Diagrammatic
representation of five
mechanisms of increased
vascular permeability in
inflammation.
 Acute Inflammation
- Responses of Lymphatic Vessels
- Lymph flow is increased and helps drain edema fluid (+ leukocytes & cell
debris) that accumulates due to increased vascular permeability 
proliferation
- Lymphangitis & lymphadenitis. Inflamed lymph nodes are often enlarged
because of hyperplasia of the lymphoid follicles and increased numbers of
lymphocytes and macrophages. This constellation of pathologic changes is
termed reactive, or inflammatory, lymphadenitis.
 Acute Inflammation
• REACTIONS OF LEUKOCYTES IN INFLAMMATION
– The most important leukocytes in typical inflammatory reactions are
the ones capable of phagocytosis, namely neutrophils and
macrophages. Leukocytes also produce growth factors that aid in
repair. Leukocyte products that destroy microbes and necrotic tissues
can also injure normal host tissues.
– The processes involving leukocytes in inflammation consist of:
their recruitment from the blood into extravascular tissues,
recognition of microbes and necrotic tissues, and removal of the
offending agent.
 Acute Inflammation
1. Recruitment of Leukocytes to Sites of Infection and Injury
• The journey of leukocytes from the vessel lumen to the interstitial tissue, called
extravasation, can be divided into the following steps[13] ( Fig. 2-4 ):
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
 Acute Inflammation
a) Leukocyte Adhesion to Endothelium.
• Margination  rolling (Selectins)  adhesion (Cytokines)
• There are three types of selectins: one expressed on leukocytes (L-selectin), one
on endothelium (E-selectin), and one in platelets and on endothelium (P-selectin).
• The ligands for selectins are sialylated oligosaccharides bound to mucin-like
glycoprotein backbones. The expression of selectins and their ligands is regulated
by cytokines produced in response to infection and injury.
• Tissue macrophages, mast cells, and endothelial cells that encounter microbes and
dead tissues respond by secreting several cytokines, including tumor necrosis
factor (TNF), interleukin-1 (IL-1), and chemokines (chemoattractant cytokines).
• Within 1 to 2 hours the endothelial cells begin to express E-selectin and the ligands
for L-selectin.
• Other mediators such as histamine, thrombin, and platelet-activating factor (PAF),
stimulate the redistribution of P-selectin from its normal intracellular stores in
endothelial cell granules (called Weibel-Palade bodies) to the cell surface.
 Acute Inflammation
• Leukocytes express L-selectin at the tips of their microvilli and also express ligands
for E- and P-selectins, all of which bind to the complementary molecules on the
endothelial cells.
• Firm adhesion is mediated by a family of heterodimeric leukocyte surface proteins
called integrins.
• TNF and IL-1  endothel ligands for integrins, mainly vascular cell adhesion
molecule 1 (VCAM-1, the ligand for the VLA-4 integrin) and intercellular adhesion
molecule-1 (ICAM-1, the ligand for the LFA-1 and Mac-1 integrins).
• Chemokines bind to and activate the rolling leukocytes VLA-4 and LFA-1
integrins on the leukocytes  high-affinity state  The leukocytes stop rolling,
their cytoskeleton is reorganized, and they spread out on the endothelial surface.
 Acute Inflammation
b) Leukocyte Migration through Endothelium (transmigration/diapedesis).
• Occurs mainly in post-capillary venules.
• Chemokines
• Several adhesion molecules present in the intercellular junctions between
endothelial cells are involved in the migration of leukocytes: PECAM-1 (platelet
endothelial cell adhesion molecule) or CD31 and several junctional adhesion
molecules.
• Leukocytes pierce the basement membrane (collagenases) and enter the
extravascular tissue (integrins and CD44)  leukocytes are retained at the site
where they are needed.
 Acute Inflammation
c) Chemotaxis of Leukocytes.
• : locomotion oriented along a chemical gradient emigration of leukocytes in
tissues toward the site of injury.
• Chemoattractants:
– Exogenous agents: bacterial products, including peptides that possess an N-
formylmethionine terminal amino acid, and some lipids.
– Endogenous chemoattractants:
(1) cytokines, particularly those of the chemokine family (e.g., IL-8);
(2) components of the complement system, particularly C5a; and
(3) arachidonic acid (AA) metabolites, mainly leukotriene B4 (LTB4).
All these chemotactic agents bind to specific seven-transmembrane G protein–
coupled receptors on the surface of leukocytes.
Figure 2-6 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 in activating the neutrophils to increase
avidity of integrins (in green); integrins in firm adhesion; and CD31 (PECAM-1) in
transmigration.
Endothelial Molecule Leukocyte Receptor Major Role
P-selectin Sialyl-Lewis X Rolling (neutrophils,
monocytes, lymphocytes)
PSGL-1
E-selectin Sialyl-Lewis X Rolling, adhesion to
activated endothelium
(neutrophils, monocytes, T
cells)
ICAM-1 CD11/CD18 (integrins) Adhesion, arrest,
transmigration (all
leukocytes)
(LFA-1, Mac-1)
VCAM-1 a4b1 (VLA4) (integrins) Adhesion (eosinophils,
monocytes, lymphocytes)
a4b7 (LPAM-1)
GlyCam-1 L-selection Lymphocyte homing to high
endothelial venules
CD31 (PECAM) CD31 Leukocyte migration
through endothelium
 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: they are more numerous
in the blood, they respond more rapidly to chemokines, and they may attach more
firmly to the adhesion molecules that are rapidly induced on endothelial cells,
such as P- and E-selectins.
• After entering tissues, neutrophils are short-lived; they undergo apoptosis and
disappear after 24 to 48 hours.
• Monocytes not only survive longer but may proliferate in the tissues, and thus
become the dominant population in chronic inflammatory reactions.

• Question: Exceptions? Therapies?

 Acute Inflammation
2. Recognition of Microbes and Dead Tissues
- Receptors for microbial products: Toll-like receptors (TLRs)
- G-protein-coupled receptors
- Receptors for opsonins
- Receptors for cytokines

- Question: Which parts of microbes they recognize?

Effects?
 Acute Inflammation
3. Removal of the Offending Agents
• Phagocytosis :
(1) recognition and attachment of the particle to be ingested by the leukocyte;
(2) engulfment  phagocytic vacuole;
(3) killing or degradation of the ingested material.[30]
• Mannose receptors, scavenger receptors, and receptors for various opsonins all
function to bind and ingest microbes..
• The major opsonins are IgG antibodies, the C3b breakdown product of
complement, and certain plasma lectins, notably mannan-binding lectin, all of
which are recognized by specific receptors on leukocytes.
 Acute Inflammation
• Engulfment.
• After a particle is bound to phagocyte receptors, extensions of the cytoplasm
(pseudopods) flow around it, and the plasma membrane pinches off to form a
vesicle (phagosome) that encloses the particle. The phagosome then fuses with a
lysosomal granule, resulting in discharge of the granule's contents into the
phagolysosome. During this process the phagocyte may also release granule
contents into the extracellular space.
 Acute Inflammation
• Killing and Degradation.
• Microbial killing is accomplished largely by reactive oxygen species (ROS, also
called reactive oxygen intermediates) and reactive nitrogen species, mainly derived
from NO.
• Microbial killing can also occur through the action of other substances in leukocyte
granules: elastase, defensins, cationic arginine-rich granule peptides that are toxic
to microbes; cathelicidins, antimicrobial proteins found in neutrophils and other
cells[37]; lysozyme, which hydrolyzes the muramic acid–N-acetylglucosamine bond,
found in the glycopeptide coat of all bacteria; lactoferrin, an iron-binding protein
present in specific granules; major basic protein, a cationic protein of eosinophils,
which has limited bactericidal activity but is cytotoxic to many parasites; and
bactericidal/permeability increasing protein, which binds bacterial endotoxin and
is believed to be important in defense against some gram-negative bacteria.
Acute Inflammation
 Acute Inflammation
• Release of Leukocyte Products and Leukocyte-Mediated
Tissue Injury
• Leukocytes are important causes of injury to normal cells and tissues under several
circumstances:
• As part of a normal defense reaction against infectious microbes, when
adjacent tissues suffer “collateral damage.” In some infections that are difficult to
eradicate, such as tuberculosis and certain viral diseases, the prolonged host
response contributes more to the pathology than does the microbe itself.
• When the inflammatory response is inappropriately directed against host
tissues, as in certain autoimmune diseases.
• When the host reacts excessively against usually harmless environmental
substances, as in allergic diseases, including asthma.
 Acute Inflammation
• lysosomal enzymes, present in the granules, and reactive oxygen and nitrogen
species.
• The contents of lysosomal granules are secreted by leukocytes into the
extracellular milieu by several mechanisms: frustrated phagocytosis, phagocytosis
of membrane-damaging substances, such as urate crystals, may injure the
membrane of the phagolysosome and also lead to the release of lysosomal granule
contents.
 Acute Inflammation
• Defects in Leukocyte Function
• Inherited defects in leukocyte adhesion
defects of integrins and selectin-ligands  leukocyte adhesion deficiencies types 1
and 2. The major clinical problem in both is recurrent bacterial infections.
• Inherited defects in phagolysosome function.
Chédiak-Higashi syndrome, an autosomal recessive condition characterized by
defective fusion of phagosomes and lysosomes in phagocytes (causing
susceptibility to infections), and abnormalities in melanocytes (leading to
albinism), cells of the nervous system (associated with nerve defects), and
platelets (causing bleeding disorders). The main leukocyte abnormalities are
neutropenia (decreased numbers of neutrophils), defective degranulation, and
delayed microbial killing. Leukocytes contain giant granules, which can be readily
seen in peripheral blood smears and are thought to result from aberrant
phagolysosome fusion. The gene associated with this disorder encodes a large
cytosolic protein called LYST, which is believed to regulate lysosomal trafficking.
 Acute Inflammation
• Inherited defects in microbicidal activity.
chronic granulomatous disease, characterized by defects in bacterial killing and
render patients susceptible to recurrent bacterial infection. The name of this
disease comes from the macrophage-rich chronic inflammatory reaction that tries
to control the infection when the initial neutrophil defense is inadequate. This
often leads to collections of activated macrophages that wall off the microbes,
forming aggregates called granulomas.
• Acquired deficiencies.
Clinically, the most frequent cause of leukocyte defects is bone marrow
suppression, leading to decreased production of leukocytes. This is seen following
therapies for cancer (radiation and chemotherapy) and when the marrow space is
compromised by tumors, which may arise in the marrow (e.g., leukemias) or be
metastatic from other sites.
 Acute Inflammation
• TERMINATION OF THE ACUTE INFLAMMATORY RESPONSE
Inflammation declines:
– the mediators of inflammation are produced in rapid bursts, only as long as
the stimulus persists,
– have short half-lives,
– 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; 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[45]; and neural impulses
(cholinergic discharge) that inhibit the production of TNF in macrophages.[46]
Mediators of Inflammation
 Mediators of Inflammation
• Cell derived mediators
– Vasoactive amines: Histamine and serotonin
– Arachidonic Acid (AA) metabolites:
Prostaglandins, leukotrienes, and lipoxins
– Platelet-Activating Factor (PAF)
– Reactive Oxygen Species (ROS)
– Nitric Oxide (NO)
– Cytokines and chemokines
– Lysosomal constituents of leukocytes
– Neuropeptides
 Mediators of Inflammation
• Plasma protein-derived mediators:
– Complement system
– Coagulation and kinin systems
Mediators of Inflammation
Mediators of Inflammation
 Mediators of Inflammation
• Question:
anti-inflammatory drugs
Outcomes of Acute Inflammation
 Outcomes of Acute Inflammation
• Complete resolution:
– Injury is limited  little tissue destruction
– Removal of microbes and cellular debris by macrophages and
resorption of edema fluid by lymphatics.
• Healing by connective tissue replacement (fibrosis):
– Tissues are incapable of regeneration
– Abundant fibrin exudation in tissue or serous cavity
– Organization: connecting tissue grows into the area of damage
or exudate, converting it into a mass of fibrous tissue
• Proggresion to chronic inflammation:
– Agents of injury are persistent
– Disturbance of normal healing process
Outcomes of Acute Inflammation
 Outcomes of Acute Inflammation
• Question:
What causes the difference?
Morphologic Patterns of
Acute Inflammation
 Morphologic Patterns of
Acute Inflammation
• Serous inflammation
– Plasma or secretion of mesothelial cells
 Morphologic Patterns of
Acute Inflammation
• Fibrinous inflammation
– Vascular permeability  fibrinogen  fibrin
– Vascular leaks are large or local procoagulant
stimulus
 Morphologic Patterns of
Acute Inflammation
• Suppurative or purulent inflammation; abscess
– Pus/purulent exudate: neutrophils, liquefactive necrosis, and edema
fluid.
– Abscess: localized collections of purulent inflammatory tissue caused
by suppuration, buried in a tissue, an organ, or a confined space
 Morphologic Patterns of
Acute Inflammation
• Ulcers
: local defect, or excavation, of the surface of an
organ or tissue that is produced by the sloughing
(shedding) of inflamed necrotic tissue.
 Morphologic Patterns of
Acute Inflammation
• Question:
– Why do we need to recognize the gross and
microscopic appearance of inflammation?
Chronic Inflammation
 Chronic Inflammation
• : inflammation of prolonged duration (weeks
or months) in which inflammation, tissue
injury, and attempts at repair coexist, in
varying combinations.
• May follow acute inflammation or begin
insidously (RA, atherosclerosis, TB, pulmonary
fibrosis).
 Chronic Inflammation
• Causes of chronic inflammation:
– Persistent infections
– Immune-mediated inflammatory diseasses
• Autoimmune diseases  chronic tissue damage and
inflammation (RA & multiple sclerosis)
• Unregulated immune respones against microbes (IBS)
• Allergic diseases (bronchial asthma)
– Prolonged exposure to potentially toxic agents
 Chronic Inflammation
• Morphologic features:
– Infiltration of mononuclear cells: macrophages,
lymphocytes, plasma cells
– Tissue destruction
– Proliferation of blood vessels (angiogenesis) and
fibrosis
Figure 2-28 The roles of activated
macrophages in chronic
inflammation.
Macrophages are activated by
cytokines from immune-activated
T cells (particularly IFN-g) or by
nonimmunologic stimuli such as
endotoxin.
 Chronic Inflammation
• Other cells in chronic inflammation:
– Lymphocytes
– Plasma cells
– Eosinophils
– Mast cells
 Chronic Inflammation
• Granulomatous inflammation
• 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. Recognition of
the granulomatous pattern in a biopsy specimen is important because of the
limited number of possible conditions that cause it and the significance of the
diagnoses associated with the lesions.
• Granuloma: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.
 Chronic Inflammation
• Microscopic:
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).
 Chronic Inflammation
1. 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.
2. 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.
Chronic Inflammation
Chronic Inflammation
Systemic Effects of Inflammation
 Systemic Effects of Inflammation
• Fever, characterized by an elevation of body temperature, usually by 1° to 4°C
pyrogens, endogenous & exogenous  COXs  prostaglandins  Hypothalamus
• Elevated ESR and serum levels of CRP
• Leukocytosis is a common feature of inflammatory reactions, especially those
induced by bacterial infections. The leukocyte count usually climbs to 15,000 or
20,000 cells/μL, but sometimes it may reach extraordinarily high levels of 40,000
to 100,000 cells/μL.
• Other manifestations of the acute-phase response include increased pulse and
blood pressure; decreased swatinge, mainly because of redirection of blood flow
from cutaneous to deep vascular beds, to minimize heat loss through the skin;
rigors (shivering), chills (search for warmth), anorexia, somnolence, and malaise,
probably because of the actions of cytokines on brain cells.
• sepsis organisms and LPS >>  TNF and IL-1 disseminated intravascular
coagulation, cardiovascular failure, and metabolic disturbance, which are
described as septic shock.
 Consequences of
Defective or Excessive Inflammation
 Consequences of
Defective or Excessive Inflammation
• Defective inflammation typically results in increased susceptibility to infections,
because the inflammatory response is a central component of the early defense
mechanisms that immunologists call innate immunity. It is also associated with
delayed wound healing, because inflammation is essential for clearing damaged
tissues and debris, and provides the necessary stimulus to get the repair process
started.
• Excessive inflammation is the basis of many types of human disease. Allergies, in
which individuals mount unregulated immune responses against commonly
encountered environmental antigens, and autoimmune diseases, in which
immune responses develop against normally tolerated self-antigens, are
disorders in which the fundamental cause of tissue injury is inflammation. These
include atherosclerosis and ischemic heart disease, and some neurodegenerative
diseases such as Alzheimer disease.