new

Inflammation
 Inflammation is a response of vascularized
tissues to infections and damaged tissues
that brings cells and molecules of host
defense from the circulation to the sites
where they are needed, in order to eliminate
the offending agents.
 Steps of inflammatory reaction.
 The offending agent, which is located in extravascular
tissues, is recognized by host cells and molecules.
 Leukocytes and plasma proteins are recruited from the
circulation to the site where the offending agent is
located.
 The leukocytes and proteins are activated and work
together to destroy and eliminate the offending
substance.
 The reaction is controlled and terminated.
 The damaged tissue is repaired.
 Fundamental properties.
 Components of the inflammatory response. The major
participants in the inflammatory reaction in tissues are
blood vessels and leukocytes.
 Harmful consequences of inflammation.
 Autoimmune diseases, Allergies, Genetic disorders.
 Local and systemic inflammation. The reaction is
largely confined to the site of infection or damage.
 sepsis, which is one form of the systemic inflammatory
response syndrome.
 Mediators of inflammation..
 Acute and chronic inflammation.
 Termination of inflammation and initiation of
tissue repair.
 Advantages of Inflammation.
 Inflammation usually functions in a
beneficial manner and serves to destroy,
dilute or wall off the injurious agent, remove
necrotic debris and other exudates and
 prepare the remaining tissue framework for
reparative cells to effect tissue repair.
 Disadvantages
 Inflammation and repair may be potentially
harmful. Inflammatory reactions underlie some
life threatening hypersensitivity reactions to insect
bites, drugs and toxins and
 some common chronic diseases such as
rheumatoid arthritis, atherosclerosis, and lung
fibrosis.
 Repair by fibrosis may produce disfiguring scars or
fibrous bands leading to intestinal obstruction and
decreased mobility of joints.
 The steps of the inflammatory response can
be remembered as the five Rs:
 (1) recognition of the injurious agent,
 (2) recruitment of leukocytes,
 (3) removal of the agent,
 (4) regulation (control) of the response, and
 (5) resolution (repair).
 Causes of Inflammation
 Infections (bacterial, viral, parasitic) and
microbial toxins.
 Trauma (blunt and penetrating)
 Physical and chemical agents (thermal
injury, e.g. burns or frost bite; irradiation;
some environmental chemicals)
 Tissue necrosis (from any cause)
 Foreign bodies (splinters, dirt, sutures)
 Immune reactions (also called
hypersensitivity reactions).
 Types of Inflammation
 Acute inflammation.
 Chronic inflammation.
Recognition of Microbes and
Damaged Cells
 Cellular receptors for microbes. The best defined of
these receptors belong to the family of Toll-like
receptors (TLRs).
 The receptors are expressed on many cell types,
including epithelial cells (through which microbes enter
from the external environment), dendritic cells,
macrophages, and other leukocytes.
 These receptors triggers production of molecules
involved in inflammation, including adhesion
molecules on endothelial cells, cytokines, and other
mediators.
 Sensors of cell damage : These molecules include uric
acid (a product of DNA breakdown), ATP (released from
damaged mitochondria), reduced intracellular K+
concentrations.
 Other cellular receptors involved in inflammation.
Directly recognizing microbes, many leukocytes express
receptors for the Fc tails of antibodies and for complement
proteins. These receptors recognize microbes coated with
antibodies and complement (the coating process is called
opsonization)
 Circulating proteins: mannose-binding lectin, collectin.
 Acute inflammation
 Celsus (30 A.D. Rome): Four cardinal signs of
inflammation. These signs are typically more prominent in
acute inflammation.
 1. Rubor-redness
 [Link]-swelling
 3. Calor-heat
 4. Dolor-pain
 In 1858, Virchow added fifth sign-
Functio laesa- loss of function.
 Acute : is rapid in onset (seconds or minutes) and is
of relatively short duration, lasting for minutes,
several hours, or a few days.
 The predominant cell is neutrophil and
 main characteristic features are exudation of fluid
and plasma protein and emigration of leukocytes
predominantly neutrophils.
 2. Chronic : is of longer duration and is associated
histologically with presence of lymphocyte and
macrophages,
 the proliferation of blood vessels, fibrosis and
tissue necrosis.
 Acute inflammation -Terminology
 Exudation: The escape of fluid, proteins, and blood cells
from the vascular system into the interstitial tissue or body
cavities is known as Exudation.
 Exudate: An exudate is an inflammatory extravascular fluid
that has high protein concentration, cellular debris, and a
specific gravity above 1.020.
 Transudate: Is a fluid with low protein content (most of
which is albumin), and a specific gravity below 1.020.
 Edema: denotes an excess of fluid in the interstitial or
serous cavities. It can be either transudate or exudate.
 Pus or purulent exudates: It is an inflammatory exudates
rich in leukocytes (mostly neutrophils), the debris of dead
cells, and, in many cases, microbes.
 Inflammatory response
 1. Vascular reaction
 [Link] reaction
The component of acute and
chronic inflammatory response.
Acute inflammation
 Three major components:
 (1) Dilation of small vessels leading to an increase
in blood flow,
 (2) Increased permeability of the microvasculature
enabling plasma proteins and leukocytes to leave
the circulation, and
 (3) Emigration of the leukocytes from the
microcirculation, their accumulation in the focus
of injury, and their activation to eliminate the
offending agent.
 Vasodilation is induced by the action of several
mediators, notably histamine, on vascular smooth
muscle. The result is increased blood flow, which is
the cause of heat and redness (erythema) at the site of
inflammation.
 Vasodilation is quickly followed by increased
permeability of the microvasculature, with the
outpouring of protein-rich fluid into the
extravascular tissues.
 The loss of fluid and increased vessel diameter lead to
slower blood flow, concentration of red cells in small
vessels, and increased viscosity of the blood. This
condition is termed stasis.
 As stasis develops, blood leukocytes, principally
neutrophils, accumulate along the vascular
endothelium.
 Increased Vascular Permeability (Vascular Leakage) is
the hallmark of acute inflammation
 Contraction of endothelial cells resulting in increased
inter endothelial spaces is the most common
mechanism of vascular leakage.
 It is elicited by histamine, bradykinin, leukotrienes,
and other chemical mediators
 Increased vascular permeability
 Formations of endothelial gaps in venules due to
endothelial cells contraction. It occurs within minutes and
lasts for 15-30 minutes.

 *Direct injury to endothelial cells resulting in endothelial

cells necrosis and detachment. It occurs in arterioles,
capillaries, and venules. This response begins immediately
and is sustained at a high level for several hours until the
damaged vessels are thrombosed or repaired .
 *Delayed prolonged leakage: begins after delay of 2-12
hours lasting for several hours to days. The mechanism is
unclear
 *leukocyte mediated endothelial injury WBC adhere to
endothelium release toxic oxygen species and proteolytic
enzymes, which then cause endothelial cells injury. It is
seen in venules, pulmonary and glomerular capillaries.
 *Increased transcytosis occurs across the endothelial
cytoplasm by channels consisting of vesicles and vacuoles.
VEGF
 * Leakage from new blood vessels: New blood vessel
sprouts remains leaky until endothelial cell matures.
 Lymphatic vessels also participate in acute
inflammation. The system of lymphatics and lymph
nodes filters and polices the extravascular fluids.
 The lymphatics may become secondarily inflamed
(lymphangitis),as the draining lymph nodes
(lymphadenitis).
 Cellular Events
 A) Leukocytes extravasation : The sequence of events in
the journey from lumen to interstitial tissue is called
extravasation.

 B) Phagocytosis.
A) Steps of extravasation :
 [Link], rolling, and adhesion of neutrophil,
monocytes, lymphocytes, eosinophils, and basophils to
endothelium.
 2. Diapedesis or transmigration across the endothelium.
 3. Migration in interstitial tissue toward a chemotactic
stimulus.
 The attachment of leukocytes to endothelial cells is
mediated by complementary adhesion molecules on
the two cell types whose expression is enhanced by
cytokines.
 Adhesion molecules : Selectin & Integrin
 The initial rolling interactions are mediated by a family of
proteins called selectins .
 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 mucinlike 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),
IL1, and chemokines (chemoattractant cytokines).
 Firm adhesion is mediated by a family of
heterodimeric leukocyte surface proteins called
integrins.
 TNF and IL1 induce endothelial expression of ligands
for integrins, mainly vascular cell adhesion molecule 1
(VCAM1, the ligand for the β1 integrin VLA4) and
intercellular adhesion molecule1 (ICAM1, the ligand
for the β2 integrins LFA1 and Mac1).
 The next step in the process of leukocyte recruitment
is migration of the leukocytes through the
endothelium, called transmigration or diapedesis

 Transmigration of leukocytes occurs mainly in

postcapillary venules. Chemokines act on the adherent
leukocytes and stimulate the cells to migrate through
interendothelial spaces toward the chemical
concentration gradient, that is, toward the site of
injury or infection where the chemokines are being
 produced.
 Several adhesion molecules present in the intercellular
junctions between endothelial cells are involved in the
migration of leukocytes.
 These molecules include a member of the immunoglobulin
superfamily called CD31 or PECAM-1 (platelet endothelial
cell adhesion molecule).
 After traversing the endothelium, leukocytes pierce the
basement membrane, probably by secreting collagenases,
and enter the extravascular tissue.
 The cells then migrate toward the chemotactic gradient
created by chemokines and other chemoattractants and
accumulate in the extravascular site.
 The multistep process of leukocytes
migration

 Rolling of leukocytes (selectins)------activation of

leukocytes (chemokines in activating neutrophils
to increase avidity of integrins)-----adhesion of
leukocytes (integrins)--- transmigration across the
endothelium (CD31)----piercing of basement
membrane----migration towards the
chemoattractants emanating from source of injury

 Chemotaxis of Leukocytes

 After exiting the circulation, leukocytes move in the

tissues toward the site of injury by a process called
chemotaxis, which is defined as locomotion along a
chemical gradient. Both exogenous and endogenous
substances can act as chemoattractants.
 Chemo attractants are both exogenous (e.g. bacterial
products and endogenous (complements-C5a, LTB4, IL-8).
 How chemotaxis occur?
 Binding of chemotactic agent to specific receptors on
leukocytes results in activation of phospholipase C and
increased cytosolic calcium triggers the assembly of
contractile elements such as actin, myosin responsible for
cell movement.
Leukocyte migration through blood
vessel.
 Recognition of microbes or dead cells induces
several responses in leukocytes that are
collectively called leukocyte activation.
 Phagocytosis: It involves three distinct but interrelated
steps:
 Recognition and attachment of the particle to be ingested
by the leukocytes.
 Engulfment with subsequent formation of a phagocytic
vacuole.
 Killing or Degradation of the ingested material by oxygen
dependent mechanism and oxygen independent
mechanism.
 Phagocytic Receptors. Mannose receptors, scavenger
receptors, and receptors for various opsonins bind and
ingest microbes.
 The macrophage mannose receptor is a lectin that binds
terminal mannose and fucose residues of glycoproteins and
glycolipids.
 These sugars are typically part of molecules found on
microbial cell walls,
 whereas mammalian glycoproteins and glycolipids contain
terminal sialic acid or Nacetylgalactosamine.
 Therefore, the mannose receptor recognizes microbes and
not host cells.
 Scavenger receptors were originally defined as molecules
that bind and mediate endocytosis of oxidized or
acetylated low density lipoprotein (LDL) particles that can
no longer interact with the conventional LDL receptor.
 Macrophage scavenger receptors bind a variety of microbes
in addition to modified LDL particles.
 Macrophage integrins, notably Mac1 (CD11b/CD18), may
also bind microbes for phagocytosis.
 The efficiency of phagocytosis is greatly enhanced when
microbes are opsonized by specific proteins (opsonins) for
which the phagocytes express highaffinity receptors.
 The major opsonins are IgG antibodies, the C3b breakdown
product of complement, and certain plasma lectins,
notably mannosebinding lectin, all of which are recognized
by specific receptors on leukocytes.
 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.
 Intracellular Destruction of
Microbes and Debris

 Killing of microbes is accomplished by reactive oxygen

species (ROS, also called reactive oxygen
intermediates)and reactive nitrogen species, mainly
derived from nitric oxide (NO), and these as well as
lysosomal enzymes destroy phagocytosed debris.
 This is the final step in the elimination of infectious
agents and necrotic cells.
 The killing and degradation of microbes and dead cell
debris within neutrophils and macrophages occur
most efficiently after activation of the phagocytes.
 Killing and degradation:
Bacterial killing occurs largely by Oxygen dependent
mechanism.
 Phagocytosis stimulates a burst in oxygen consumption,
glycogenolysis, increased glucose oxidation via HMP shunt
and production of reactive oxygen metabolites.
 The generation of oxygen metabolites involves rapid
activation of an oxidase, which oxidizes NADPH producing
superoxide anion, which undergoes spontaneous
dismutation to hydrogen peroxide within lysosome.
 Hydrogen peroxide is insufficient to induce effective
killing of bacteria so it in presence of MPO and halide
such as Cl- converts H2O2 to HOCL that destroy
bacteria by halogenation or lipid peroxidation.
 The dead microorganism is then degraded by the
action of lysosomal hydrolases.
 Oxygen independent mechanism takes place
through the action of substance in leukocyte
granules including BPI (bactericidal permeability
increasing protein),lysozyme, lactoferrin, major
basic protein, defensin.
 After killing, acid hydrolases degrade the bacteria
within phagolysosome.
 Neutrophil Extracellular Traps
 Neutrophil extracellular traps (NETs) are extracellular
fibrillar networks that provide a high concentration of
antimicrobial substances at sites of infection and
prevent the spread of the microbes by trapping them
in the fibrils.
 They are produced by neutrophils in response to
infectious pathogens (mainly bacteria and fungi) and
inflammatory mediators (e.g., chemokines, cytokines
[mainly interferons], complement proteins, and ROS).
 Chemical Mediators
 Cellular
 a) Preformed mediators in secretory granules-
Histamine, Serotonin, lysosomal enzymes.
 b) Newly synthesized- Prostaglandins, Leukotrienes,
Platelet activating factor, activated oxygen species, NO,
Cytokines.
 Plasma derived-

 Factor XII (Hageman factor) activation .

* Kinin system,
*Coagulation/Fibrinolytic system
 Complement activation-
*C3a, C5a, C3b, C5b-9 (MAC).
Mediators of Inflammation
 The mediators of inflammation are the substances
that initiate and regulate inflammatory reactions.
 The most important mediators of acute inflammation
are vasoactive amines, lipid products (prostaglandins
and leukotrienes), cytokines (including chemokines),
and products of complement activation.
 Mediators are either secreted by cells or generated
from plasma proteins.
 The major cell types that produce mediators of acute
inflammation are the sentinels that detect invaders
and damage in tissues, that is, macrophages, dendritic
cells, and mast cells.
 Active mediators are produced only in response to
various stimuli.
 Most of the mediators are short-lived. They
quickly decay, or are inactivated by enzymes, or they
are otherwise scavenged or inhibited.
 One mediator can stimulate the release of other
mediators.
 Vasoactive amines, mainly histamine: vasodilation and
increased vascular permeability.
 Arachidonic acid metabolites (prostaglandins and
leukotrienes): several forms exist and are involved in
vascular reactions, leukocyte chemotaxis, and other
reactions of inflammation; antagonized by lipoxins
 Cytokines: proteins produced by many cell types; usually
act at short range; mediate multiple effects, mainly in
leukocyte recruitment and migration; principal ones in
acute inflammation are TNF, IL-1, and chemokines
 Complement proteins: Activation of the complement
system by microbes or antibodies leads to the generation of
multiple breakdown products, which are responsible for
leukocyte chemotaxis, opsonization, and phagocytosis of
microbes and other particles, and cell killing
 Kinins: produced by proteolytic cleavage of precursors;
mediate vascular reaction, pain.
 Prostaglandin
 Synthesized from arachidonic acid from cyclooxygenase
pathway in leukocytes, platelets, and endothelial cells in
response to induction from mediators. Arachidonic acid is
membrane bound component of phospholipids, released
via activation of phospholipases or from C5a.
Cyclooxygenase produces PGs and TXAs from AA.
Lipooxygenase produce LTs from AA.
 Function
 a) PGI2 is a potent inhibitor of platelet aggregation and
vasodilator.
 b) PGD2, PGE2, PGF2 are vasodilators.
 c) PG contributes to pain and fever in inflammation.
 Morphologic Patterns of Acute
Inflammation
 The morphologic hallmarks of acute inflammatory
reactions are dilation of small blood vessels and
accumulation of leukocytes and fluid in the
extravascular tissue.
 Serous Inflammation
 Serous inflammation is marked by the exudation of
cell poor fluid into spaces created by cell injury or into
body cavities lined by the peritoneum, pleura, or
pericardium.
 Fibrinous Inflammation.
 Purulent (Suppurative) Inflammation, Abscess
Purulent inflammation is characterized by the
production of pus, an exudate consisting of
neutrophils, the liquefied debris of necrotic cells, and
edema fluid.
 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
Outcomes of Acute Inflammation
 Complete resolution.
 Healing by fibrosis.
 Abcess formation.
 Chronic inflammation.
Outcome of acute inflammation
Chronic inflammation
 Chronic inflammation is a response of prolonged
duration (weeks or months) in which inflammation,
tissue injury and attempts at repair coexist, in varying
combinations.
Causes of Chronic Inflammation

 Persistent infections by microorganisms.

 Hypersensitivity diseases.
 a)autoimmune diseases.
 b)allergic diseases, such as bronchial asthma.
 Prolonged exposure to potentially toxic agents,
either exogenous or endogenous.
 Silicosis, Atherosclerosis
 Chronic inflammation is characterized by:
 Infiltration with mononuclear cells, which include
macrophages, lymphocytes, and plasma cells.
 Tissue destruction, induced by the persistent
offending agent or by the inflammatory cells
 Attempts at healing by connective tissue replacement
of damaged tissue, accomplished by angiogenesis
(proliferation of small blood vessels) and, in particular,
fibrosis.
 Cells of chronic inflammation
 Macrophages.
 Plasma cell.
 Lymphocytes.
 Eosinophils.
 Mast cell.
 There are two major pathways of macrophage
activation, called classical and alternative.
 Classically activated macrophages are induced by
microbial products and cytokines, particularly IFN-γ.
They phagocytose and destroy microbes and dead
tissues and can potentiate inflammatory reactions.
 Alternatively activated macrophages are induced by
other cytokines and are important in tissue repair and
the resolution of inflammation
 Classical activated macrophage : ROS, NO, lysosomal
enzymes- Microbicidal actions: phagocytosis and
killing of many bacteria and fungi.
 IL-1, IL-12, IL-23, chemokines Inflammation.
 Alternatively activated macrophage (M2):
 Growth factors, TGF-β: Tissue repair, fibrosis
 IL-10, TGF- β: Anti-inflammatory effects.
Granulomatous inflammation
 Granulomatous inflammation is a form of chronic
inflammation characterized by collections of activated
macrophages, often with T lymphocytes, and
sometimes associated with central necrosis.
 The activated macrophages may develop abundant
cytoplasm and begin to resemble epithelial cells, and
are called epithelioid cells.
 Some activated macrophages may fuse, forming
multinucleate giant cells.
 Types of granulomas
 There are two types of granulomas :
 Foreign body granulomas are incited by relatively
inert foreign bodies, in the absence of T cell–mediated
immune responses.
 Foreign body granulomas form around materials such
as talc (associated with intravenous drug abuse) ,
sutures, or other fibers.
 Immune granulomas are caused by a variety of agents
that are capable of inducing a persistent T cell–
mediated immune response.
 This type of immune response produces granulomas
usually when the inciting agent is difficult to eradicate,
such as a persistent microbe or a self antigen.
 In such responses, macrophages activate T cells to
produce cytokines, such as IL-2, which activates other
T cells, perpetuating the response, and IFN- γ, which
activates the macrophages. It is not established which
macrophage-activating cytokines (IL-4 or IFN-γ)
transform the cells into epithelioid cells and
multinucleate giant cell.
 Morphology
 In the usual hematoxylin and eosin preparations , the
 activated macrophages in granulomas have pink granular
cytoplasm with indistinct cell boundaries and are called
epithelioid cells .
 The aggregates of epithelioid macrophages are
surrounded by a collar of lymphocytes, a rim of fibroblasts
and connective tissue.
 Multinucleated giant cells 40 to 50 μm in diameter are
found in granulomas, these are called Langhans giant
cells. They consist of a large mass of cytoplasm and many
nuclei, and they derive from the fusion of multiple
activated macrophages.
 Central zone of necrosis.
 Grossly, this has a granular, cheesy appearance and is
therefore called caseous necrosis.
 Microscopically, this necrotic material appears as
amorphous, structureless, eosinophilic, granular
debris, with complete loss of cellular details.
 Caseating granuloma present in Tuberculosis.
 Non-caseating. granulomas in Crohn disease,
sarcoidosis.
Granuloma
Examples of granulomatous inflammation
 Syphilis- 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- rounded or stellate granuloma
containing central granular debris and
recognizable neutrophils; giant cell uncommon.
 Others: Sarcoidosis- Noncaseating granuloma.
 Lymphogranuloma inguinale, brucellosis, some
mycotic infections, berylliosis and foreign body
granuloma.
 summary
 In summary, Granulomatous inflammation is a
specific type of chronic inflammatory reaction
characterized by accumulation of modified
macrophages (epithelioid cells) and initiated by a
variety of infectious and noninfectious agents.
 The presence of poorly digestible irritants, T cell-
mediated immunity to the irritant, or both appears to
be necessary for granuloma formation.
The End