ACUTE AND CHRONIC

INFLAMMATION

Lecture 3

By Regina E.M. Baiden-Amissah

 DEFINITION
 Inflammation is “A dynamic response of living
vascularized tissue to infections, damaged tissues and
necrotic cells ,that brings cells and molecules of the
host defense from the circulation to the sites where
they are needed, in order to eliminate the offending
agents.”
 It is a protective response referred to as innate
immunity with the aim to dilute, destroy, isolate, initiate
repair.
 Inflammation is controlled and self-limited
 Components:
 Host cells (Leukocytes-white blood cells)
 Blood vessels
 Proteins
 Mediators

• Two main goals

– To get rid of initial cause of cell injury –
microorganisms, toxins etc.
– To get rid of the consequences of cell injury
 Cardinal signs of inflammation
• Redness – Rubor
• Pain – Dolor
• Heat – Callor
• Swelling – Tumor
• Loss of function – Functio Lesia

The basis of the five cardinal signs

 Increased blood flow due to vascular dilation gives redness and
heat.
 Increased vascular permeability gives oedema causing tissue
swelling.
 Certain chemical mediators stimulate sensory nerve endings giving
pain. Nerves also stimulated by stretching from oedema.
 Pain and swelling result in loss of function.
 HISTORICAL HIGHLIGHTS

YEAR SCIENTIST EVENT

3000 BC Clinical features on
Egyptian Papyrus
1st Century AD Celsus Cardinal signs (first 4)
19th Century Rudolf Virchow Cardinal sign (5th)
1793 John Hunter Inflammation is a
protective process
1839-84 Julius Cohnhein Mechanism of cardinal sign
1876 Paul Ehrlich Mast Cells
1927 Sir Thomas Lewis Role of chemical mediators
1974 Cohen and co-workers Cytokines
1979 Aarden and co-workers Interleukins

1982 Elie Metchnikoff Phagocytosis

1988 Leber Bacteria induced
chemotaxis
 Nomenclature and Types of Inflammation
• Diseases associated with inflammation are usually denoted by
adding the suffix ‘itis’. For instance,

• Tonsillitis (tonsils)
• Appendicitis (appendix)
• Dermatitis (skin)
• Arthritis (joints).
• Meningitis (meninges of the brain).
• Lymphadenitis (lymph node)
• Lymphangitis ( lymphatics)

• Types
– Acute (sec, mins, hrs)
– Chronic (days, weeks, months, yrs)
 ACUTE INFLAMMATION
The immediate and early response to an injurious agent, designed to
deliver leukocytes and plasma proteins to the site of injury

FEATURES
1. Fluid and plasma protein EXUDATION at the site of injury.

2.Predominantly NEUTROPHILLIC leukocyte accumulation.

It has 2 major components;

 Vascular changes
 Alteration in vascular caliber that leads to an increase in blood flow
 Structural changes in the microvasculature that permits plasma proteins
and leukocytes to leave the circulations.
 Cellular events:
 Emigration of the leukocytes from the microcirculation, their accumulation
in the focus of injury, and their activation to eliminate the offending agents
 Etiologies of acute inflammation
• Microbial infections: bacterial, viral, fungal, microbial toxins.

• Trauma: Blunt, penetrating, physical agents ( burns, cuts, radiation),

chemicals ( drugs, toxins etc.)

• Tissue necrosis; Ischemia, hypoxia, chemical and physical injury

• Foreign bodies (dirt, sutures, splinters)

• Immunologic reactions ( Hypersensitive reactions e.g. rheumatoid

arthritis. )
 VASCULAR EVENT
 Changes in Vascular Caliber and Flow
 Before vasodilation, there is a brief arteriolar vasoconstriction
– Engorgement of capillary beds
– Increase blood flow (warmth and redness)
– Increased intravascular/hydrostatic pressure causes an early transudate
(protein-poor filtrate of plasma) into interstitium
– Mediated by histamine and nitric oxide

Increased vascular permeability (HALL MARK)

 Increase permeability of microvasculature with outpouring of protein rich
fluid into the extravascular tissue (exudate)
 Increases interstitial/ decreases intravascular osmotic pressure
contributing to edema (water and ions)
 Fluid loss leading to hemoconcentration in small vessels and increased
viscosity of blood, reflected by stasis.
 Leukocytes (neutrophils) accumulate along vascular endothelium, stick to
the endothelium and then migrate through the vascular wall into the
 Mechanism of vascular permeability
• Endothelial Cell Contraction: This is the most
common mechanism of vascular permeability.

– Formation of endothelial gaps in venules. This is rapid,

reversible and short-lived (15-30mins), mediated by
histamine, bradykinnin, leukotrienes, the neuropeptide
and others. It is known as immediate transient response.

– Cytokine mediators (TNF, IL-1, IFN-Y) induce endothelial

cell junction retraction through cytoskeleton
reorganization. Their effect is delayed (4-6hrs) and long –
lived (24hours or more).
 Mechanism of vascular permeability
• Endothelial injury:
 Severe endothelial injury (burns, Infections), may cause
immediate direct endothelial cell damage resulting in
endothelial cell necrosis and detachment. The effect is
immediate and sustained; hence the name immediate
sustained response. Venules, capillaries and arterioles are
affected.

 Delayed prolonged leakage- it begins after a delay of 2-21

hours; last for several hours or days and involve venules
and capillaries.
e.g. bacterial toxins, mild to moderate thermal injury,
ultraviolet radiation and x-radiation
 Mechanism of vascular permeability
• Leukocyte-dependent endothelial cell injury
 Leukocyte accumulation along the vessel wall may also lead
to endothelial cell injury/detachment when activated by
releasing toxic oxygen radicals and proteolytic enzymes. It is
restricted to venules, pulmonary and glomerular capillaries.

• Increased transcytosis
 VEGF may cause increased vascular permeability via increasing the
number and sometimes size of vesiculovascuolar organelle

• Leakage from new blood vessels

 New vessels sprouts are leaky until endothelial cells are
mature and form intercellular junction.
VASCULAR EVENT
The major local manifestations of
acute inflammation, compared to
normal.

Vascular dilation and increased

blood flow (causing erythema and
warmth).

Extravasation and deposition of

plasma fluid and proteins (edema).

leukocyte emigration and

accumulation in the site of injury.
 Exudate and transudate
• Exudate – is an inflammatory extravascular fluid rich in plasma
protein, cellular debris and has a specific gravity > 1.020.

– The fluid exudates in inflammation functions to:

– Dilute irritants in tissues.
– Form fibrin clot to provide scaffolding between severed tissues, to
stop bleeding and to assist in phagocytosis.
– Release natural anti-microbial substances: opsonins and
immunoglobulins.

• Transudate – is a fluid low in protein and specific gravity

<1.012. It results from osmotic or hydrostatic imbalance
across vessel wall without an increase in vascular
permeability; hence it is a plasma ultrafiltrate.
 CELLULAR EVENTS
• Leukocyte recruitment and activation at injury site
(extravasation and phagocytosis)
• May induce tissue damage and prolong inflammation
• The sequence of events in the movement of leukocytes:
– Margination, rolling and adhesion to the endothelium.
– Transmigration across the endothelium (diapedesis)
– Migration in interstitial tissue toward a chemotactic
stimulus.
• At the site of injury:
– Phagocytosis and degranulation
– Leukocyte-induced tissue injury
 Margination and Rolling
• With increased vascular permeability, fluid leaves the vessel
causing leukocytes to settle-out of the central flow column and
“marginate” along the endothelial surface as stasis set in.

• Rolling mediated by selectin family of adhesion molecule

• During margination, endothelial cells are activated by cytokines
(TNF, IL-1,histamine,thrombin) to express adhesion molecules

• E-selectin (endothelium), P-selectin (platelets, endothelium), L-

selectin (leukocytes) bind other surface molecules (i.e.,CD34, Sialyl-
Lewis X-modified GP)

• Endothelial cells and leukocytes have complementary surface

adhesion molecules which briefly stick and release causing the
leukocyte to roll along the endothelium like a tumbleweed until it
eventually comes to a stop as mutual adhesion reaches a peak
(attach loosely/weak and transient interaction)
 Adhesion
• The endothelium is activated by TNF and IL-I which induces expression of
VCAM-I and ICAM-I (Adhesion molecule-ligands) on the endothelium.
Chemokines also activate leukocytes resulting in VLA-4, Mac1 and LFA-1
production (Adhesion molecule-integrin) .
• The interaction of the integrins on the leukocytes with their ligands on the
endothelium under the influence of chemokines, results in firm binding -
ADHESION

– Endothelial: ICAM-1, VCAM-1

– Leukocyte: LFA-1, Mac-1 (β 2 integrin) VLA-4 (β 1 integrin)
– (ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds VLA-4)

• These adhesion molecules are normally down-regulated or in an inactive

conformation, but becomes activated ones inflammation sets in
• (Intercellular Adhesion Molecule-ICAM, vascular cell adhesion molecule -
VCAM, Lymphocyte function-associated antigen -LFA, very late activation
antigen 1-VLA)
 Transmigration (diapedesis)
• Extravasation of leukocytes occurs mainly in the systemic venules
and pulmonary capillaries.

• It is facilitated by chemokines which acts on leukocytes stimulating

them to migrate through interendothelial spaces

• With the aid of Platelet Endothelial Cell Adhesion Molecule

(PECAM-1), leukocytes are able to bind and traverse the
endothelium

• Secretions of collagenases by leukocytes enable them to pierce

the basement membrane and thereby accumulate at the site of
injury

• The type of accumulating leukocytes depends on the age of the

inflammatory response. In the first 6-24hours, neutrophils
Leukocyte migration
 Chemotaxis

• Leukocytes move to injury site along a chemical gradient known as

chemotaxis
• Substances that attract leukocyte into this direction are called
chemoattractant.
• Chemoattractant are produce during infection, tissue damage and
immunologic response
• Endogenous and Exogenous type:
– Exogenous (bacterial products)
– Endogenous (C5a, IL-8, LTB4)
Mechanism
• Chemoattractants bind to specific receptors on the surface of
leukocytes, initiating intracellular signaling pathways resulting in
assembly of cytoskeletal contractile element (polymerization of
actin, localization of myosin). This causes leukocyte to move by
extending pseudopods and move it in the direction of the extension
 Leukocyte Activation.

• Enhances the following functions:

– Phagocytosis of particle
– Degranulation and secretion of Lysosomal
enzymes, nitrogen species and activation of
oxidative burst.
– Delivery of substances that destroys
extracellular microbes and dead cells
(extracellular traps)
– Secretion of cytokines and production of
arachidonic acid metabolites
 PHAGOCYTOSIS
• Three steps:
• Recognition and attachment
– Mannose receptors: Terminal mannose and fucose
residues of glycoproteins and glycolipids of microbial
cell walls
– Scavenger receptors: Bind and help endocytosis of low
density lipoproteins (oxidized or acetylated LDL)
– Receptors for opsonins: Recognize host cell proteins
that coat microbes called opsonins and attach.
Examples of opsonins include C3b and IgG antibodies.
Fc receptor (FcγRI)binds to IgG, CR1 and CR3 bind to
Cb3
• Engulfment – Pseudopods extend around the
particle forming phagocytic vacuole and
subsequent fuse with lysosome.
(Phagolysosome)
• Killing and degranulation - This is the ultimate
step in the elimination of infectious agents
and necrotic cells. Its performed by
microbicidal substances (Lysosomal enzymes
and ROS)
 Killing in phagocytosis

Oxidative or respiratory burst

– Increased oxygen consumption
– Glycogenolysis
– Increased glucose oxidation
– Formation of superoxide ion (ROS)
• 2O2 + NADPH  2O2-rad + NADP+ + H+

(NADPH oxidase)
• O2-rad + 2H+  H2O2 (dismutase)
• Hydrogen peroxide alone insufficient
• (azurophilic granules) contains MPO which converts
hydrogen peroxide to HOCl- (in presence of Cl- ), an
oxidant/antimicrobial agent
• Bacteria then killed by halogenation, or lipid and protein
 Killing in phagocytosis
• NO reacts with H2O2 to generate peroxynitrate
(ONOO)
• Other antimicrobials in leukocyte granules:
– Bactericidal permeability increasing protein (BPI)
– Lysozyme
– Lactoferrin
– Defensins (punch holes in membranes)
• After killing, acid hydrolases from the lysosome are
activated and degrade the microbes within
phagolysosomes.
 Leukocyte-induced tissue injury
• Leukocytes once activated produce destructive
enzymes that may enter extracellular and affect
normal cells and tissues
– Infections that are difficult to eradicate (TB, viral
infection)
– Membranolytic substances (urate crystals)
– Frustrated phagocytosis (Flat, Large)
– Inappropriate inflammation response again host tissues
(Autoimmune diseases, hypersensitive diseases)
– Attempt to clear damage and dead tissues after
myocardial infarction
– Premature degranulation
– Persistent leukocyte activation (emphysema)
 Defects of leukocyte function
• Reduced number of leukocyte -Neutropenia (Leukemia )

• Disorders of leukocyte adhesion

– Leukocyte adhesion deficiency1- defective synthesis of LFA-1 and
Mac-1- improper adhesion and phagocytosis-oxygen burst
– Leukocyte adhesion deficiency 2-defective fucose metabolism-
absence of sialyl–Lewis X.
• Defects in phagolysosome formation.
– Intrinsic cellular dysfunctions -e.g. Chediak-Higashi syndrome
• Defects of microbicidal activity:
– Deficiency of NADPH oxidase that generates superoxide, therefore no
oxygen-dependent killing mechanism (chronic granulomatous disease)
– Myeloperoxidase deficiency- Decrease microbial killing
• Mutations in TLRs signaling pathways and component of
inflammasomes
MORPHOLOGICAL PATTERNS OF ACUTE INFLAMMATION

• SEROUS INFLAMMATION
 Its characterized by the outpouring of watery ,protein-poor fluid
 Mesothelial cells – peritoneal pleural , pericardial cavities or plasma
E.g. Skin blister- viral ,burns. Large accumulation of serous fluid (effusion)
 PATTERNS Cont
 FIBRINOUS INFLAMMATION (hemorrhagic or rich in fibrin)
 Severe injury leading to fibrinogen passing through endothelial barrier
(Fibrin accumulation)
 Inflammation in the lining of body cavities – meninges ,pericardium,
pleura
 Entirely removed by fibrolysis- resolution
 May not be removed and become fibroblastic (fibroblast and blood
vessels) - Scarring
 PATTERNS Cont
 SUPPURATIVE OR PURULENT INFLAMMATION and ABSCESS FORMATION
 Produce large amount of pus (purulent exudates) - neutrophil, necrotic
cells and edema fluid (POCKET OF PUS)
 Pyogenic bacteria (pus forming), e.g. staphylococcus
 Abscess – Focal collection of pus with central largely necrotic region
rimmed by a layer of neutrophils.
 Surrounded by blood vessels and fibroblast-replaced by connective tissue-
scarring
 PATTERN Cont
 ULCERS
 Local defect or excavation of surface organ or tissue that is produced by
shedding of necrotic and inflammatory tissue.
 Mucosa of the mouth, stomach, intestines, or genitourinary tract
 Subcutaneous inflammation of lower extremities in older person
 Peptic ulcers- Acute (Polymorphonuclear infiltration) and Chronic –
lymphocytes, macrophages and plasma cells with scarring .
Acute inflammation
 Chronic inflammation
• Chronic inflammation is prolonged and gradual (weeks /
weeks /months /year)
• During this process:
– Continuous inflammation, tissue injury, and attempts at repair
(fibrosis)

• Mononuclear cells - Lymphocyte, macrophage, plasma cell

infiltration

• Tissue destruction by inflammatory cells

• Repair with fibrosis and angiogenesis (new vessel formation)

• May follow acute inflammation (peptic ulcer) or begin

insidiously without any manifestations of an acute reaction (Viral
infections)
 Causes of chronic inflammation
• Persistent infections
– Organisms usually difficult to eradicate and of low toxicity that invoke
delayed hypersensitivity reaction (T-lymphocyte immune response)
– M. tuberculosis, T. pallidum, certain virus and fungi
• Immune-mediated inflammatory diseases
– Auto-immune: Auto-antigens provoke self-perpetuating immune
responses that cause chronic inflammatory diseases like Rheumatoid
arthritis
– Allergies: Responses against common environmental substances
cause chronic allergic diseases, such as bronchial asthma

• Prolonged exposure to potentially toxic agents

– Exogenous agents include silica which causes silicosis in the lungs
– Endogenous causes include atherosclerosis caused by toxic plasma lipid
components (cholesterol crystals)
Chronic inflammation
 Macrophages in chronic inflammation

ORIGIN OF MACROPHAGES
• Derived from
– Hematopoietic stem cell in the bone marrow
– Progenitor cells (embryonic yolk sac,fetal liver)
• Circulating cells derived from this lineage are called
monocytes
 From the blood, monocytes migrate into various
tissues and differentiate into macrophages
– Kupffer cells - Liver
– Sinus Histiocytes - Spleen and lymph nodes
– Alveolar Macrophages – Lungs
– Microglial cells – Nervous system
Macrophages in chronic inflammation
FUNCTION
– Ingest and eliminate microbes and dead cells
– Initiate tissue repair processes
– Produce mediators of inflammation (TNF, IL-1,
chemokines etc.)
– Respond to signals from T-cell ( T-cell mediate
adaptive immunity)
– Displays antigen to T-Lymphocytes
 Macrophages in chronic inflammation
Macrophage activation

 Monocytes begin to emigrate into extravascular tissues

quite early in acute inflammation
 In chronic inflammation, as monocytes and reach site
of injury within 24 – 48 hrs and transform into
macrophages by two main pathways (Classical and
Alternative pathways)
 In chronic inflammation, macrophage accumulation
persists as a result of continuous recruitment from the
circulation and local proliferation at the site of
inflammation (multinucleated giant cell) under d
influence of IFN-γ.
 The half-life of blood monocytes is about 1 day
Macrophage activation
 Lymphocytes in chronic inflammation
T and B cells

 Engage in immune (infection) and non-immune mediated

inflammation (trauma, ischemic necrosis)
 CD4+ T lymphocyte
 TH1 cells produce the cytokine IFN-γ, (classical pathway)
 TH2 cells secrete IL-4, IL-5, and IL-13, (alternative Pathway)
 TH17 cells secrete IL-17 and other cytokines that induce the secretion of
chemokines responsible for recruiting neutrophils and monocytes into the
reaction.
 Macrophages display antigens to T cells and produce membrane
molecules (costimulators) and cytokines (notably IL-12) that
stimulate T-cell responses
 Activated T lymphocytes recruit monocytes from the circulation with
IFN-γ, a powerful activator of macrophages
 Plasma cells develop from activated B lymphocytes and produce
antibodies
 Accumulations of lymphocytes, antigen-presenting cells, and plasma
cells may assume the morphologic features of lymph nodes, called
tertiary lymphoid organs
 Other cells in chronic inflammation
• Eosinophils
– Predominantly found in immune reactions mediated by IgE and in
parasitic infections, recruited by eotaxin and other adhesion
molecules. (Associated with Allergies)
– Granules contain major basic protein, a highly cationic protein that is
toxic to parasites but also causes lysis/necrosis of host epithelial cells
• Mast cells
– Express on their surface the receptor (FcγRI) that binds the Fc portion
of IgE antibody (coated with IgE)
– Granules release histamine and AA metabolite (prostangladins) during
allergic reactions to foods, insect venom, or drugs, inducing vascular
changes in acute inflammation, sometimes with catastrophic results
(e.g. anaphylactic shock)
• Neutrophils
– Induced either by persistent microbes/necrotic cells or by mediators
produced by activated macrophages and T lymphocytes
– Neutrophilic exudate can persist for many months in osteomyelitis
– Cause chronic damage induced in lungs by smoking and other irritant
stimuli
 Granulomatous inflammation
 Chronic inflammation characterized by clusters of T cell activated
macrophages with scattered lymphocytes which engulf and surround
indigestible foreign bodies
 Encountered in a limited number of conditions
 Cellular attempt to contain an offending agent that is difficult to eradicate
(i.e. Tb)
 Consists of a microscopic aggregation of macrophages that are transformed
into epithelioid cells, surrounded by a collar of mononuclear leukocytes,
principally lymphocytes and occasionally plasma cells
 Epithelioid cells have a pale pink granular cytoplasm with indistinct cell
boundaries, often appearing to merge into one another as giant ( large mass
of cytoplasm and many nuclei, and they derive from the fusion of multiple
activated macrophages
 Foreign body granulomas are incited by relatively inert foreign bodies (i.e.
talc, sutures) in sarcoidosis-unknown etiology
 Immune granulomas are caused by several infectious agents that provoke a
cell-mediated immune response leading to macrophage activation
 Immune mediated inflammatory diseases. E.g. Crohn diseases
 Associated with central zone of necrosis-caseous necrosis- granular cheesy
appearance
 Causes of granulomas
Disease Cause Tissue Reaction
Tuberculosis Mycobacterium Caseating granuloma (tubercle): focus of activated
tuberculosis macrophages (epithelioid cells), rimmed by fibroblasts,
lymphocytes, histiocytes, occasional Langhans giant
cells; central necrosis with amorphous granular debris;
acid-fast bacilli

Leprosy Mycobacterium leprae Acid-fast bacilli in macrophages; noncaseating granulomas

Syphilis Treponema pallidum Gumma: microscopic to grossly visible lesion, enclosing

wall of histiocytes; plasma cell infiltrate; central cells
necrotic without loss of cellular outline

Cat-scratch Gram-negative Rounded or stellate granuloma containing central granular

disease bacillus debris and recognizable neutrophils; giant cells
uncommon
Sarcoidosis Unknown etiology Noncaseating granulomas with abundant activated
macrophages
Crohn disease Immune reaction Occasional noncaseating granulomas in the wall of the
(inflammatory against intestinal intestine, with dense chronic inflammatory infiltrate
bowel bacteria, self-
disease) antigens
Granuloma
 Systemic effect of inflammation
• Fever – Rise in temperature
– Pyrogens elevate prostaglandin synthesis in the
vascular and perivascular cells of the hypothalamus.
– Bacterial products e.g. lipopolyssacharide (exogenous
pyrogen) stimulate leukocytes to release cytokines
such as TNF and interleukin-1 (endogenous pyrogens)
- increase of cyclooxygenase 2 , which convert
arachidonic acid into prostaglandins.
– Stimulate the production of neurotransmitters, which
increases the temperature
– Non steroidal anti inflammatory drugs, including
aspirin. Reduce fever by inhibiting cyclooxygenase 2
 Systemic effect of inflammation
• Elevated plasma levels of acute-phase proteins.
– Are mostly plasma proteins. (C-reactive protein, fibrinogen
and Serum Amyloid A protein (SAA).)
– Synthesized by the Liver (hepatocytes) and is upregulated by
cytokines especially interleukin 6 (C-reactive protein and
fibrinogen) and IL-1 or TNF (SAA).
– CRP and SAA bind to microbial cell (opsonins and
complement) –eliminating the microbes
– Fibrinogen binds to erythrocytes forming stacks that sediment
more rapidly at unit gravity -ESR
– Their measurement (CRP and ESR) assess therapeutic
response in Rheumatoid arthritis (inflammatory disorder)
– CRP risk assessment marker in myocardial infarction
 Systemic effect of acute inflammation
• Leukocytosis
• Is a response of the bone marrow to circulating cytokines, (TNF and IL-1) and
granulocyte colony-stimulating factor, which results in increased production and
release of leukocytes to replace those consumed during inflammation.
• The increase is reffered to as Leukemoid reactions because they are similar to
those seen in leukemia.
• An elevated neutrophil count, particularly when accompanied by the presence
of immature neutrophils, prematurely released from the bone marrow is a
clinical sign of infection .e.g bacteria infection

– Bacterial infection -(neutrophilia)

– Viral infection e.g. mumps, measles - (lymphocytosis)
– Parasitic infection (eosinophilia)

• Certain infections (typhoid fever, viruses, rickettsiae, and certain protozoa) –

leukopenia (decrease WBC) due to the sequested lymphocytes into lymph
nodes.
• Other factors : Skeletal muscle protein degradation, Hypertension, decrease
CHEMICAL MEDIATORS AND REGULATORS OF
INFLAMMATION
 Shared Properties of mediators
• Cell or plasma protein derived
– Produced locally by cells at the site of inflammation, or derived from
circulating inactive precursors which are later activated at the site of
inflammation
• May or may not utilize a specific cell surface receptor which
binds to target cell for activity. E.g. ROS, Lysosomal protease
don’t bind to receptors
• They can be activated in response to various stimuli
• May also signal target cells to release other effector molecules
that either amplify or inhibit initial response (regulation)
• Are tightly regulated and short lived:
• Quickly decay (AA metabolites), are inactivated enzymatically
(kininase-bradykinin), or are scavenged (antioxidants-toxic
oxygen metabolites) or inhibited (e.g.,complement regulatory
proteins block complement activation).
 Role of Mediators in Different Reactions of Inflammation
Vasodilatation Prostaglandins
Nitric oxide
Histamine
Increased vascular permeability Vasoactive amines
C3a and C5a (through liberating amines)
Bradykinin
Leukotrienes C4, D4, E4
PAF
Substance P
Chemotaxis, C5a
leukocyte recruitment and activation Leukotriene B4
Chemokines
IL-1, TNF
Bacterial products
Fever IL-1, TNF
Prostaglandins
Pain Prostaglandins
Bradykinin
Tissue damage Neutrophil and macrophage lysosomal
enzymes
Oxygen metabolites
Nitric oxide
Mediator Principal Sources Actions
CELL-DERIVED
Histamine Mast cells, basophils, Vasodilation, increased vascular permeability, endothelial activation
platelets

Serotonin Platelets Vasodilation, increased vascular permeability

Prostaglandins Mast cells, leukocytes Vasodilation, pain, fever
Leukotrienes Mast cells, leukocytes Increased vascular permeability, chemotaxis, leukocyte adhesion and
activation

Platelet-activating factor Leukocytes, mast cells Vasodilation, increased vascular permeability, leukocyte adhesion,
chemotaxis, degranulation, oxidative burst

Reactive oxygen species Leukocytes Killing of microbes, tissue damage

Nitric oxide Endothelium, Vascular smooth muscle relaxation, killing of microbes
macrophages

Cytokines (TNF, IL-1) Macrophages, Local endothelial activation (expression of adhesion molecules),
endothelial cells, fever/pain/anorexia/hypotension, decreased vascular resistance
mast cells (shock)

Chemokines Leukocytes, activated Chemotaxis, leukocyte activation

macrophages

PLASMA PROTEIN–DERIVED
Complement products Plasma (produced in Leukocyte chemotaxis and activation, vasodilation (mast cell
(C5a, C3a, C4a) liver) stimulation)

Kinins Plasma (produced in Increased vascular permeability, smooth muscle contraction,

liver) vasodilation, pain
Proteases activated during Plasma (produced in Endothelial activation, leukocyte recruitment
coagulation liver)
 Cytokines and Chemokines
Cytokine Principal Sources
IN ACUTE INFLAMMATION
TNF Macrophages, mast cells, T
lymphocytes
IL-1 Macrophages, endothelial
cells, some epithelial cells
IL-6 Macrophages, other cells
Chemokine Macrophages, endothelial
cells, T lymphocytes, mast
cells, other cell types
IN CHRONIC INFLAMMATION
IL-12 Dendritic cells, macrophages
IFN-γ T lymphocytes, NK cells
IL-17 T lymphocytes
Principal Actions in Inflammation
Stimulates expression of endothelial adhesion
molecules and secretion of other cytokines;
systemic effects
Similar to TNF; greater role in fever
Systemic effects (acute-phase response)
Recruitment of leukocytes to sites of inflammation;
migration of cells to normal tissues
Increased production of IFN-γ
Activation of macrophages (increased ability to kill
microbes and tumor cells)
Recruitment of neutrophils and monocytes