ACUTE INFLAMMATION

Dr Abba Z. Bukar
Consultant Histopathologist
Introduction
 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.
 The unique feature of the inflammatory process is the
reaction of blood vessels, leading to the accumulation of
fluid and leukocytes in extravascular tissues.
 The inflammatory response is closely related with the
process of tissue repair.
Introduction cont.
 Repair begins in the early phases of inflammation
but reaches completion usually after the injurious
agent has been neutralized.
 Inflammation serves to destroy, dilute, or wall off
injurious agent, and it sets in motion a series of
events that try to heal and reconstitute the damaged
tissue.
 Inflammation is not a disease but it is terminated
when the offending agent is eliminated.
Historic perspective of inflammation
 The clinical features of inflammation were described in an Egyptian
papyrus dated around 3000 BC,
 Celsus, a Roman writer of the first century AD, first listed the four
cardinal signs of inflammation:
1. rubor (redness),
2. tumor(swelling),
3. calor (heat), and
4. dolor (pain).
 These signs are hallmarks of acute inflammation.
 A fifth clinical sign, loss of function (functio laesa), was added by
Rudolf Virchow in the 19th century.
Cardinal sign of inflammation
Cont.
In 1793, the Scottish surgeon John Hunter noted that
inflammation is not a disease but a stereotypic response
that has a useful effect on its host.
In the 1880s, Russian biologist Elie Metchnikoff
discovered the process of phagocytosis.
He concluded that the purpose of inflammation was to
bring phagocytic cells to the injured area to engulf
invading bacteria.
Cont.
Sir Thomas Lewis, studying the inflammatory
response in Skin, established the concept that
chemical substances, such as histamine, mediate
the vascular changes of inflammation.
This fundamental concept underlies the important
discoveries of chemical mediators of inflammation
and the use of anti-inflammatory drugs in clinical
medicine.
NB:
Therefore inflammation is not a disease
rather is a response of vascularised tissues
to injury that eliminates noxious agents
paving way for repair.
Inflammation is define as the response of
vascularized living tissue to injury.
Purpose of inflammation
 Production of an exudate which
 dilutes toxins & transports inflammatory cells to the site of
injury to eliminate the offending agent.
 Walling off the injurious agent or slowing down spread of the
insult.
 Clearing the tissue debris which sets the stage for repair
Classification of inflammation
 Inflammation is divided into:
a. Acute
b. Chronic
 Acute Inflammation- is a rapid response to an injurious
agents that serves to deliver mediators of host defence –
leukocytes and plasma proteins- to the site of injury.
 Chronic Inflammation-is of prolonged duration in which
 active inflammation
 tissue destruction and
 attempts at repair are going on
Acute Inflammation
 Stimuli for Acute Inflammation
a. Infections – bacteria, virus, etc
b. Trauma – blunt or penetrating injury
c. Physical and chemical agents – burns, frostbite
d. Tissue necrosis
e. Foreign bodies
f. Immune reactions
Components of acute inflammation
A. Alterations in vascular caliber that lead to increased blood
flow.
B. Structural changes in the microvasculature that permit
plasma proteins and leukocytes to leave the circulation.
C. Emigration of the leukocytes from the microcirculation,
their accumulation in the focus of injury, and their
activation to eliminate the offending agents.
Process of acute inflammation
1. Vascular events
2. Cellular events
Vascular Changes
a. changes in vascular flow and caliber
i. Vasodilation induced by histamine and NO
ii. Increased permeability of microvasculature and
extravasation of protein –rich fluid
iii. Increased viscosity and stasis
iv. Accumulation of leukocytes along the vascular
endothelium.
b. Increased vascular permeability (oedema)
This leads to accumulation of protein rich-fluid in the
extravascular space, reduction of intravascular osmotic
pressure and increased osmotic pressure of interstitial fluid.
 Mechanisms of vascular leakage
1. Formation of endothelial gaps in venules, this is mediated by
histamine, bradykinins, leukotrienes and neuropeptide,
substance P
2. Direct endothelial injury, resulting in endothelial necrosis and
detachment seen in severe burns and lytic bacterial infections;
3. Leukocyte-mediated endothelial injury
4. Increased transcytosis across the endothelial cytoplasm
mediated by VEGF
5. Leakage from new blood vessels (angiogenesis) this occurs
during repairs mediated by VEGF, histamine, substance P
Stage 1
Transient vasoconstriction of arterioles
Vasodilatation: 1st arterioles, then opening of new capillary
beds leading to increased blood flow.
This causes heat and redness. Induced by mediators notably
histamine and nitric oxide (NO)
Stage 2.
This is followed by increased permeability of the
microvasculature with outpouring of protein rich fluid into
the extravascular tissue.
Stage 3
Concentration of rbc’s in small vessels and increased
viscosity of blood will lead to vascular congestion and slowing
of circulation referred to as Stasis
Accumulation of blood leucocytes along vascular endothelium.
Endothelial cells are activated by mediators produced at sites
of infection leading to increased expression of adhesion
molecules, adherence of leucocytes to the endothelium and
migration into the interstitial tissue.
Mediators of Vasodilatation
 HISTAMINE (< 1 min.)

 KININS (3 hr.)

 PROSTAGLANDINS (3 hr.)

 LEUKOTRIENES (3 hr.)

 PLATELET ACTIVATION FACTOR (3 hr.)

Cellular Events
Leukocytes Extravasation and Phagocytosis
This is divided into 3 phases

a. In the lumen: margination, rolling, and adhesion to the endothelium.

b. Transmigration across the endothelium (diapedesis)

c. Migration in interstitial tissues toward a chemotactic stimulus

Cont.
 Leukocyte Adhesion and Transmigration
A regulated by binding of complementary adhesion molecules on the leukocyte
and endothelial surfaces.
 The adhesion receptors are divided into four:
A. Selectins- E-selectin (CD62E) P-selectin (CD62P) and L-selectin (CD62L).
They bind through their lectin domain to sialyated forms of oligosaccharides
which themselves are covalently bound to mucin-like glycoproteins
(GlyCAM-1, and CD34)
B. Immunoglobulin family molecules, ICAM-1 (intercellular adhesion
molecule 1) and VCAM-1 (vascular cell adhesion molecule 1), these serves as
ligands for integrins found on leukocytes
cont.
C. Integrins are transmembrane heterodimeric glycoproteins,
made up of α and β chains, that are expressed on many cells
and bind to ligands on endothelial cells, leukocytes and
extracellular matrix.
β2 integrins- LFA-1 and Mac-1 bind to ICAM-1 and
β1 integrins-VLA-4 bind VCAM-1.

D. Mucin-like glycoproteins, such as heparan sulfate serve as

ligands for the leukocyte adhesion molecule called CD44.
These glycoproteins are found in the extracellular matrix and on
cell surfaces.
Chemotaxis
After extravasation, leukocytes emigrate in tissues toward the site of
injury by a process of, chemotaxis, defined as locomotion oriented
along a chemical gradient(unilateral directional movement).
Chemoattractants can be divided into 2:
a. exogenous – bacterial products- peptides that possess
N- formyl-methionine terminal amino acid
b. endogenous :
(i) components of complement system, particularly C5a
(ii) product of the lipoxygenase pathway, mainly leukotriene
B4(LTB4);
(iii)cytokines, particularly those of chemokine family- IL-8.
All these bind to seven-transmembrane G-protein-coupled
receptors on the surface of leukocytes
The functional responses that are induced on leukocyte
activation include the following:
a. production of arachidonic acid metabolites from
phospholipids as a result of activation phospholipase A2 by
increased intracellular calcium
b. degranulation and secretion of lysosomal enzymes and
activation of the oxidative burst
c. secretion of cytokines
d. modulation of leukocyte adhesion molecules
Receptors expressed by Leukocytes
(pattern recognition receptors)
a. Toll-like receptors
b. Seven-transmembrane G-protein-coupled
receptors
c. Receptors for cytokines – IFN-γ
d. Receptors for opsonins – antibodies, IgG.
Complement proteins, C3b and lectins.
Phagocytosis
 Phagocytosis and the release of enzymes by the neutrophils
and macrophages are responsible for eliminating the injurious
agents and thus constitute two major benefits derived from
the accumulation of leukocytes at the inflammatory focus.
Phagocytosis involves 3 distinct but interrelated steps.
a. Recognition and Attachment- Mannose and
Scavenger receptors
b. Engulfment
c. Killing and Degradation
 Opsonization inhence the process of phagocytosis
 Common opsonis includes
 IgG, lectin, C3b
 Soluble pattern recognition proteins produce by the liver also
help in phogocytosis this includes amyloid and c-reactive
proteins
Oxygen-independent killing
It can be done by various enzymes and proteins like
 Lysozyme: Cause hydrolysis of glycopeptide coat of bacteria.
 Lactoferrin: It is an iron binding protein.
 Defensins: These are arginine rich peptides toxic to the
microbes.
 Cathelicidins: These are antimicrobial proteins in the
neutrophils and other cells. They are highly effective against
M. tuberculosis
 Proteases
 DNAases
 Mature macrophages lack the enzyme MPO.
– bactericidal activity by producing OH– ions and
superoxide singlet oxygen (O’)
 H2O2 in the presence of O’2 (Haber-Weiss reaction) or
in the presence of Fe++ (Fenton reaction)
Oxygen dependent killing
H2O2-MPO-halide System
 NADPH-------NADP => Oxygen + superoxide
NADPH Oxidase

 Superoxide……….Hydrogen peroxide(H2O2)

Spontaneous dismutation

 Hydrogen Peroxide + Halide(Cl-)…...Hypochlorite(OCL-)

MPO (myeloperoxidase)
NB: H2O2- MPO- Halide system is the most efficient
bactericidal system of neutrophils.
Oxygen dependent killing
Oxygen dependent killing
o NADPH +O2
 L-Arginine----------------NO +L-Citrulline

• NOS

 NO + O----------Peroxynitrite(ONOO-)

Important actions of NO
• Potent vasodilator
• Reduction of platelet aggregation
• Endogenous regulator of leucocyte recruitment
• Also possess microbicidal action:
NO acts as a free radical and can also be converted to highly
reactive peroxynitrite anion (ONOO–) as well as NO2 and NO3.
Outcomes of Acute Inflammation
a. Complete resolution
b. Abscess formation
c. Healing by connective tissue
replacement
d. Progression to chronic inflammation
 Morphologic pattern of Acute Inflammation fluid
formation which can be:-
a. serous
b. fibrinous
c. purulent or suppuration
d. mixed
Cells of acute inflammation are
Neutrophils
Eosinophils
Basophils
Acute inflammation fluids
a. Exudate- an inflammatory extravascular fluid that has
a high protein concentration, cellular debris and a SG
>1.020
b. Transudate- fluid with low protein content and a SG
<1.020, this is an ultra-filtrate of blood plasma that
results from osmotic or hydrostatic imbalance across
the vessel wall without an increase in vascular
permeability.
c. Oedema excess fluid in the interstitial or serous cavity
d. Pus - a purulent exudate rich in leukocytes, debris of
dead cells and in many cases microbes.
Purulent exudates in acute meningitis
Pyogenic meningitis
Lobar Pneumonia
Fibrinous pericarditis
Purulent exudate(pericardium)
Nomenclature of inflammation
 The suffix –itis- is added to the organ affected eg;-
 Appendex-Appendicitis
 Bronchi –Bronchitis
 Testis –orchitis
 Sinuses- sinusitis
 Pharynx -pharyngitis
 Lungs-pneumonia
 Skin - dermatitis
Chemical Mediators of Inflammation
 Mediators are the substances that initiate and regulate
inflammatory reactions.
 These are: cell derived or plasma protein derived
Chemical mediators of inflammation
 Chemical mediators of inflammation
These are responsible for the events of inflammation.
A. Vasoactive amines, histamine, serotonin
B. Plasma proteins – complement, kinin and clotting systems.
C. Arachidonic acid metabolites – PG, Leukotrienes and
Lipoxins
D. Platelet-activating factor
E. Cytokines and chemokines-TNF, IL-1, IL-8, monocyte
chemoattractant protein (MCP-1)
Vasoactive Amines: Histamine and
Serotonin
 Acts on blood vessels.
• First mediators
Histamine
• Mast cells are richest source of histamine
• Histamine stored as granules and released by
degranulation in response to various stimuli
1. physical injuries
2.Antibodies mediated – hypersensitivity reaction
3. Complement products- anaphyltoxin C3a, C5a.
4. Neuropeptides (e.g., substance P) and cytokines
(IL1, IL8)
 Histamine causes dilation of arterioles and
increases the permeability of venules.
 Principal mediator of the immediate transient
phase.
 It increased vascular permeability, producing
inter-endothelial gaps in venules.
 Act via H1 receptors present on microvascular
endothelial cells.
 Serotonin((5-hydroxytryptamine)
• preformed mediator
• Present in plateletes and certain neuroendocrinal cells like
GIT.
• primary function is as a neurotransmitter.
• vasoconstriction
Arachidonic Acid Metabolites
 The lipid mediators prostaglandins and leukotrienes are
produced from arachidonic acid (AA) present in membrane
phospholipids
 Stimulate vascular and cellular reactions.
 Arachidonic acid derived from dietary sources or by
conversion from the linoleic acid.
 Mechanical, chemical, and physical stimuli or other
mediators (e.g., C5a) release AA from membrane
phospholipids through the action of cellular phospholipases,
mainly phospholipase A2
 Phospholipase A2 Activation occur via increase in cytosolic
Ca2 + and kinase in response to external stimuli.
 Prostaglandins
• Produced by mast cells , macrophages,
endothelial cells, .
• It involved in vascular and systemic reactions of
inflammation.
• COX-1 & COX-2 is involved in synthesis of
prostaglandins
Pharmacologic Inhibitors of Prostaglandins and
Leukotrienes
 Cyclooxygenase inhibitors- aspirin and other
nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit
both COX-1 and COX-2
 COX1 is responsible for the production of
prostaglandins that are involved in both inflammation
and homeostatic functions (e.g., fluid and electrolyte
balance in the kidneys, cytoprotection in the
gastrointestinal tract)
 COX2 generates prostaglandins that are involved only in
inflammatory reactions.
 Lipoxygenase inhibitors- Zileuton
 Corticosteroids - broad spectrum antiinflammatory
Reduce the transcription of genes encoding COX2, phospholipase
A2, proinflammatory cytokines (e.g., IL1 and TNF), and iNOS
Chemokines
 Are family of small proteins that act as chemoattractants for specific
types of leucocytes. They stimulate leucocyte recruitment and control of
cell migration through tissues
 Four majour groups are:
 C-X-C chemokines. IL-8 causes activation and chemotaxis of
neutrophils
 C-C chemokines: The CC chemokines, which include monocyte
chemoattractant protein (MCP1), eotaxin, macrophage inflammatory
protein1α (MIP1α), and RANTES (regulated and normal Tcell
expressed and secreted)
 C chemokines(e.g., lymphotactin) are relatively specifc for lymphocyte
 CX3C chemokines: (CXCR4, CCR5) act as coreceptors for a
viral envelope glycoprotein
Complement system
Complement system outcome
 REGULATORY MOLECULES OF COMPLEMENT
SYSTEM
• Decay accelerating factor (DAF) increases the dissociation
of C3 convertase.
• Factor I proteolytically cleaves C3b.
• CD59 (Membrane inhibitor of reactive lysis) inhibits
formation of MAC.
• Factor H, factor I and CD46 prevent excessive alternate
pathway activation.
Coagulation and kinin systems
 Hageman factor (factor XII) is a protein synthesised by the
liver that circulates in an inactive form until it encounters
collagen, basement membrane, or activated platelets.
 Activated Hageman factor (factor XIIa) initiates four systems
1. The kinin system
2. The clotting system inducing the activation of thrombin,
fibrinopeptides, and factor X
3. The fibrinolytic system
4. The complement system
ACUTE CHRONIC
 Rapid onset  Slow onset
 Brief duration  Prolonged
 Stereotyped  Modulated
 Exudation & PMN  Inflammation & Injury
emigration & Repair
 Neutrophils  Varied cell response
 Local and systemic sign Lymphocytes,
prominent macrophages, mast cell
 Less local sign
THANK YOU FOR YOUR ATTENTION