The Inflammation

 Definition: Inflammation is a response (reaction) of living vascularized tissues to

endogenous and exogenous stimuli
 Aetiology: occurs due to injurious agents e.g, ischaemic, physical, chemical, infectious,
immunological agents.
 Terms ending in the suffix “–itis” denote inflammation .e.g., appendicitis, meningitis,
cystitis, some exceptions ;like (pneumonia)
 Types of inflammation:

1. Acute inflammation : Rapid onset and short duration

2. Chronic inflammation: Gradual onset and longer duration

 Time course – rapid and acute, or slow and chronic (depends on the pathogenic
mechanism, persistence of the injurious agent and presence of certain cell types)

Acute inflammation

 Acute inflammation is an immediate and early response to an injurious agent and it is

relatively of short duration, lasting for minutes, several hours or few days.
 It is characterized by exudation of fluids and plasma proteins and the emigration of
predominantly neutrophilic leucocytes to the site of injury.
 The five cardinal signs of acute inflammation are

1. Redness (rubor) which is due to dilation of small blood vessels within damaged
tissue as it occurs in cellulitis.
2. Heat (calor) which results from increased blood flow (hyperemia) due to regional
vascular dilation

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 3. Swelling (tumor) which is due to accumulation of fluid in the extravascular space
which, in turn, is due to increased vascular permeability.
4. Pain (dolor), Some chemicals of acute inflammation, including bradykinins,
prostaglandins and serotonin are also known to induce pain.
5. Loss of function: The inflamed area is inhibited by pain while severe swelling may
also physically immobilize the tissue.
• Chemical mediators in inflammation:

Chemical mediators derive from plasma, leukocytes, local tissue, and bacterial products.

 Examples and functions of chemical mediators:

a. Vasodilation
• Examples—histamine, nitric oxide, prostaglandin
b. Vasoconstriction
• Example—thromboxane A2 (TXA2)
c. Increasing vascular permeability
• Examples—histamine, bradykinin, leukotreins, C3a, and C5a
d. Producing pain
• Examples—prostaglandin, bradykinin
e. Producing fever
• Examples—,prostaglandin, IL-1, TNF
f. Chemotaxis
• Examples—C5a, Leukotreins, IL-8
g. Liver synthesis of acute phase reactants (APRs) e.g., : C-reactive protein (CRP),
fibrinogen, and serum amyloid A (SAA) protein.

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 Events of acute inflammation

1. Local changes in acute inflammation

2. Systemic changes in acute inflammation

1. Local changes in acute inflammation:

 Acute inflammation is categorized into an early vascular and a late cellular
responses.
 In acute inflammation there is local tissue damage and release of chemical
mediators
 The inflammatory response include:
1. Early Vascular response: formation of inflammatory fluid exudates
2. Late Cellular response: formation of inflammatory cellular exudates
• 1.Vascular Response
A. Transient vasoconstriction
B. Vasodilatation of arterioles
C. Increase the vascular permeability and formation of exudate
D. Swelling of tissue (edema(
E. Reduced blood flow (stasis)

A. transient vasoconstriction: due irritation of vessel wall leads to stimulation of

vasoconstrictor nerves, lasts for seconds or minutes.
B. Arteriolar dilatation : occurs after vasoconstriction .
 Histamine and other vasodilators (e.g., nitric oxide) relax vascular smooth
muscle, causing increased blood flow.
 Increased blood flow due to vasodilatation of arterioles increases hydrostatic
pressure (HP) in venule lumens.
C. Increased vascular permeability and formation of exudate:
 The presence of the exudates clinically appears as swelling (edema) .

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  Histamine and other mediators contract endothelial cells in venules, producing
endothelial gaps exposing bare basement membrane.
 Increasing vascular permeability leads to the movement of protein-rich fluid and
even blood cells into the extravascular tissues
 This in turn increases the osmotic pressure of the interstitial fluid, leading to more
outflow of water from the blood into the tissues.
 The resulting protein rich fluid accumulation is called an exudate.
 Exudates must be distinguished from transudates (what is the difference between
exudates and transudates?)
D. Swelling of tissue ( edema)
Net outflow of fluid from venules surpasses the capacity of lymphatics to remove
fluid hence, there is swelling of tissue.
E. Reduced blood flow
• Reduced blood flow eventually occurs because of outflow of fluid into the and
increased uptake of fluid by lymphatics.
 Formation of inflammatory fluid exudates:
Mechanism of formation :
1. Increase capillary hydrostatic pressure( increase in blood flow)
2. Increased vascular permeability leakage of fluid rich in plasma proteins(
mainly fibrinogen)
3. Reduced intravascular osmotic pressure(OP) and increased interstitial OP( due to
loss of protein in the exudate)
 Function of inflammatory exudates:
1. Dilute bacterial toxins
2. Provides opsonins (IgG, C3b) to assist in phagocytosis
3. Brings chemical mediators
4. Contains fibrinogen which is converted to fibrin (due to activation of clotting
system.

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 Function of fibrin:
a. Helps localized the infection by surrounding the inflammed area and blocking some
lymphatics
b. Forms a net work upon which phagocytic cells can move towards their target
c. The fibrin also allows movement of proliferating fibroblast during the repair process
Fate of the inflammatory exudates:
lymphatics drain the inflammatory fluid exudate from the tissues,
while this helps to limit swelling, it raises the possibility of inflammation of lymphatic
vessels( lymphangitis), the draining lymph nodes(lymphadenitis) or even systemic spread
of infectious agents.

 2.Cellular Responses:
Polymorphonuclear leukocytes are attracted (chemotaxis) to the site of acute
inflammation where they ingest foreign and degenerate material:
1. Neutrophils – produced in large numbers in bone marrow, first cells to arrive .
2. Eosinophils and basophils – limited phagocytic activity, recruited in inflammatory
reactions derived from some specific immune responses.
3. Macrophages are derived from monocytes (bone marrow) – the majority of
macrophages in inflammatory processes migrate directly from blood vessels.
 Steps of cellular response:
The cellular response has the following stages:
A. Margination, rolling& adhesion of leukocytes
B. Transmigration of leukocytes
C. Chemotaxis
D. Phagocytosis

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A) Margination, rolling and adhesion of leukocytes

 Margination is a peripheral positioning of white cells along the endothelial cells.

 Slowing of blood flow and clumping of erythrocytes (rouleaux formation) forces
leukocytes to the periphery (margination).
 Subsequently, rows of leukocytes tumble slowly along the endothelium in a process
known as rolling
 In time, the endothelium can be virtually lined by white cells.
 Expression of adhesion molecules between leukocytes and the endothelium occurs
(pavementing).Thereafter, the binding of leukocytes with endothelial cells is
facilitated by cell adhesion molecules such as selectins, Integrins , which result in
adhesion of leukocytes with the endothelium.
 Interleukin-1 (IL-1) and tumor necrosis factor (TNF) stimulate the expression of
integrins on the surface of neutrophils and selectin on endothelial cells.
B) Transmigration of leukocytes

 Transmigration (diapedesis) of neutrophils

 Neutrophils moving along the venular endothelium dissolve the venular basement
membrane (release type IV collagenase) exposed by previous histamine-mediated
endothelial cell contraction and enter the interstitial tissue.
 Plasma-derived fluid rich in proteins and cells accumulates in the interstitial tissue.

C) Chemotaxis:

 A unidirectional attraction of leukocytes from vascular channels towards the site of

inflammation within the tissue space guided by chemical gradients (including
bacteria and cellular debris)
 The most important chemotactic factors for neutrophils are components of the
complement system (C5a), bacterial and mitochondrial products of arachidonicacid
metabolism such as leukotriene B4 and cytokines (IL-8).

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  Chemotactic mediators bind to neutrophil receptors.
 Binding causes the release of calcium, activation of cytoskeletal elements which
increases neutrophil motility (pseudopodia) !

D) Phagocytosis:

 Phagocytosis is the process of engulfment and internalization by specialized cells of

particulate material, which includes invading microorganisms, damaged cells, and
tissue debris.
 These phagocytic cells include polymorphonuclear leukocytes (particularly
neutrophiles), monocytes and tissue macrophages.

 The PMNs are the first line of defence, migrating 30-40 minutes after injuryoccurs
and reaching a maximum 6-8 hours later. They have a short life spanand limited
killing potential.
 Monocytes and macrophages appear after 4 hours and peak 16-24 hours

 Phagocytosis involves three steps:

1) Recognition and attachment of the particle to be ingested by the leukocytes:

 Phagocytosis is enhanced if the material to be phagocytosed is coated with certain

plasma proteins called opsonins .Opsonins attach to bacteria (or foreign bodies).
 These opsonins promote the recognition and attachement between the particulate
material( bacteriai or foriegn bodies) and the phagocyte’s cell membrane.

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  examples of opsonins are: the Fc fragment of the immunoglobulin(IgG)
and Components of the complement systemC3b .
 Bruton agammaglobulinemia is an opsonization defect, in Bruton
agammaglobulinemia, pre–B cells cannot mature to B cells; therefore
plasma cells, which are derived from B cells, cannot synthesize immunoglobulins
(i.e., IgG).

2) Engulfment:

 During engulfment, extension of the cytoplasm (pseudopods) flow around the

object to be engulfed, eventually resulting in complete enclosure of the particle
within the phagosome created by the cytoplasmic membrane of the phagocytic cell.
 As a result of fusion between the phagosome and lysosome, a phagolysosome is
formed and the engulfed particle is exposed to the lysosomal enzymes.
 In Chédiak-Higashi syndrome there is a defect in microtubule function, which
prevents lysosomes from fusing with phagosomes to produce aphagolysosome.

3) Killing or degradation

The ultimate step in phagocytosis of bacteria is killing and degradation. There are two
forms of bacterial killing

a) Oxygen-independent mechanism:

 This is mediate by lysozymes

 killing by lysosomal enzymes
 The lysosomal enzymes are, essential for the degradation of dead organisms within
phagosomes.

b) Oxygen-dependent mechanism by the( O2-dependent myeloperoxidase (MPO) system)

 MPO is a neutrophil/monocyte lysosomal enzyme.

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  MPO system most potent microbicidal system available to neutrophils and
monocytes
 1.Production of superoxide free radicals (FRs)
 NADPH oxidase enzyme complex converts molecular O2 to superoxide FRs(
peroxide (H2O2) ), which releases energy called the respiratory, or oxidative, burst.
 2. Production of bleach (HOCl•)
 MPO in the phagolysosome combines H2O2 with chloride (Cl–) to form
hypochlorous FRs (HOCl•), which kill bacteria and some fungi.
 Chronic granulomatous disease (CGD) and MPO deficiency are examples of
diseases that have a defect in the O2-dependent MPO system.

Systemic effects of inflammation

1.Pyrexia:
 Mediated by interleukin (IL-1), and TNF (endogenous pyrogens)

 Stimulating prostaglandin synthesis in hypothalamus.

 In the hypothalamus the prostaglandins stimulate the production of
neurotransmitters, which function to reset the temperature set point at a higher
level.
2. Leukocytosis:
 Induced by cytokines (TNF, IL-1)

 These cytokines accelerates release of cells from the bone marrow

3. .Elevated plasma levels of acute-phase proteins:

 These are synthesized in the liver

 Their concentration increase several hundred-fold In acute inflammation,
 Three of the best known of these proteins are: C-reactive protein (CRP),
fibrinogen, and serum amyloid A (SAA) protein.
 Synthesis of is stimulated by cytokines, especially IL-6.

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  functions of acute phase proteins:
 CRP and SAA, act as opsonins and fix complement, thus promoting
the elimination of the microbes.
 Fibrinogen binds to erythrocytes and causes them to form stacks (rouleaux)
that sediment more rapidly at unit gravity than individual erythrocytes.
 This is the basis for measuring the erythrocyte sedimentation rate (ESR) as a
simple test for the systemic inflammatory response,

4.Endocrine change– an increase in glucocorticoid steroid hormone production due to

Stress

The consequences (Outcomes) of Acute Inflammation

1. Resolution: the tissue is returned to its normal state ( without healing) occurs when ,
the inflammation is limited and the damage is minimal
2. Healing: the inflammation is subside and the tissue is gradually repaired (e.g,
fibrosis)
3. Progression and spread: the bacteria may spread:
i. Direct spread
ii. Lymphatic spread: causing lymphangitis and lymphadinitis
iii. Blood spread may lead to bacteremia or septicemia
4. Chronic inflammation: if the injurious agent did not eliminated completely

Morphological patterns of acute inflammation:

1. Serous inflammation:
 It is characterized by the outpouring of a watery, protein-poor fluid
 depending on the site of injury, derives either from the plasma or from the
secretions of mesothelial cells lining the peritoneal, pleural, and pericardial cavities
 Examples:
.The skin blister: resulting from a burn or viral infection
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There is an accumulation of a serous fluid beneath the epidermis of the skin
.Effusion: Fluid in a serous cavity, e.g, pleural effusion, pericardial effusion....
2. Fibrinous inflammation :
 occurs due to more severe injuries, resulting in greater vascular permeability, with
deposition of a fibrin-rich exudate on the surface of the tissue.
 Commonly occurs on the serosal lining of the pericardium, peritoneum, or pleura .
 examples: fibrinous pericarditis , fibrinous pleuritis secondary to pneumonia
Small bowel obstruction .
Small bowel obstruction: results from serosal adhesions between other loops of bowel
may occur from peritoneal irritation related to previous abdominal surgery
. If the fibrin exists between two serosal surfaces, such as between gut and gut or
between pleura and pleura, then the fibrosis can result in permanent adhesions , this
can also occur in pericardial space leading to restriction in myocardial function
 Morphology:
Grossly: serosa will appear dull
Microscopically: the accumulated extravascular fibrin appears as an eosinophilic
meshwork of threads
3. Suppurative (purulent) inflammation:
When acute bacterial infection is accompanied by intense neutrophilic infiltrate in
the inflamed tissue, it results in tissue necrosis (liquifactive necrosis).
 These are manifested by the collection of large amounts of purulent exudate (pus)
consisting of neutrophils, necrotic cells
 Causative organism: pyogenic organisms(e.g., staphylococci, streptococci)
 Mechanism of pus formation:
 Pyogenic organism causes:
1. Remarkable necrosis
2. Attraction of large number of neutrophils
3. Death of many neutrophils due to high virulence of bacteria

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4. Dead neutophils (pus cells) release proteolytic enzymes leading to liquefaction of
necrotic tissue
The liquefied material mixed with pus cells and fluid exudate formed a turbid
creamy fluid called pus.
Abscesses
 are focal collections of pus
 Aetiology: Staphylococus aureus contains coagulase, which cleaves fibrinogen into
fibrin and traps bacteria and neutrophils, and therefore keeps the lesion localized
 Morphology:
Abscesses typically have a:
 Central necrotic region rimmed by a layer of preserved neutrophils with a
surrounding zone of dilated vessels
 Fibroblast proliferation indicative of attempted repair.
 As time passes, the abscess may become completely walledoff and eventually be
replaced by connective tissue formation is scarring.
 Complications of abscess:
1. Lymphatic spread leads to (lymphangitis and lymphadenitis)
2. Hematogenous spread: may leads to toxemia, septicemia, pyaemia
3. Ulcer
4. Sinus: tract of granulation tissue (one blind end) connecting deep abscess with skin
surface
5. Fistula: tract of granulation tissue (two open ends) connecting two epithelial
surfaces . E.g, anorectal fistula
6. keloid : excessive fibrous tissue during healig process
7. chronic abscess: if the abscess is neither spoteneously or surgically evacuated, it
gets surrounded by fibrosis and becomes chronic abscess
8. compression effects: in case of brain abscess increased intracranial tension,
liver abscess obstructive jaundice

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  4. An ulcer:
.It is a local defect, of the surface of an organ or tissue that is produced by
necrosis of cells and sloughing (shedding) of necrotic and inflammatory tissue
 Ulceration can occur only when tissue necrosis and resultant inflammation exist on
or near a surface
 Ulcers are most commonly encountered in
(1) the mucosa of the mouth, stomach, intestines, or genitourinary tract
(2) the subcutaneous tissues of the lower extremities in older persons who have circulatory
disturbances predisposing affected tissue to extensive necrosis.

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