PART IX.

INFLAMMATION

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 Inflammation („phlogosis” in Greek) is a complex evolutionary
developed standard reaction evolving in response to tissue injury that is
caused by phlogogen and characterized by active participation at the process
of microcirculatory bed, with the involvement of blood cells and connective
tissue. Main roles of inflammation are localization, destruction and/or
removal of phlogogen from organs and tissues and also the restoration of
their structure and functions.
Cornelius Celsus was first who described four clinical signs of
inflammation in the 2nd century AD: rubor (redness), calor (heat), dolor
(pain) and tumor (swelling). A Greek scientist Galen has added to four
known external signs of inflammation one more – “functio laesa” (loss of
function). Nowadays these external signs of inflammation are labeled as a
“Celsus-Galen pentade”.
Depending upon the defense capacity of the host and duration of
response, inflammation can be classified as acute and chronic. Acute
inflammation is characterized by short duration, accumulation of fluid and
plasma components in the affected tissue (prominent exudative component)
and presence of polymorphonuclear neutrophils in the site of inflammation.
Chronic inflammation may follow acute inflammation or be insidious in
onset. It is of longer duration and is associated with the presence of
lymphocytes and macrophages, the proliferation of blood vessels, fibrosis,
and tissue destruction (prominent proliferative component).
Causes of an inflammation (phlogogens) can be:
 Microorganisms: bacteria, viruses, fungi, parasites or prions;
 Foreign bodies (foreign protein, e.g., pollen; asbestos or silicon
crystals);
 Tissue destruction (cuts, stabs, scratches or foreign bodies, necrosis);
 Chemical compounds (acids or alkalis);
 Physical influences (cold, heat, radiation);
 Endogenous causes (disintegrating tumor cells, extravascular blood,
autoimmune reactions, or crystals of substances precipitated in the
body (uric acid, calcium oxalate, calcium phosphate, and cholesterol).

“Infectious” and “sterile” inflammation

Depending on the phlogogen nature, inflammation can be subdivided
to “infectious” and “sterile” (or aseptic). Pathways triggering both
“infectious” and “sterile” inflammation are illustrated in the Fig. 9-1.

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 Multiple cell types that are resident in tissues prior to infection 
express so-called pattern recognition receptors (PRRs) that are capable of 
recognizing pathogen associated molecular patterns (PAMPs). Examples
of PAMPs are lipopolysaccharide (LPS) and peptidoglycan from the 
cell walls of gram-negative and gram-positive bacteria, respectively.
The best characterized PRRs are the Toll-like receptors (TLRs), an 
ancient family of transmembrane proteins. TLRs are expressed by 
phagocytic cells, such as macrophages, neutrophils, and dendritic cells, 
and they link recognition of conserved components of bacteria, 
viruses, fungi, and protozoa to activation of these cells.

Figure 9-1. “Infectious” and

“sterile” inflammation

A number of endogenous molecules that are released when cells
die by necrosis have been proposed to be indicative of sterile cell 
injury. These endogenous ligands or damage-associated molecular patterns
(DAMPs) include heat shock proteins (HSPs), nucleic acids, nuclear high-
mobility group box protein (HMGB1), hyaluronan, β-defensin, uric acid 
crystals, and numerous other biomolecules. Advanced glycated end
products (AGEs), oxidized low density lipoproteins are also in fact “danger
signals for the immune system” and they are can be recognized by PRRs.

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 Activation of PRRs initiates a conserved signaling cascade that 
culminates in the activation of nuclear transcription factor NF-KB 
(Nuclear Factor Kappa B) and inflammasome assembling. Inflammasome is
a multiprotein cytoplasmic complex that mediates the activation of
inflammatory caspases and conversion of proinflammatory cytokines
precursors to their active forms. For example, caspase-1 cleavages and
activates IL-1, IL-18, and IL-33. Disorders of the inflammasome can lead
to autoinflammatory diseases. The prototypic syndromes known as
familial cold autoinflammatory disease, Muckle-Wells disease, and
neonatal-onset multisystem infammatory disease are due to nonconserved
mutations in the NLR gene that encodes cryopyrin (also known as
NALP3). These three rare diseases are characterized by abnormal
inflammasome activation with aberrant release of processed IL-1β. The
clinical manifestations, including fever, rash, hearing impairment, and
arthritis, depend on the specific amino acid substitution as well as other less
well-defined genetic influences. The inflammasome also appears to play a
key role in other more common diseases, such as gout, in which urate crystals
can activate the inflammasome.

Role of NF-KB activation in the inflammatory response

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 Activation of the transcription factor NF-KB by nuclear translocation
of cytoplasmic complexes plays a central role in inflammation through its
ability to induce transcription of proinflammatory genes. Under physiologic
conditions NF-KB exists in the cytoplasm in an inactive form associated with
regulatory proteins called inhibitors of KB (IKB). Phosphorylation of IKB
after stimulation of the cell led to ubiquitination and degradation of this
subunit by 26S proteasome. Thus, NF-KB translocates in the nucleus and
then binds to KB enchancer elements of target genes and induces
transcription of proinflammatory genes. Activation of NF-KB may result in a
wide range of cellular events: increased expression of adhesion molecules,
proinflammatory cytokines, matrix metalloproteinases, chemokines,
inducible NO-synthase and COX-2 and modulation of apoptosis. Sustained
activation of NF-KB play a significant role in the pathogenesis of the
following inflammatory diseases: rheumatoid arthritis, atherosclerosis,
multiple sclerosis, chronic inflammatory demyelinating polyradiculoneuritis,
asthma, inflammatory bowel disease, Helicobacter Pylori-associated gastritis
and systemic inflammatory response syndrome. Hence, therapeutic strategies
aimed at blocking NF-KB activity may have advantage in the treatment of
different inflammatory disorders. There are many methods of the inhibiting
of NF-KB activity: preventing of IKB phosphorylation, or NF-KB decoy
oligonucleotids treatment, preventing degradation of ikB. A wide range of
drugs and non-drugs substances may interfere with NF-KB activity:
corticosteroids, aspirin, 5-aminosalicylic acid, sulfasalazine, antioxidants,
PPARs agonists (see Fig. 11-5), proteasome inhibitors, NO, acetylcholine,
some proteins of bcl-2 family, curcumin, and others.
Induced by infection or non-infectious phlogogens tissue injury is
followed with three basic events:
 Local blood flow alteration in the site of inflammation;
 Increase in vascular permeability;
 Leukocytes extravasation and migration to the site of
inflammation.

Local blood flow changes during inflammation

1. Irrespective of the type of injury, immediate vascular response is of
transient arterioles vasoconstriction. This process is mediated by both
neurogenic and chemical mediators. With mild form of injury, the blood
flow may be reestablished in 3-5 seconds while with more severe injury the
vasoconstriction may last for about 5 minutes.

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 2. Next follows persistent progressive vasodilatation which involves
mainly the arterioles (active hyperemia), but to a lesser extent, affects other
components of the microcirculation like venules and capillaries. This
change is obvious within half an hour of injury. Vasodilatation results in
increased blood volume in microvascular bed of the area, which is
responsible for redness and warmth at the site of acute inflammation.
Progressive vasodilatation, in turn, may elevate the local hydrostatic
pressure resulting in transudation of fluid into the extracellular space. This
is responsible for swelling at the local site of acute inflammation.
Transudate further may compress venules leading to the passive
hyperemia.
3. Slowing or stasis of microcirculation occurs next. Slowing is
attributed to the increased permeability of microvasculature that results in the
increased concentration of red cells, and thus, raising blood viscosity.

Increase in vascular permeability during inflammation

Several mechanisms are responsible for the increased vascular
permeability:
1. Contraction of endothelial cells resulting in increased
interendothelial spaces is the most common mechanism of
vascular leakage and is elicited by several inflammatory
mediators such as histamine, bradykinin, leukotrienes, the
neuropeptide substance P and others. It occurs rapidly after
exposure to the mediator but is usually short-lived (15–30
minutes). In some forms of mild injury (e.g. after burns, X-
irradiation or ultraviolet radiation, and exposure to certain
bacterial toxins), vascular leakage begins after a delay of 2 to 12
hours, and lasts for several hours or even days.
2. Increased transcytosis through endothelial cells. This process
may involve channels consisting of interconnected, uncoated
vesicles and vacuoles called the vesiculovacuolar organelle,
many of which are located close to intercellular junctions.
Certain factors, such as VEGF can promote vascular leakage in
part by increasing the number and perhaps the size of these
channels.
3. Retraction of endothelial cells caused by the structural
cytoskeleton reorganisation. This changes affect mainly
venules and are mediated by cytokines such as interleukin-1
(IL-1) and tumor necrosis factor (TNF). The onset of response
takes 4-6 hours after injury and lasts or more (somewhat
delayed and prolonged leakage).

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 4. Direct damage, necrosis and sloughing of endothelial cells lead
to leukocytes and plasma leakage in the inflamed tissue. It starts
immediately after injury and is sustained for several hours until
the damaged vessels are thrombosed or repaired.
5. Apoptosis of endotheliocytes starts following 2-12 hours after
injury and lasts for several hours to several days.
6. Damage of endothelial cells by activated leukocytes.
7. Increased vascular permeability in new formed microcirculatory
vessels.
Increased vascular permeability plays a significant role in the
exudation and edema formation during inflammation. In the initial stage, the
escape of fluid is due to vasodilatation and consequent elevation in
hydrostatic pressure. This is transudate in nature. But subsequently, the
characteristic inflammatory edema, exudate, appears by increased
vascular permeability of microcirculation. Differences between exudates
and transudates are presented in the Table 9-1.

Table 9-1. Exudate and transudate: clinical implications

Feature Transudate Exudate
Mechanism of Dysbalance in Starling Increased vascular
formation forces, increased permeability results in
plasma filtration an inflammatory edema
without any changes in
the vascular
permeability. It may
lead to a non-
inflammatory edema.
Proteins content Low (3 g/dl); mainly High (3 g/dl), readily
albumin, low coagulates due to high
fibrinogen, has no content of fibrinogen
tendency to coagulate and other coagulation
factors
Glucose Same as in the blood Lower in patients
concentration sample samples with tumors
and infections
Relative density Low (1015) High (1018)
pH >7,3 <7,3
Lactate Low High
dehydrogenase
(LDH) activity

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 Cellular content Lack of cells, mainly A quantity of cells
mesothelial cells and (leukocytes, especially
cellular debris polysegmented
neutrophils and
parenchymal cells)
Clinical examples Edema in congestive Purulent exudate (pus)
heart failure

Leukocytes extravasation and migration to the site of inflammation

The escape of leukocytes from the vessel lumen to the interstitial tissue,
called extravasation, can be divided into the following steps (Fig. 9-2):
 in the vessel lumen: margination, rolling, and adhesion to endothelium;
 Migration across the endothelium and vessel wall;
 Migration in the tissues toward a chemotactic stimulus.

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 Figure 9-2. Leukocytes migration in the site of inflammation

In normally flowing blood in venules, red cells are confined to a

central axial column, displacing the leukocytes toward the wall of the vessel.
Because blood flow slows early in inflammation, wall shear stress decreases,
and more white cells assume a peripheral position along the endothelial
surface. This process of leukocyte redistribution is called margination.
Subsequently, individual and then rows of leukocytes adhere transiently to
the endothelium, detach and bind again, thus rolling on the vessel wall. The
cells finally come to rest at some point where they adhere firmly (resembling
pebbles over which a stream runs without disturbing them).
The adhesion of leukocytes to endothelial cells is mediated by
complementary adhesion molecules on the two cell types. 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
mucin-like glycoprotein backbones. The expression of selectins and their
ligands is regulated by cytokines produced in response to infection and
injury.

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 Firm adhesion is mediated by a family of heterodimeric leukocyte
surface proteins called integrins. Proinflammatory cytokines TNF and IL-1
induce endothelial expression of 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). Leukocytes normally express integrins in a low-affinity
state. Chemokines activate the rolling of leukocytes and converse of VLA-4
and LFA-1 integrins on the leukocytes to a high-affinity state. Inherited
disorders of leukocytes adhesion are listed in the Table 9-2.

Table 9-2. Inherited forms of leukocytes adhesion defects (LAD)

Type Defects Clinical manifestations
LADI Defective subunit common Delayed separation of
to leukocyte integrins; umbilical cord, sustained
impaired leukocyte neutrophilia, recurrent
adhesion, aggregation, infections of skin and
spreading and chemotaxis mucosa, gingivitis,
periodontal disease
LADII Impaired phagocyte rolling Less severe than LADI.
along ECs due to reduced Mental retardation, short
phagocyte surface ex- stature, Bombay HH blood
pression of Sialyl-Lewis X phenotype, recurrent
infections, neutrophilia

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 The next step in the process of leukocyte recruitment is migration of
the leukocytes through the endothelium, which is called transmigration or
diapedesis. Transmigration of leukocytes occurs mainly in post-capillary
venules. 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
PECAM-1 (platelet endothelial cell adhesion molecule) or CD31 and several
junctional adhesion molecules. 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 accumulate in the extravascular site. This process is called
chemotaxis. The agents acting as potent chemotactic substances for
leucocytes are called chemoattractants. They can be exogenous and
endogenous. Different soluble bacterial products such as formylated
peptides are exogenous chemoaatractants. Leukotrienes B4, C4, D4,
components of complement system (C 3a, C5a, C5a-desarg), plasma
fibronectin, fibrin degradation products (FDPs) and chemokines are
endogenous chemoaatractants.
Chemokines (chemoattractive cytokines) attract cells along a gradient
of low to high chemical concentration. Like cytokines, chemokines are
pleiotropic. All chemokines have a similar structure relating to the
confguration of cysteine residues that gives rise to four families:
 Two cysteines separated by any other amino acid residue (X) is
CXC. These cytokines recruit neutrophils predominantly.
 Two cysteines next to each other is CC. Recruitment of
monocytes, eosinophils, basophils and lymphocytes occurs after
their action.
 One cysteine is C. These chemokines recruit lymphocytes
predominantly.
 Two cysteines separated by any three amino acids are CX3C
which recruit NK-cells and CD4 lymphocytes predominantly.
Receptors on the surface are denoted by ‘R’, and are all
distinctive G-coupled protein receptors with seven transmembrane
spanning domains. Anti-inflammatory drugs that block chemokine
functions, or drugs that promote cell activation and migration, for example
into tumors, are being developed.

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 An inherited disorder of chemotaxis is seen in hyper-IgE-recurrent
infections (Job’s syndrome). The type of inheritance is autosomal-dominant.
Main defects are decreased chemotaxis and impairment of T-regs activity. As
a result, dermatitis (exematous or pruritic), cold skin abscesses, recurrent
pneumonias, candidiasis, restrictive lung diseases are common in affected
patients.
Once leukocytes (neutrophils and monocytes) have been recruited to a
site of infection or cell death, they must be activated to perform their
functions. Activation results from signaling pathways that are triggered in
leukocytes, resulting in increases in cytosolic Ca 2+ and activation of enzymes
such as protein kinase C and phospholipase A2. The functional responses that
are most important for destruction of microbes and other offenders are
phagocytosis and intracellular killing.

Phagocytosis
Phagocytosis (“cell eating” in Greek) is the process of engulfment and
internalization by specialized cells (polymorphonuclear leukocytes,
monocytes and macrophages) particulate material including invading
microorganisms, damaged cells and tissue debris. Phagocytosis involves the
following steps:
1. Attachment (opsonization).
2. Engulfment.
3. Killing and degradation.
Phagocytosis is enchanced if the material to be phagocytosed is coated
by certain plasma proteins called opsonins. Opsonins promote the adhesion
between the particulate material and the phagocyte cell membrane. This
process is termed opsonization. There are following classes of opsonins:
 Specific antibodies of IgG class;
 The activated third component of complement (C3b) and its
inactivated form C3bi.
 Collectins (plasma lectins).
The opsonised particle is engulfed by pseudopodia and enclosed in a
membrane bound vesicle termed a phagocytic vacuole or phagosome. As a
result of fusion between the phagosome and lyzosomes a phagolyzosome is
formed and the engulfed particle is exposed to lyzosomal enzymes.

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 There are two types of microorganisms killing during phagocytosis:
oxygen-dependent and oxygen-independent. Oxygen-dependent mechanisms
occur with main participants – reactive oxygen and nitrogen species. Both
ROS and RNS are formed during “respiratory burst”. This burst is
characterized by increased oxygen consumption, activation of the hexose-
monophoshate shunt and assembly of a multicomponent NADPH-oxidase
complex. NADPH-oxidase begins to produce superoxide anion (O2.).Then
SOD converts O2. to hydrogen peroxide (H2O2). Myeloperoxidase (MPO)
acts on H2O2 in the presence of chloride to form hypochlorous acid (HOCl)
which is more potent antibacterial agent than H2O2. The later also can be
reduced by the Haber-Weiss or Fenton reaction to form the highly reactive
hydroxyl radical (OH.):
Н2О2 + О2- → ОН. + ОН- + О2 (Haber-Weiss reaction)
Н2О2 + Fe2+ → ОН. + ОН- + Fe3+ (Fenton reaction)
ROS are particularly useful in eliminating microbial organisms that
grow within phagocytes e.g. M. tuberculosis, Histoplasma capsulatum. In
addition to ROS, recently role of nitric oxide (NO) and its metabolites in
inflammatory reaction has been established. NO is produced from the
aminoacid L-arginine. Different inflammatory mediators increase expression
of inducible isoform of NO-synthase (iNOS) in different cells including
macrophages. Interaction of NO with O2. results in peroxynitrite formation
(ONOO.). Peroxynitrite damages the lipids, proteins, and nucleic acids of
microbes as they do with host macromolecules. Moreover, it was shown that
both a large amounts of nitric oxide produced by iNOS and peroxynitrite
play a significant role in the vascular hyporeactivity during sepsis.
Oxygen-independent bactericidal mechanisms are mediated by
substances releasing from the primary or secondary granules of phagocytes.
Primary granules release cathepsins, azurocidin, elastase, proteinase 3,
defensins and myeloperoxidase. Secondary granules are sources of
collagenase, heparinase, gelatinase, lysozyme and sialidase.
During phagocytosis injury of cells surrounding inflamed tissue may
occur. Such injury may be contributed to the escape of lyzosomal enzymes
from neutrophils granules during phagocytosis.

Disorders of phagocytosis
Disorders of phagocytosis may be inherited (Table 9-3) and
acquired.

Table 9-3. Selected inherited forms of phagocytosis disturbances

Type of Defects Clinical manifestations
inheritance
Chronic granulomatous disease

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70% - X- Insufficiency of Severe infections of skin,
linked, respiratory burst due to ears, lungs, liver and bone
30% - the lack of one of four with catalase-positive
autosomal- NADPH oxidase microorganism; excessive
recessive subunits in the inflammation with
neutrophils, monocytes granulomas; lymph node
and eosinophils suppuration
Chediak-Higashi syndrome
Autosomal- Decreased chemotaxis; Reccurent pyogenic
recessive impaired phagolyzosome infections, lymphoma-like
fusion; increased illness during adolescence,
respiratory burst; periodontal disease, mental
defective egress of retardation in some patients
leukocytes from bone
marrow

Specific granules deficiency

Unknown Impaired chemotaxis, Recurrent infections of
respiratory burst; skin, ears, sinopulmonary
decreased bactericidal tract, decreased
killing due to lack of inflammation, bleeding
specific granules in the disorders
neutrophils or defects in
their transcription
Myeloperoxidase deficiency
Autosomal- Absence of Clinically normal except
recessive myeloperoxidase due to patients with underlying
pre- and posttranlational diseases such as diabetes
defects mellitus; then fungal
infections

Impaired phagocyte activity

X-linked and Impaired activation by Ectodermal dysplasia,
autosomal- proinflammatory pyogenic and encapsulated
recessive cytokines, endotoxin bacterial infections,
through TLRs and other resistance to mycobacteria
pathways; lack of NF-kb
activity
Mycobacteria susceptibility

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Autosomal- Low IFN-g production, Severe local or
dominant and mutation in IFN-g disseminated infections
recessive receptors, IL-12, STAT, with bacilla Calmette-
NEMO; inability to kill Guerin, poor granuloma
microorganism formation

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 Acquired forms of phagocytosis disturbances are common findings
in patients with secondary immunodeficiency syndromes. These
disturbances may be:
 Situational, due to stress, excitement, vigorous exercise.
 Metabolic resulted from ketoacidosis, acute renal failure,
eclampsia, acute poisoning.
 Drug-induced (epinephrine, glucocorticoids, non-steroidal
antiinflammatory drugs, lithium salts treatment).
 Assosiated with diseases or pathologic states such as metastatic
carcinoma, acute hemorrhage, hemolysis, hemodialysis, thermal
injury, sepsis, diabetes mellitus, viral infections.

Macrophage as a “band-master” of the inflammation

Functional heterogeneity of macrophages during inflammation
Macrophages are present in virtually all tissues. They differentiate
from circulating peripheral-blood mononuclear cells, which migrate into
tissue in the steady state or in response to inflammation. An important role of
macrophages in the inflammation is supposed by their ability to:
 Detect the exogenous and endogenous danger signals;
 Phagocytose phlogogenous particles;
 Secrete proinflammatory and antiinflammatory cytokines;
 Produce chemoattractants;
 Produce ROS, RNS, release lysosomal hydrolases, cationic
proteins, prostanoids, components of complement, components
of blood coagulation, which may lead to the secondary tissue
damage;
 Regulate resolution of inflammation;
 Synthesize or induce production of profibrotic factors (growth
factors, factors, stimulated angiogenesis, matrix
metalloproteinases and their inhibitors).
Moreover, macrophages clear approximately 2x1011 erythrocytes each
day; this equates to almost 3 kg of iron and haemoglobin per year that is
‘recycled’ for the host to reuse. This clearance process is a vital metabolic
contribution without which the host would not survive. Thus macrophages
can store iron and participate in the pathogenesis of so-called anemia of
chronic inflammation which is a part of the acute phase response.
Macrophages are also involved in the removal of cellular debris that is
generated during tissue remodelling, and rapidly and efficiently clear cells
that have undergone apoptosis. The receptors that mediate these homeostatic
clearance processes include scavenger receptors, phosphatidyl serine
receptors, the thrombospondin receptor, integrins and complement receptors.

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 Macrophages have remarkable plasticity that allows them to efficiently
respond to environmental signals and change their phenotype. In the modern
point of view, macrophages are classified into M1 and M2 where the M1
designation are reserved for classically activated macrophages and the M2
designation for alternatively activated macrophages (Fig. 9-3). The
combination of two signals, interferon-γ (IFNγ) and tumor-necrosis factor
(TNF) results in a M1 phenotype which is characterized by high microbicidal
or tumoricidal capacity and secretion of high levels of pro-inflammatory
cytokines and mediators. The pro-inflammatory cytokines that are produced
by classically activated macrophages are an important component of host
defence, but they can cause extensive damage to the host. For example, IL-1,
IL-6 and IL-23 are produced by classically activated macrophages and have
been associated with the development and expansion of TH17 cells. These
cells produce IL-17, a cytokine that is associated with high levels of
polymorphonuclear leukocyte recruitment to tissues, which can contribute to
inflammatory autoimmune pathologies.

T-helper 1 cytokines T-helper 2 cytokines

(IFN-, TNF-) (IL-4, IL-13)

Classically activated macrophages M1 Alternatively activated macrophages M2

Secretion of IL-10, TGF-β, production of IL-1Ra, sIL-1R type II
Production of IL-12 and NO in a large amounts and arginase

Phagocytosis; Profibrotic factors; suppression of M1 activity

antigen processing and presentation;
T-cell activation

Figure 9-3. M1 and M2 macrophages

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 TH2 cells can promote the development of wound-healing
macrophages (or alternatively mediated macrophages M2). These
macrophages are poor antigen-presenting cells and may even inhibit T-cell
proliferation. In healthy subjects M2 macrophages are predominantly found
in the placenta and lung, where they promote tolerance to self antigens. M2
macrophages are able to inhibit M1-mediated inflammatory response by the
following mechanisms:
(1) they secrete soluble IL-1 receptor antagonists which may
suppress inflammation;
(2) They express high levels of arginase-1. This enzyme directly
competes with iNOS for L-arginine. Thus, concentration of
substrate for NO synthesis will be decreased.
M2 macrophages promote fibrosis via: production of TGF-β,
fibronectin, proline and tissue inhibitors of matrix metalloproteinase activity
(TIMPs) and by increasing secretion of IL-10 and CC chemokine ligand 17.
These cytokines may recruite fibroblasts in the site of inflammation.
The regulatory macrophages were described relatively recently.
Reprogramming of macrophages in this phenotype occurs after
glucocorticoids therapy; in the later stages of adaptive immune response;
after prostaglandins exposure; phagocytosis of apoptotic cells; IL-10 and
some ligands for G-protein-coupled receptors; adenosine, dopamine,
histamine, sphingosine 1-phosphate, melanocortin, vasoactive intestinal
peptide, adiponectin influences. Some tumor-associated macrophages may
share characteristics of the regulatory macrophage population. Regulatory
macrophages produce IL-10 in sufficient amounts but lack of IL-12. Unlike
wound-healing macrophages, these regulatory macrophages do not contribute
to the production of the extracellular matrix, and many of these regulatory
cells express high levels of co-stimulatory molecules (CD80 and CD86) and
therefore can present antigens to T cells.
Imbalance in the macrophage differentiation may have adverse
outcomes. For example, macrophages that are normally involved in wound
healing can promote fibrosis, exacerbate allergic responses and be exploited
by pathogens for intracellular survival. Regulatory macrophages can
contribute to the progression of neoplasia. Classically activated macrophages
can cause damage to host tissues, predispose surrounding tissue to neoplastic
transformation and influence glucose metabolism by promoting insulin
resistance.

Mediators of inflammation
The primary sources of these mediators are cells and plasma.

Cell-derived mediators of inflammation

 Vasoactive Amines: Histamine and Serotonin
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 They are stored as preformed molecules in cells and are therefore
among the first mediators to be released during inflammation. The
richest sources of histamine are the mast cells that are normally present
in the connective tissue adjacent to blood vessels. It is also found in
blood basophils and platelets. Histamine is released by mast cell
degranulation in response to a variety of stimuli: physical injury;
binding of antibodies to mast cells, which underlies allergic reactions;
fragments of complement called anaphylatoxins (C3a and C5a);
histamine-releasing proteins derived from leukocytes; neuropeptides
(e.g., substance P); and cytokines (IL-1, IL-8). Histamine causes
dilation of arterioles and increases the permeability of venules mainly
via binding to H1 receptors on microvascular endothelial cells.
Serotonin (5-hydroxytryptamine) is present in platelets and certain
neuroendocrine cells, e.g. in the gastrointestinal tract. Release of
serotonin (and histamine) from platelets is stimulated when platelets
aggregate after contact with collagen, thrombin, adenosine
diphosphate, and antigen-antibody complexes. The platelet release
reaction, which is a key component of coagulation, also results in
increased vascular permeability.
 Arachidonic Acid metabolites
Arachidonic acid is a 20-carbon polyunsaturated fatty acid that is
derived from dietary sources or by conversion from the essential fatty
acid linoleic acid. Different stimuli release arachidonic acid from
membrane phospholipids through the action of cellular phospholipases,
mainly phospholipase A2. Arachidonic acid-derived mediators, also
called eicosanoids, are synthesized by two major classes of enzymes:
cyclooxygenases (which generate prostaglandins) and lipoxygenases
(which produce leukotrienes and lipoxins) (Fig. 9-4).

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 Figure 9-4. Arachidonic acid metabolism
COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; HPETE,
hydroperoxyeicosatetraenoic acid; LTs, leukotriens; LO, lipoxygenase; LX,
lipoxins; PGs, prostaglandins; TX, thromboxane

Prostaglandines are produced by two cyclooxgenases, the

constitutively expressed COX-1 and the inducible enzyme COX-2.
PGD2 is the major prostaglandin made by mast cells; along with PGE 2
(which is more widely distributed), it causes vasodilation and increases
the permeability of post-capillary venules, thus potentiating edema
formation. PGF2α stimulates the contraction of uterine and bronchial
smooth muscle and small arterioles, and PGD 2 is a chemoattractant for
neutrophils. In addition to their local effects, the prostaglandins are
involved in the pathogenesis of pain and fever in inflammation. TxA2
is a potent platelet-aggregating agent and vasoconstrictor. Prostacyclin
(PGI2) is a vasodilator, a potent inhibitor of platelet aggregation, and
also markedly potentiates the permeability-increasing and chemotactic
effects of other mediators.
The three different lipoxygenases are responsible for the
production of leukotrienes, which are secreted mainly by leukocytes,
are chemoattractants for leukocytes, and also have vascular effects.
LTB4 is a potent chemotactic agent and activator of neutrophils,
causing aggregation and adhesion of the cells to venular endothelium,
generation of ROS, and release of lysosomal enzymes. The
cysteinylcontaining leukotrienes C4, D4, and E4 (LTC4, LTD4, LTE4)
cause intense vasoconstriction, bronchospasm (important in asthma),
and increased vascular permeability. Leukotrienes are much more
potent than is histamine in increasing vascular permeability and
causing bronchospasm.
Lipoxins are products of transcellular metabolism which are
generated from arachidonic acid by the lipoxygenase pathway, but they
are inhibitors of inflammation. Neutrophils, produce intermediates in
lipoxin synthesis, and these are converted to lipoxins by platelets
interacting with the leukocytes. The principal actions of lipoxins are to
inhibit neutrophil chemotaxis and adhesion to endothelium Lipoxins
play an important role in the resolution of inflammation.

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 Platelet-Activating Factor (PAF) is a phospholipid-derived mediator.
Platelets, basophils, mast cells, neutrophils, macrophages, and
endothelial cells, can elaborate PAF. In addition to platelet
aggregation, PAF causes vasoconstriction and bronchoconstriction,
and at extremely low concentrations it induces vasodilation and
increased venular permeability. PAF also causes increased leukocyte
adhesion to endothelium, chemotaxis, degranulation, and the oxidative
burst. PAF also boosts the synthesis of other mediators.
 Cytokines are proteins produced by many cell types (principally
activated lymphocytes and macrophages, but also endothelial,
epithelial, and connective tissue cells) that modulate the functions of
other cell types. TNF and IL-1 are two of the major cytokines that
mediate inflammation. They are produced mainly by activated
macrophages. The secretion of TNF and IL-1 can be stimulated by
endotoxin and other microbial products, immune complexes, physical
injury, and a variety of inflammatory stimuli. Their most important
actions in inflammation are their effects on endothelium, leukocytes,
and fibroblasts, and induction of systemic acute-phase reactions (see
later). They enhance the expression of endothelial adhesion molecules;
synthesis of chemical mediators, including other cytokines,
chemokines, growth factors, eicosanoids, and NO; production of
enzymes associated with matrix remodeling; and increases in the
surface thrombogenicity of the endothelium. IL-1 and TNF (as well as
IL-6) induce the systemic acute-phase responses associated with
infection or injury. TNF also regulates energy balance by promoting
lipid and protein mobilization and by suppressing appetite.

Plasma protein-derived mediators

 Complement System
The complement system consists of more than 20 proteins. This system
functions in both innate and adaptive immunity for defense against
microbial pathogens. C3a, C5a and C4a are called anaphylatoxins.
They stimulate histamine release from mast cells and thereby increase
vascular permeability and cause vasodilation. C5a is also a powerful
chemoattractant. In addition, C5a activates the lipoxygenase pathway
of arachidonic acid metabolism in neutrophils and monocytes. C3b and
C3bi act as opsonins and promote phagocytosis by neutrophils and
macrophages. The membrane attack complex (C5-C9) increases
cellular permeability to water and ions and results in lysis of the cells
(see Fig. 14-6).
 Coagulation and Kinin Systems

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 Inflammation and blood clotting are often interlinked. FXIIa initiates
four systems involved in the inflammatory response: (1) the kinin
system, which produces vasoactive kinins; (2) the clotting system,
which induces formation of thrombin, which has inflammatory
properties; (3) the fibrinolytic system, which produces plasmin and
degrades fibrin to produce fibrinopeptides, which induce inflammation;
and (4) the complement system, which produces anaphylatoxins and
other mediators. The kinin and coagulation systems are also intimately
connected. FXIIa converts plasma prekallikrein into an active
proteolytic form, the enzyme kallikrein, which cleaves a plasma
glycoprotein precursor, high-molecular-weight kininogen, to produce
bradykinin. Bradykinin increases vascular permeability and causes
contraction of smooth muscle, dilation of blood vessels, and pain when
injected into the skin. Kallikrein itself is a potent activator of Hageman
factor, allowing for autocatalytic amplification of the initial stimulus.
Kallikrein has chemotactic activity, and it also directly converts C5 to
the chemoattractant product C5a. At the same time that factor XIIa is
inducing fibrin clot formation, it activates the fibrinolytic system. This
cascade counterbalances clotting by cleaving fibrin, thereby
solubilizing the clot. Kallikrein, as well as plasminogen activator
(released from endothelium, leukocytes, and other tissues), cleaves
plasminogen, a plasma protein that binds to the evolving fibrin clot to
generate plasmin, a multifunctional protease.

Outcomes of the acute inflammation

The acute inflammatory process can culminate in one of the
following outcomes:
1. Resolution, which is complete return to normal tissue following
acute inflammation. This occurs when tissue changes are slight and the
cellular changes are reversible e.g. resolution in lobar pneumonia.
2. Healing by scarring, which takes place when the tissue
destruction is so extensive that there is no tissue regeneration but actually
there is healing by fibrosis.
3. Progression to suppuration. In case of pyogenic bacteria invasion
the inflammatory process may progresses to suppuration. Initially, there is
intense neutrophilic infiltration. Subsequently, mixture of neutrophils,
bacteria, fragments of necrotic tissue, cell debris and fibrin comprise pus
which is contained in a cavity to form an abscess. The abscess, if not
drained, may get organised by dense fibrous tissue, and in time, get
calcified.
4. Progression to chronic inflammation. In this case the processes of
inflammation and healing proceed side by side.
5. Generalization of the inflammation and sepsis development.

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 Acute phase response
The acute-phase response, or the systemic inflammatory response
syndrome consists of several clinical changes: fever (an elevation of body
temperature), increased synthesis of acute-phase proteins, leukocytosis (an
increase leukocytes count in the peripheral blood), alteration of pulse and
blood pressure; rigors (shivering), chills (search for warmth), anorexia,
somnolence, malaise, anemia of chronic disease, cachexia. Basic mechanism
of the acute-phase response is increased synthesis of proinflammatory
cytokines affecting different cells and their functions (Fig. 9-5).
Pathogenesis of fever during inflammation: primary pyrogens
(exogenous) → synthesis of secondary pyrogens (endogenous) → activation
of the cyclooxygenase in the hypothalamus → synthesis of PGE 2 → ↑
production of the cAMP in the hypothalamic neurons → resetting of the
temperature set point at a higher level → ↑ heat production and ↓ heat loss.

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 Figure 9-5. Systemic and local effects of proinflammatory cytokines

Acute phase proteins are plasma proteins, mostly synthesized in the

liver. According with their concentration in the blood acute phase proteins
are subdivided into positive and negative (Table 9-4).

Table 9-4. Acute phase proteins

↑ concentration in the blood (positive) ↓
concentration
in the blood
(negative)
Complement system: C3, C4, C9, C1-inhibitor, C4b- Albumin,
binding protein transferrin,
Components of the coagulation and fibrinolytic system: transthyrein,
fibrinogen, plasminogen, tissue plasminogen activator, -fetoprotein,
urokinase, protein S, plasminogen activator inhibitor-1 thyroxin-
Antiproteases: 1-protease inhibitor, 1-antichimotrypsin, binding
pancreatic secretory trypsin inhibitor globulin,
Transport proteins: ceruloplasmin, haptoglobin, insulin-like
hemopexin growth factor-
Proteins participating in the inflammatory response: 1 (IGF-1),
secreted phospholipase A2, LPS-binding protein, IL-1 FXII
receptor antagonist, colony-stimulating factors
Others: C-reactive protein (CRP), serum amyloid A, 1
acid glycoprotein, fibronectin, ferritin, angiotensinogen

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 Mechanisms of leukocytosis during inflammation are following: (1)
demargination in the blood vessels after cortisol exposure; (2) release of
leukocytes from the bone marrow postmitotic reserve pool caused by
cytokines, including TNF and IL-1; (3) proliferation of leukocytes precursors
in the bone marrow, caused by increased production of colony-stimulating
factors. However, sometimes severe inflammation may accompany by
leucopenia.

Resolution of inflammation
Resolution of inflammation is an active and continuous process,
which involves activation of endogenous programs with production and
activation of different biochemical mediators and signaling pathways to
ensure rapid and successful restoration of tissue homeostasis. There are
several steps of resolution of inflammation:
1. Decrease production of inflammatory mediators and decrease
recruitment of leukocytes in the site of inflammation.
2. Induction of granulocytes apoptosis in the inflamed tissue.
3. Enchancing efferocytosis (non-phlogistic phagocytosis of dying from
apoptosis neutrophils by macrophages).
4. Increase non-phlogistic recruitment of macrophages.
5. Induction of macrophage reprogramming from M1 to M2.
6. Synthesis of pro-resolving molecules.
Different cellular mechanisms are involved in the resolution of
inflammation:
 The influx of cells can be decreased by suppressing chemotactic factor
production and vascular adhesion molecule expression.
 Lymphocytes can be released from the tissue and return to the
circulation through lymphatics.
 Stressed cells can undergo necrosis with the release of their contents
into the local environment. The most critical mechanism for clearing
cells from an inflammatory site is programmed cell death, or apoptosis.
This clearance process does not elicit an inflammatory response, in
contrast to cell death by necrosis. Defective apoptosis or even
persistence of apoptotic cells that escape clearance may contribute to
chronic inflammatory and autoimmune diseases.

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  Mesenchymal cells, especially fibroblasts, proliferate and produce new
matrix that can contract to form a fibrotic scar. Locally produced
growth factors such as PDGF and TGF-β induce DNA synthesis of
these stromal cells. In addition, mesenchymal stem cells that either
reside in the tissue or migrate from the peripheral blood can
differentiate into the appropriate organ-specific lineage. The
pluripotential cells, in the presence of the appropriate milieu, can
become adipocytes, chondrocytes, bone cells, or other terminally
differentiated stromal cells.
Humoral mechanisms play an important role of resolution of
inflammation. They include increase synthesis of antiinflammatory cytokines
(Transforming Growth Factor- β (ТGF-β), IL-10, IL-4, IL-13); formation of
proinflammatory cytokines antagonists; synthesis of arachidonic acid
metabolites promoting resolution of the inflammation; rise in antioxidants
activity and increase activity of proteinases inhibitors.
A variety of anti-inflammatory cytokines are released by resident and
infiltrating cells. TGF-β and IL-10 are examples that are produced by
macrophages, interstitial fibroblasts, or T cells. These antiinflammatory
cytokines suppress synthesis of proinflammatory cytokines, chemokines,
cellular adhesion molecules, modulate activity of macrophages, enhance
activity of tissue inhibitors of metalloproteinases but down regulate activity
of metalloproteinases and stimulate fibroblasts proliferation, collagen
synthesis and in general induce fibrosis. The repair phase is abnormal in
diseases in which tissue fibrosis represents a major pathologic manifestation.
For example, scleroderma is marked by diffuse fibrosis and is accompanied
by high levels of TGF-β and increased production of extracellular matrix.
Cytokine decoy receptors can also downregulate the inflammatory
response. Receptors can also be shed from the cell surface after proteolytic
cleavage and can absorb cytokines, thereby preventing them from ligating
functional receptors on cell membranes (Fig. 9-6).

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 These cytokine inhibitors can be released as a coordinated attempt to
prevent unregulated inflammation, as in septic shock, in which endotoxin
induces production of soluble receptors after initial massive production of
TNF and IL-1. Other types of cytokine-binding proteins are also produced as
counter-regulatory mechanisms, including IL-18-binding protein, which is an
immunoglobulin superfamily-related receptor that captures IL-18. The need
for tight control of the pro-inflammatory cytokine IL-1 is demonstrated by
the existence of two separate mechanisms. An IL-1 decoy receptor, known as
the type II IL-1R, has both cell membrane and soluble forms that neutralize
IL-1 activity. In addition, a natural IL-1 antagonist, IL-1Ra, can bind to
functional IL-1 receptors and compete with IL-1α or IL-1β. However, IL-1Ra
does not transduce a signal to the cell and blocks the biologic functions of
ambient IL-1. The balance of IL-1 and IL-1Ra production depends on many
influences. For instance, monocytes produce more IL-1, whereas mature
macrophages produce IL-1Ra.

Figure 9-6. Resolution of inflammation: role of the proinflammatory

cytokines antagonists

During inflammation different lipid mediators with both

proinflammatory and antiinflammatory activity are synthesized (Fig. 9-7).
Initially, mediators, such as classic prostaglandins and leukotrienes, which
activate and amplify the cardinal signs of inflammation, are generated.

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 Next, prostaglandin E2 and prostaglandin D2, by inducing the
production of key enzymes, gradually promote the synthesis of mediators that
have both anti-inflammatory and proresolution activities, such as the
lipoxins, resolvins and protectins. These families of endogenous pro-
resolution molecules are not immunosuppressive, but instead function in the
resolution of inflammation by activating specific mechanisms to promote
homeostasis. In general, pro-resolution molecules stimulate and accelerate
resolution via mechanisms at the tissue level that are multi-factorial. Specific
lipoxins and members of the resolvin and protectin families provide potent
signals that selectively stop neutrophil and eosinophil infiltration; stimulate
non-phlogistic recruitment of monocytes (that is, without elaborating pro-
inflammatory mediators); activate macrophage phagocytosis of
microorganisms and apoptotic cells; increase the exit of phagocytes from the
inflamed site through the lymphatics; and stimulate the expression of
molecules involved in antimicrobial defence.
The prostanoids also can serve as ligands for peroxisome proliferator-
activated receptors (PPARs). There are three main classes of PPAR receptors
– PPARα, PPARβ/δ, and PPARγ – all of which bind to DNA as heterodimers
in association with the retinoid X receptor. Activation of PPARγ by
cyclopentenone prostaglandins is associated with the suppression of activator
protein 1 (AP-1) and signal transducer and activator of transcription (STAT)
transcriptional pathways in macrophages. A variety of natural and synthetic
PPAR agonists have demonstrated efficacy in different models of
inflammatory diseases (see Fig. 11-5).

Figure 9-7. Comparative characteristic of the biologic activity of

eicosanoids derived from different substrates
COX, cyclooxygenase; LTs, leukotriens; LOX, lipoxygenase; PGs,
prostaglandins; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid

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 Antioxidant enzymes that can inactivate the toxic intermediates and
protect normal tissues include catalase and superoxide dismutase. Catalase is
a peroxisomal enzyme that catalyzes the conversion of hydrogen peroxide to
water and oxygen. Superoxide dismutases (SOD) catalyze the dismutation of
superoxide to hydrogen peroxide, which is then removed by catalase or
glutathione peroxidase. Glutathione peroxidases and glutathione reductase
are additional mechanisms for maintaining redox balance and removal of
toxic metabolites. Insufficient production of intracellular antioxidants such as
glutathione can suppress lymphocyte responses and could account for
defective T-cell receptor signaling and blunted immunity in T cells derived
from rheumatoid arthritis synovium. Interactions of free radicals with
surrounding molecules can generate secondary radical species in a self-
propagating chain reaction. Chain-breaking antioxidants are small molecules
that can receive or donate an electron and thereby form a stable byproduct
with a radical. These antioxidant molecules are categorized as either aqueous
phase (vitamin C, albumin, reduced glutathione) or lipid phase (vitamin E,
ubiquinol-10, carotenoids, and flavonoids). In addition, transition metal-
binding proteins (ceruloplasmin, ferritin, transferrin, and lactoferrin) can
serve as antioxidants by sequestering cationic iron and copper and thereby
inhibiting the propagation of hydroxyl radicals.

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 Protease inhibitors regulate the function of endogenous proteases and
reduce the likelihood of collateral damage to tissues. These proteins form two
functional classes, active site inhibitors and α2-macroglobulin (α2M). The
latter class of protease inhibitors acts by covalently linking the protease to the
α2M chain and thereby blocking access to substrates. α2M binds to all
classes of proteases and, after forming a covalent bond, conveys them to cells
through receptor-mediated endocytosis with subsequent enzymatic
inactivation. The family of inhibitors of serine proteases (SERPINs) are the
most abundant members of the former class of protease inhibitors and play a
major role in regulation of blood clot resolution and inflammation, as
indicated by many of their names: antithrombin III, plasminogen activator
inhibitors 1 and 2, α2-antiplasmin, α1-antitrypsin, and kallistatin. The tissue
inhibitor of metalloproteinases (TIMP) family blocks the function of most
matrix metalloproteinases (MMPs). The TIMPs bind to activated MMPs and
irreversibly block their catalytic sites. Examples of disease states with an
unfavorable balance between TIMPs and MMPs include loss of cartilage in
arthritis and regulation of tumor metastasis. TIMP-MMP imbalance in
destructive forms of arthritis appears be caused by the limited production
capacity for protease inhibitors, which is overwhelmed by the prodigious
expression of MMPs. Whereas IL-1 and TNF-α induce MMPs, IL-6, TGF-β,
and several other growth factors suppress production of MMPs and increase
levels TIMPs. Therefore, the cytokine profile has a pivotal influence on the
status of remodeling. When pro-inflammatory cytokines predominate, the
balance favors matrix destruction; in the presence of pro-inflammatory
cytokine inhibitors and growth factors, matrix protein production increases,
and MMPs are inhibited by TIMPs.

Role of the cholinergic anti-inflammatory reflex

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 This reflex controls innate immune responses by a mechanism that
targets the regulatory transcription factor nuclear factor-ΚB (NF-ΚB).
Exogenous and endogenous molecular products of infection and injury
interact with receptors that are expressed by cells of the innate immune
system (PRRs). Ligand–receptor interactions activate innate immune
responses and induce the secretion of pro-inflammatory cytokines. These
molecules also activate afferent sensory neurons, which constitute the
sensory arc of the inflammatory reflex. Axons travelling in the vagus nerve
relay this information as action potentials to the brain stem. This in turn
activates the efferent arc, which is known as the cholinergic anti-
inflammatory pathway. This inhibits innate immune responses in the spleen
through inhibitory signals that arise in the brain stem, traverse the vagus
nerve and signal through nicotinic acetylcholine receptor subunit α7
(α7nAChR), which is expressed by cytokine-producing immune cells. This
leads to the suppression of NF-ΚB activation and the inhibition of innate
immune responses.

Systemic low-grade inflammation

Low-grade chronic inflammation is characterized by a two- to
threefold increase in the systemic concentrations of cytokines such as TNF-α,
IL-6, and CRP without any significant local and systemic changes. Low-
grade inflammation plays an important role in the pathogenesis of the
diabetes mellitus type 2, atherosclerosis, obesity, metabolic syndrome,
irritable bowel syndrome, depression, cancer and any others pathologies.

Particular features of the chronic inflammation

Granulomatous inflammation
Inflammation arising in response to immunological insults that cannot
be resolved in days/weeks gives rise to chronic inflammation. Examples
include infectious agents (chronic viral infections such as hepatitis B and
C or intracellular bacteria such as mycobacteria) and environmental
toxins such as asbestos and silicon. Chronic inflammation is also a hallmark
of some forms of allergic disease, autoimmune diseases and organ graft
rejection. The common feature of these pathological processes is that the
inciting stimulus is not easy to remove. For example, some viruses and
mycobacteria remain hidden intracellularly; antigens that incite allergy
(allergens) may be constantly present in the host’s environment; self or
donated organs are a resident source of antigens. In many ways, the
pathology that results is thus inadvertent; the immune system is caught
between the repercussions of not dealing with the infection/insult, and the
tissue damage that is caused by chronic activation of lymphoid and
mononuclear cells. Dysregulation of connective tissue deposition and its
deposition is the hallmark of the chronic inflammation (Fig. 9-8).

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 Chronic inflammation may lead to permanent organ damage or
impaired vascular function and can be fatal. If the inciting stimulus is
removed, inflammation resolves. However, inflammation returns rapidly (24
– 48 hours) on re-exposure. This rapid recall response is the basis for
patch testing to identify the cause of contact dermatitis, another form of
chronic inflammation, and also for the Mantoux test of tuberculosis
immunity. Together, these forms of immunopathology used to go under the
umbrella term ‘Type IV hypersensitivity’. The main immunological event is
the presence of a proinflammatory focus comprising T and B
lymphocytes and APCs, especially macrophages. If antigen persists,
inflammation becomes chronic and the macrophages in the lesion fuse to
form giant cells and epithelioid cells. Both Th1 and Th2 reactivity is
recognized, but specific syndromes may be polarized towards one or the
other (e.g. chronic mycobacterial or viral infection engenders Th1 responses,
chronic allergic inflammation Th2). When the inflammation is sufficiently
chronic it may take on the appearance of organized lymphoid tissue
resembling a lymph node germinal centre (e.g. in the joints in rheumatoid
arthritis). There is massive cytokine production by T cells and APCs, which
contributes to local tissue damage. Granulomata, which ‘wall off’ the
inciting stimulus, may also arise and result in fibrosis and calcification.

Production of extracellular matrix components Degradation of extracellular matrix components

(fibroblasts) (leukocytes – MMP/TIMP)

Fibrosis Abnormal tissue repair

Figure 9-8. Mechanisms of fibrosis during inflammation

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 Granuloma is defined as a circumscribed, tiny lesion, about 1 mm in
diameter, composed predominantly of collection of modified macrophages
called epithelioid cells, and rimmed at the periphery by lymphoid cells. The
word 'granuloma' is derived from granule meaning circumscribed granule-
like lesion, and -oma which is a suffix commonly used for true tumours but
here indicates inflammatory mass or collection of macrophages. Epithelioid
cells, so called because of their epithelial cell-like appearance, are modified
macrophages which are somewhat elongated, having pale-staining
abundant cytoplasm, lightly-staining slipper-shaped nucleus and the cell
membrane of adjacent epithelioid cells is closely apposed. Epithelioid cells
are weakly phagocytic. Besides the presence of epithelioid cells and lym-
phoid cells, granulomas may have giant cells, necrosis and fibrosis. The
giant cells are formed by fusion of adjacent epithelioid cells and may have
20 or more nuclei. These nuclei may be arranged at the periphery like horse-
shoe or ring or clustered at the two poles (Langhans' giant cells), or they
may be present centrally (foreign body giant cells). The former are
commonly seen in tuberculosis while the latter are common in foreign body
tissue reactions. Like epithelioid cells these giant cells are weakly
phagocytic but produce secretory products which help in removing the
invading agents.

Treatment of chronic inflammatory diseases: modern approaches

 Adequate physical activity. Regular physical activity is reported to
decrease markers of inflammation, however results depend upon
training intensity. Low-intensity training can reduce resting pro-
inflammatory markers (CRP, IL-6), while moderate-intensity training
has milder and less-established anti-inflammatory benefits. There is a
strong relationship between exhaustive exercise and chronic low-grade
inflammation. Marathon running may enhance IL-6 levels as much as
100 times over normal and increases total leuckocyte count and
neturophil mobilization. Several studies show that markers of
inflammation are reduced following longer-term behavioural changes
involving both reduced energy intake and a regular program of
increased physical activity. In contrast, an inactive lifestyle is strongly
associated with the development and progression of multiple
inflammatory diseases.
 Use of adequate amounts (200-400 g per week) of oily sea fish,
uncooked fruits and vegetables, species.
 Polarization of the immune response (control of balance between T-
reg, Th1, Th2 and Th17 activity).
 Blockage of PRRs.

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 Blockage of intracellular signaling pathways in activated leukocytes
(asatioprine); biologic therapy: “anticytokine” therapy: antibodies to
the TNF-a, g-IFNS, recombinant IL-10; kinases inhibitors, lipoxins).
 Suppression or stimulation activity of different lymphocytes subsets.
 Suppression of leukocytes recruitment in the site of inflammation
(cellular adhesion molecules antagonists, chemokines receptors
antagonists).
 Stimulation of neoangiogenesis and tissue repair (colony stimulating
factors, growth factors).

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