INFLAMMATION

Inflammation is a complex reaction of the vascular connective tissue that occurs in order to eliminate both the factors
that causes cell damage and the emerging dead cells and tissues. There are two forms: Acute and chronic inflammation.

ACUTE INFLAMMATION

It is a rapid and early response that occurs when neutrophils reach the injury site.
There are 5 classic local manifestations of acute inflammation: Calor (increased temperature), Rubor (redness), Tumor
(swelling), Dolor (pain), and limitation of organ function.

• The most common cause of acute inflammation is infections.

• HIF 1-alpha (hypoxia-stimulated factor) protein is produced in hypoxic cells and this protein causes VEGF release.
Neovascularization is observed secondary to VEGF release. Thus, the blood supply of the tissues is increased.

Acute inflammation has 2 main components: changes in vascular structures and basic movement of leukocytes.

VASCULAR CHANGES

• Vasodilation: It is the earliest sign of acute inflammation. The most important mediator causing this change is
Histamine. As a result, capillary congestion and tissue erythema develop. (Redness)
• Increased microvascular permeability: It is the most basic component of acute inflammation. It is especially
observed in postcapillary venules. It causes fluid accumulation in the interstitial space. (swelling - tumor)
• Stasis: Slowing of blood flow and increase in blood viscosity following fluid extravasation.

Leukocyte movements: After stasis, leukocytes (Neutrophils firstly) approach towards the vessel wall. (Margination)

Causes of increased microvascular permeability:

• Endothelial contraction and increase in interendothelial space: It creates an immediate temporary response to
inflammation and is short-lived. It is formed by Histamine, Kinin and Leukotrienes.

ü Endothelial contraction is the main cause of increased microvascular permeability.

ü The increase in permeability after burns and radiation starts after 2-12 hours and this situation is
called prolonged delayed response. The most typical example of a delayed response is sunburns.

• Endothelial cell damage, necrosis and detachment: It can be observed due to severe burns, microbial infections and
sometimes leukocytic origin. It starts suddenly and lasts for a long time.
• Increased transcytosis: Increased transport of fluid and proteins from the endothelium. Mainly caused by VEGF.

Increased lymphatic drainage is observed in inflammation and this reduces interstitial fluid
accumulation/edema. However, in this process, the lymphatic channels may become secondarily infected
(Lymphanginitis) and the infection may spread to the lymph nodes (Lymphadenitis). Redness in the form of lines on the
skin wound edges is a sign of lymphanginitis.
LEUKOCYTE RECRUITMENT

The most important leukocytes that play a role in the inflammation process are Neutrophils and Monocytes. These cells
have the ability to phagocytize bacteria by passing from the vessel to the extracellular space.

ü In this process, the basic leukocyte movement observed in the vascular lumen are respectively: Margination,
Rolling and Adhesion.
ü After adhesion, neutrophils migrate through endothelium to the extracellular space. (Diapedesis).
ü Leukocytes move in the tissues towards the bacteria. (Chemotaxis)

Margination/Rolling/Adhesion

The approach of leukocytes towards the vessel wall at the beginning of inflammation is called Margination, rolling of
leukocytes along the endothelial wall of postcapillary venules (Rolling), and the tight adhesion of leukocytes to the vessel
endothelium is called Adhesion.
The main adhesion molecules that play a role in this process are Selectin and Integrins.

Selectins play a role in rolling. The main selectins are: E, P and L selectin.
• P selectin in endothelium and platelets adheres to sialysed oligosaccharides (Sialyl Lewis X) in leukocytes.
• E-selectin in the endothelium adheres to Sialyl Lewis X.
• L selectin found in lymphocytes and neutrophils binds to GlyCAM-1, CD34 and MadCAM-1 in endothelial cells.

Integrins play a role in adhesion. β1 integrin (VLA-4) and β2 integrin (LFA-1 and MAC-1)
• VLA-4 and α4β7 bind to VCAM-1 in endothelial cells.
• LFA-1 and MAC-1 bind to ICAM-1 in endothelial cells.
The main cytokines that play a role in activating the substances that ensure the adhesion of neutrophils to the vessel wall
are: IL-1 and TNF-alpha.

Diapedesis (Transmigration)
The transition of leukocytes from the vessel wall space to the intercellular space is called diapedesis. Typically observed in
postcapillary venules.

• The main adhesion molecule that plays a role in the diapedesis process is PECAM (CD31) (Homotypic interaction).

ADHESION MOLECULES
Selectin L selectin Sialyl Lewis X Rolling
E selectin Sialyl Lewis X Rolling
P selectin Sialyl Lewis X Rolling
Integrin LFA-1 ICAM-1/2 Adhesion
MAC-1 ICAM-1/2 Adhesion
VLA-4 VCAM -1 Adhesion
α4β7 VCAM -1 Adhesion
Immunoglobulin CD31 (PECAM-1) CD31 (PECAM-1) Transmigration
Chemotaxis

Leukocytes are pulled to the damaged area with the help of chemotactic agents, this is called chemotaxis. First neutrophil
(Acute), then macrophage (Chronic) infiltration is observed.

Examples of several inflammation and dominant cells in the tissues:

ü Intense neutrophil infiltrates are observed in patients with chronic osteomyelitis.

ü Pseudomonas infections and H. pylori gastritis involve continuous and recurrent neutrophil stimulation.
ü Neutrophil dominance is observed in the lung in smokers, and neutrophil dominance in the liver in
alcoholics.
ü Lymphocyte dominance is observed in viral infections and plasma cell dominance is observed in
autoimmune diseases.
ü Mast and Eosinophil cell infiltrations are observed in allergic (Type 1 hypersensitivity) reactions.

Th17 and its product IL-17 also play a role in acute inflammation. IL-17 specifically causes neutrophil chemotaxis.
• Neutrophil chemotaxis is impaired in Th17 deficiency pathologies (i.e. Job Syndrome). Severe bacterial and fungal
infections with neutrophil-poor cold abscesses are observed in these pathologies.

Main chemotactic agents:

ü The most common exogenous source is bacterial products. (Peptide and lipids containing N-formyl
methionine)
ü The main endogenous chemotactic agents are IL-8 from cytokines, C5a from complement system products,
Leukotriene B4 from arachidonic acid products.

Cytokines that cause chemotaxis

C-X-C chemokines IL-8 (CXCL8). It is effective on neutrophils.
C-C chemokines MCP-1 (CCL2), MIP-1 (CCL3) RANTES Eotaxin (CCL11)
C chemokines Lymphotactin (XCL1)
CX3C chemokines Fractalkin (CX3CL1)

Recognition and Phagocytosis of Microorganisms by Leukocytes

After leukocytes are directed to the inflammation tissue, they recognize foreign particles with the help of opsonizing
substances. It envelops them with the help of a phagocytic vacuole, phagocytizes them, breaks them down inside the cell
and kills them.

Major opsonizing substances:

• C3b
• Fc part of IgG
• Plasma lectins (mannose binding lectin)

Microorganisms are mainly killed by reactive oxygen species (respiratory burst), reactive nitrogen products and lysosomal
enzymes.
 The killing of microorganisms by reactive oxygen
species and NO of leukocytes.

The first step in the formation of reactive oxygen species is the activation of the phagocyte oxidase (NADPH oxidase)
enzyme.
• Hydrogen peroxide and myeloperoxidase (H2O2-MPO-halide system), which are effective in advanced steps, are the
most effective antibacterial systems among neutrophils.
• Hypochlorite formed as a result of this system is the strongest antibacterial among neutrophils.

MORPHOLOGICAL PATTERNS OF ACUTE INFLAMMATION

Serous inflammation: It is characterized by transudate (protein and cell-poor) effusions. It is observed on serous surfaces
(pleura, peritoneum and pericardial cavity) and skin vesicles (sunburns, viral infection and bullous skin diseases).
Fibrinous inflammation: It causes exudative fluid accumulation rich in protein and cellular residues. Fibrinous exudate is
observed if vascular leakage is abundant or if there is a local procoagulant stimulus (cancer).
• If the healing is not complete, adhesions and cicatrices may develop.
• It is the characteristic inflammation of the meninges, pericardium and pleura.
Suppurative inflammation: It is characterized by purulent exudate (pus). It consists of neutrophils, necrotic cells and fluid.
• Typical examples are abscess and acute appendicitis. Staph. aureus infections are especially common. It is associated
with lichenification necrosis.
Ulceration: It is a lesion characterized by necrotic loss on an epithelial surface. The most typical example is peptic ulcers
in the stomach and duodenum.

DISORDERS of LEUKOCYTE FUNCTION

LEUKOCYTE ADHESION DEFICIENCY (LAD)

Delayed wound healing and recurrent bacterial infections are seen in children.

ü Leukocyte Adhesion Deficiency-1 (LAD-1): It is observed as a result of deficiency in leukocyte beta2 integrins
(LFA-1 and MAC-1 (CD11/18)) that play a role in adhesion.

ü Leukocyte Adhesion Deficiency-2 (LAD-2): It is observed as a result of fucosyl transferase enzyme mutation
(encoding Sialyl Lewis X which plays a role in rolling).
PHAGOLYSOSOME DEFICIENCY

Chediak-Higashi Syndrome: The main reason that plays a role in the pathogenesis of this autosomal recessive syndrome
is the LYST gene mutation responsible for granule transport.
• Defective degranulation and secondary phagosome and lysosome fusion disorder occur in neutrophils.
• Neutropenia and giant (defective) lysosomal granules are observed in neutrophils.
• Albinism due to melanin transport disorder, bleeding disorders and neurological disorders due to granule transport
disorder in platelets are observed.

DISORDERS OF MICROBICIDAL ACTIVITY

Pediatric Chronic Granulomatous Disease: There is a defect in the enzyme NADPH oxidase (phagocyte oxidase).
• Superoxide and other oxygen radicals cannot form in the cell, and phagocytosis is not followed by oxygen-
dependent killing.
• Infections with catalase-positive organisms such as staphylococci are common.

Classic (M1) and Alternative (M2) Activated Macrophages

Some macrophages are called classically activated macrophages, which are stimulated by IFN-ƴ and inhibited by
IL-4 and IL-13. These macrophages are responsible for the microbicidal activity.
Some macrophages are called alternatively activated macrophages, which are stimulated by IL-4 and IL-13 and
inhibited by IFN-ƴ. These macrophages show anti-inflammatory effect by synthesizing IL-10 and TGF-β. They are
responsible for tissue repair and fibrosis.

Abnormal Activation of Leukocytes and Associated Diseases

Disease Cell involved in damage
Acute Lung Injury (ARDS) Neutrophil
Atherosclerosis Macrophage, lymphocyte
Asthma Eosinophil, IgE antibodies
Glomerulonephritis Immune complex complement activation, Neutrophil and Monocyte
Septic Shock Cytokine (TNF-NO)
Arthritis Lymphocyte, Macrophage
Pulmonary Fibrosis Macrophage, Fibroblast

CHRONIC INFLAMMATION
The main findings of chronic inflammation are the presence of mononuclear cell infiltration, tissue damage, fibrosis and
angiogenesis.
• Macrophage is the basic cell of chronic inflammation. Tissue damage may occur as a result of chronic inflammation.

Main anti-inflammatory agents protecting against chronic inflammation:

• TGF-beta, IL-10, IL-4 and IL-13
• Lipoxin, Resolvin and NO

GRANULOMATOUS INFLAMMATION
It is an inflammation type that is an example of specific incarcerated chronic inflammation the body develops against
agents that it cannot eliminate.
• Indispensable basic cell of granulomatous inflammation are epithelioid cells.
• The main cytokine that plays a role in the formation of granulomas is IFN-ƴ released from Th1.
• The second important cytokine is IL-12 released from monocyte-macrophages. Other cytokines involved in
granulomatous inflammation are TNF-alpha and IL-2.

In granulomas observed in tuberculosis, leprosy and sarcoidosis; Langhans type giant cells are characterized by large
cytoplasm, 20 or more nuclei located in the periphery of the cytoplasm.
The main cells that make up granulomas are epithelioid cells. In addition, giant cells, fibroblasts and fibrosis can be
observed.
In tuberculosis infections, cheese-like caseification necrosis is observed in the center of the granuloma and is called
caseifying granuloma.
Necrosis is not characteristically observed in sarcoidosis, Crohn's and foreign body granulomas.

Causes of Granulomatous Inflammation

Bacterial Tuberculosis, Leprosy, Syphilitic gum, Cat scratch disease, Brucellosis, Lymphogranuloma
venereum
Fungal Histoplasma Capsulatum, Blastomycosis, C.immitis, C.neoformans
Parasitic Schistosomiasis, Trichinosis, Filariasis
Inorganic metals and salts Beryliosis
Foreign body Suture, vascular grafts, breast prostheses
Other reasons Sarcoidosis, Chron, Primary biliary cirrhosis, Wegener's granulomatosis

Specific Examples of Granulomatous Inflammation

Sarcoidosis Noncaseating (no necrosis) granulomas, Langhans type giant cells within granulomas,
Schauman and Asteroid bodies, CD4+ T lymphocytes
Leprosy Acid-resistant bacillus but noncaseating granuloma
Syphilis Plasma cell infiltration, Central cogaulation necrosis, epithelioid histiocytes (GOM)
Cat-scratch Disease Stellate (star) granulomas characterized by central neutrophils and granular debris (also
seen in lymphogranuloma venerum)
Tuberculosis Caseified granuloma (Tubercle), Acid-resistant bacilli, Epitheloid histiocytes, Langhans
type giant cell, caseification necrosis, fibroblast and lymphocytes.
Crohn Noncaseating (no necrosis) granuloma

CHEMICAL MEDIATORS OF INFLAMMATION

Classification of mediators that play a role in inflammation:

• It is divided into two as cell-derived or plasma protein-derived. Those from plasma protein are produced by the
liver (Coagulation products, Kinin and Complement). Other mediators are of cell origin.

• Mediators are further divided into two; those that are readily stored in the cell and those that are subsequently
produced during inflammation. Mediators stored in the cell are known as vasoactive amines (Histamine and
Serotonin). Other mediators are synthesized during inflammation.
 MEDIATORS STORED IN THE CELL

VASOACTIVE AMINES (HISTAMINE, SEROTONIN)

Histamine

It causes increased permeability and arteriolar dilatation by endothelial contraction/interendothelial space formation
in venules.
• Histamine is the most important mediator of increased vascular permeability.
• Histamine is mainly released from Mast cells, as well as basophils and platelets.

Serotonin

Serotonin is released in platelets and enterochromaffin cells. It is not found in mast cells. It acts as a neurotransmitter in
the Gastrointestinal and Central Nervous System. It also has a vasoconstrictor effect, but its role in inflammation is
unclear.

MEDIATORS SYNTHESIZED DURING INFLAMMATION

During the inflammation process, there are 3 separate systems synthesized from plasma proteins and related to each
other. Coagulation system, Kinin system and Complement system.

• The coagulation system is initiated by Hageman factor (FXII) synthesized from the liver.
• Systems activated by Hageman factor: Kinin System, Complement System, Coagulation system and Fibrinolytic
System

KININ

The main mediator of the kinin system, bradykinin, is produced from high molecular weight kininogen (HMK) with the
effect of the Hageman factor.
• Bradykinin has a similar effect to histamine and causes dilatation of arterioles, increased vascular permeability and
contraction of extravascular smooth muscles.
• In addition, it plays a role in the formation of pain when injected under the skin.
• Bradykinin plays a role as a mediator in some forms of allergy (hereditary angioneuritic edema, anaphylaxis, etc.).

COMPLEMENT SYSTEM

The complement system is activated by C3 activation and proteolysis. It has three ways:

1. Classical pathway: It is activated as a result of fixation of immunocomplexes containing IgM and IgG with C1.
2. Alternative pathway: Activated by endotoxins, Lipopolysaccharide, IgA, cobra toxin. The alternative way requires the
participation of molecules such as properdin, factor B and factor D.
3. Lectin-related pathway: MBP (mannose binding protein) and CRP synthesized in the liver directly activate C1 by
binding to the surface of some bacteria and fungi.
The main function of the complement system is bacterial cell membrane lysis. It occurs at the end of these three
pathways, mediated by the membrane attack complex MAC (C5b-9). MAC increases the permeability of bacterial cell
membranes. It kills bacteria such as Neisseria.
Other important effects of the complement system apart from bacterial cell membrane damage:

ü C3b facilitates phagocytosis of microorganisms (Opsonization).

ü C3a, C4a and C5a increase histamine release from mast cells, resulting in increased vascular permeability and
vasodilation.
ü C5a is chemotactic for neutrophils, monocytes, eosinophils and basophils.
ü C5a increases vascular permeability by increasing leukotriene synthesis from arachidonic acid with the activation
of lipoxygenase.

Complement regulatory proteins:

C1 inhibitor (C1 inh) inhibits the activation of C1. Hereditary deficiency (of C1inh) is a cause of Hereditary Angioedema.
DAF (CD55) prevents the formation of C3 convertase. CD59 inhibits MAC formation.
Complement Factor H inhibits C3 activation in the alternative complement pathway.
• CD55 and CD59 deficiency as a result of PIGA gene mutation and continuous uncontrolled complement activation
secondary to this condition are observed. (Paroxysmal Nocturnal Hemoglobinuria)
• Factor H mutation is observed in Atypical Hemolytic Uremic Syndrome and Macular Degeneration.

Complement system deficiencies:

C2 deficiency is the most common complement deficiency. Although the frequency of infections increases in C2 and C4
deficiencies, clinical findings are not seen because the alternative pathway is active.

ü C1q deficiency results in a lupus like autoimmune disease.

ü The frequency of recurrent pyogenic infections increases in Properdin and Factor D deficiencies, the
components of the alternative pathway.
ü C3 deficiency increases the risk of severe bacterial infections (Streptococcus). In particular, the frequency of
immunocomplex glomerulonephritis increases.
ü Recurrent Neisseria infections are observed in C5b-9 (MAC) deficiency.
ü In mannose-binding lectin deficiency, the lectin-dependent pathway is not activated thus the frequency of
bacterial infections increases.
ü Excessive bradykinin production is observed in Hereditary Angioedema (OD) disease, which develops as a result
of C1 inh deficiency. In this disease; asphyxia, nausea, vomiting and diarrhea attacks are observed in cases of
mild trauma and emotional stress.

ARACHIDONIC ACID METABOLITES

Arachidonic acid is synthesized from phospholipids in the cell membrane by the enzyme phospholipase A2.
• Leukotrienes are synthesized from arachidonic acid via 5-lipooxygenase pathway.
• Prostaglandins are synthesized by cyclooxygenase pathway.

Leukotrienes
The main cells that produce leukotrienes are leukocytes and Mast cells. 5-lipoxygenase is the predominant pathway in
neutrophils. This enzyme converts AA to 5-hydroxyeicosatetraenoic acid (5-HETE).
• 5-HETE is the precursor of leukotrienes and is chemotactic for neutrophils.
• LTB4 is a potent chemotactic agent for neutrophils. It causes neutrophil activation, aggregation, ROS production and
lysosomal enzyme release.
• LTC4 and LTD4, LTE4 are called slow reactant substances of anaphylaxis (SRS-A). These leukotrienes cause
vasoconstriction, bronchospasm, and increased vascular permeability. Its vascular permeability increasing effects
are more potent than histamine. They are the most potent vasoactive and spasmogenic mediators.
Lipoxins (LXA4 and LXB4) are formed by 12 lipoxygenase enzymes. (It occurs as a result of transcellular biosynthesis, that
is, Neutrophil and Platelet interaction)
• Lipoxins have anti-inflammatory effects (Neutrophil chemotaxis and adhesion inhibition). It antagonizes the effect of
leukotrienes.

Arachidonic Acid Products

Prostaglandins
• PGD2 is the major prostaglandin released from mast cells and together with PGE2 they are responsible for
vasodilation and increased permeability of postcapillary venules. PGD2 also acts as a chemoattractant for
neutrophils. PGD2 also causes bronchospasm and increased mucus production.
• PGF2α stimulates contraction of uterine smooth muscle, bronchial smooth muscle and small arterioles.
• PGE2 responsible for the formation of pain and fever. (Hyperalgesic effect)
• TXA2 (Thromboxane) is produced from platelets with the help of thromboxane synthetase enzyme. It causes platelet
aggregation and vasoconstriction.
• PGI2 (Prostacyclin) and its final product PGF1α are produced from endothelial cells. PGI2 is released from the
endothelium, causing vasodilation and inhibiting platelet aggregation.

Eicosanoids and Their Effects

Vasodilation PGI2 (prostacyclin), PGE1, PGE2, PGD2
Vasoconstriction Thromboxan A2, leukotriene C4, D4, E4
Increased vascular permeability Leukotriene C4, D4, E4
Chemotaxis, leukocyte adhesion Leukotriene B4, HETE

PLATELET ACTIVATING FACTOR (PAF)

It is a mediator that causes platelet aggregation produced from membrane phospholipids. In addition, it causes
vasoconstriction and bronchoconstriction. It is much more effective than histamine at very low concentrations, causing
vasodilation and increased permeability of the venules.
NITRIC OXIDE (NO)

NO is a molecule with anti-inflammatory properties and a very short half-life. It increases cGMP by activating guanylate
cyclase in the endothelium (called EDRF-endothelium-derived relaxing factor) and provides smooth muscle relaxation.
• It vasodilates the vessels and stimulates the vascular response of inflammation. (inflammatory effect)
• It shows anti-inflammatory effect by preventing leukocyte accumulation. It reduces platelet aggregation and
adhesion.
• It acts as a vascular smooth muscle relaxant in septic shock and reduces hypotension and myocardial contractility.
(İ-NOS)
• It has a microbicidal effect on activated macrophages.

NEUROPEPTIDS

Neuropeptides are substances that play a role in inflammation. Two major neuropeptides play a role in inflammation:
Substance P and Neurokinin A.
• Substance P is abundant in nerve fibers in the lung and GIS.
• Substance P functions: Transmission of pain signals, stimulation of leukocytes, increased vascular permeability and
blood pressure regulation.

CYTOKINS

Cytokines are proteins that regulate immune and inflammatory reactions produced by many cells.

ü The main cytokines released from Th1 are IFN-ƴ and IL-2.
ü The main cytokines released from Th2 are IL-4, IL-5 and IL-13.
ü The main cytokine released from Th17 is IL-17.
ü The main cytokines released from macrophage are IL-1, TNF-alpha, IL-6, IL-8, IL-10, IL-12.

Th1-derived cytokines

• Interferon gamma (IFN-ƴ): Released from Th1 and sometimes NK cells. With macrophage activation, it increases the
capacity of macrophages to kill tumor cells and microorganisms. It causes granuloma formation in chronic
inflammation and plays a role in type 4 delayed hypersensitivity reaction.
• IL-2: It is released from Th1 lymphocytes and causes an increase in T cells in particular. T lymphocytes have a specific
receptor that responds to IL-2; IL-2R (CD25). It also activates NK and Macrophage.

Th2-derived cytokines

• IL-4: Plays a role in humoral immunity. It has an autoproliferative effect on Th2 increase and plays a role in IgE
synthesis.
• IL-5: It plays a role in eosinophil increase and B cell differentiation by stimulating eosinophil colony in the bone
marrow.
• IL-13: It plays a role in IgE synthesis and allergic reactions. It stimulates mucus secretion in epithelial cells.
Macrophage-derived cytokines
IL-1 and TNF-alpha
• Cause endothelial cell activation. Increased expression of endothelial adhesion molecules is observed. The secretion
of many cytokines and mediators increases and procoagulant activity increases.
• They cause systemic acute phase response. It does this in conjunction with IL-6. Fever, leukocytosis and increase in
acute phase proteins are also observed.
• TNF and IL-1 play a role in Leukocyte adhesion and migration.
• TNF also reduces appetite and is responsible for cachexia. It is the main cytokine responsible for weight loss in
chronic inflammation and neoplastic diseases.
• TNF causes the activation of macrophages and increases the killing capacity by stimulating NO production.
• TNF is also associated with insulin resistance and decreased cardiac output.
• IL-1 stimulates proliferation of fibroblast and mesenchymal cells. It helps in collagen synthesis. It also stimulates the
Th17 response.
IL-6: It is responsible for systemic acute phase response, increased sedimentation, increased fibrinogen, amyloid
production and osteoclast activation.
IL-8: It has chemotactic effect on neutrophils.
IL-10: It has anti-inflammatory effect.
IL-12: Stimulates interferon gamma production and activates NK cells to kill microorganisms. It plays a role in chronic
inflammation.
SYSTEMIC EFFECTS OF INFLAMMATION
• The main cytokines that cause the acute phase response are TNF, IL-1, IL-6 and Type 1 interferons.
• The main components of the acute phase response are: Fever, Increase in acute phase proteins and Leukocytosis. In
addition; tachycardia, hypertension, decreased sweating, fatigue, loss of appetite are also included in this response.

ü The main cytokines that cause fever are IL-1 and TNF, which cause an increase in PGE2.
ü The most important acute phase proteins are CRP, Fibrinogen and SAA.
ü The main factor for the increase in CRP and Fibrinogen is IL-6.
ü The main factor for the increase in SAA is IL-1 or TNF.
ü Elevated serum CRP levels are a very important indicator of an increased risk of MI.
ü Hepcidin also increases as an acute phase protein and causes anemia of chronic disease by disrupting iron
metabolism.
ü The cytokines that are the main cause of leukocytosis are IL-1 or TNF.
ü Bacteria cause neutrophilia, viral infections cause lymphocytosis and parasites cause eosinophilia. Leukopenia
is observed in typhoid fever, Rickettsia and some protosa infections.
ü The main cytokines that are the main cause of septic shock are IL-1 and TNF.

IL-1 is controlled by the inflammasome. The inflammasome provides activation of caspase proteases, which convert IL-1
to its active products. Mutations in the genes encoding the inflammasome complex cause the development of
inflammatory diseases.
• The best known example of these syndromes is Familial Mediterranean Fever (FMF). There is continuous IL-1
production in these patients, and inflammatory reactions and acute phase reactions caused by this cytokine are
observed.
• Gout is an example of an autoinflammatory syndrome with an increase in IL-1.
 Role of Mediators in Different Reactions of Inflammation
Vasodilation Histamine, Prostaglandin, Nitric oxide and Lipoxin
Increased vascular permeability C3a-C5a, Histamine and Serotonin, Bradykinin, Leukotriene C4 D4 E4,
PAF and Substance P
Chemotaxis-Leukocyte activation IL-1, TNFalpha, Chemokines, C3a, C5a, Leukotriene B4
Bacterial products
Fever IL-1, TNFalpha and Prostaglandin E2
Pain Prostaglandin, Bradykinin, and Substance P
Mucus Production Histamine, IL-13 and PGD2
Tissue damage Reactive oxygen radicals, Lysosomal enzymes and Nitric Oxide

Mediators and Their Effects in Inflammation

Mediator Source Major effects
Plasma protein originated
Proteases activated during Plasma (produced in the liver) Endothelial activation, Leukocyte
coagulation recruitment
Kinins Plasma (produced in the liver) Increased vascular permeability,
smooth muscle contraction,
vasodilation, pain
Complement Plasma (produced in the liver) Vasodilation (mast cell
stimulation), leukocyte chemotaxis
and activation, opsonization
Cell-originated
Histamine Mast, basophil, Platelet Vasodilation, increased vascular
permeability, endothelial activation
Serotonin Platelet Vasodilation, increased vascular
permeability
Prostaglandins Mast, Leukocytes Vasodilation, pain, fever
Leukotrienes Mast, Leukocytes Increased vascular permeability,
chemotaxis, leukocyte adhesion
and activation
Platelet activating factor Leukocytes, Endothelium Vasodilation, increased vascular
permeability, leukocyte adhesion,
chemotaxis, degranulation,
oxidative destruction
Reactive oxygen species Leukocytes Killing of microorganisms, tissue
damage
Nitric oxide Endothelium, Macrophage Vascular smooth muscle relaxation,
killing microorganisms
Chemokines Leukocytes, activated macrophages Chemotaxis, leukocyte activation
Cytokines (TNF-IL-1) Macrophage, lymphocyte, Local endothelial activation
endothelium, mast cell (increase of adhesion molecules),
systemic acute phase response,
severe infections, septic shock