ACUTE INFLAMMATION

Type of inflammantion
Type of inflammantion includes acute and chronic.
Definition
Inflammation is general typical pathological process of local character. It includes both local damage of
tissues and the local protective inflammatory reaction which are response to this damage
Inflammatory reaction is the directed tissue response to noxious and injurious external and internal stimuli.
Acute inflammation includes an immediate response to injury with short duration. It is the hallmark of
mammalian tissue response to injury.
1. Overview of inflammation
Until the late 18th century, acute inflammation was regarded as a disease. John Hunter (17281793, London
surgeon and anatomist) was the first to realize that acute inflammation was a response to injury that was
generally beneficial to the host: "But if inflammation develops, regardless of the cause, still it is an effort whose
purpose is to restore the parts to their natural functions."
Advantages and disadvantages
Advantages
Inflammation serves to localize and isolate the injured (or infected) tissue area, thereby protecting the
surrounding healthy tissue. It tends to neutralize and inactivate the toxic substances that are produced by
humoral factors and enzymes. It destroys or limits the growth of infecting microorganisms and counteracts their
effects. It prepares the area for wound healing and repair by disposing of devitalized tissue and cell debris.
Disadvantages
The pain and swelling associated with inflammation lead t varying degrees of disability. Inflammation may
lead to rupture of viscus (e.g., perforating appendicitis) or to serious hemorrhage (e.g., from an enlarging
pulmonary tuberculous granuloma). It n lead to the formation of excessive scar tissue, with contractures,
adhesions, and keloids. It may result in fistula formation, such as an abdominal perineal fistula or
bronchopleural fistula and pleural empyema, with accompanying normal tissue breakdown by neural proteases.
Inflammation may propagate further inflammation by destruction of the surrounding healthy tissue. Damage
caused by inflammation can lead to the development of inflammatory diseases, such as: Glomerulonephritis,
Arthritis, Allergic reactions (e.g., allergic bronchitis), Myocarditis, and Encephalitis
Cardinal Clinical Signs
Clinically, acute inflammation is characterized by 5 cardinal signs: rubor (redness), calor (increased heat),
tumor (swelling), dolor (pain), and functio laesa (loss of function). The first four were described by Celsus (ca
30 BC38 AD); the fifth was a later addition by Virchow in the nineteenth century. Redness and heat are due to
increased blood flow to the inflamed area; swelling is due to accumulation of fluid; pain is due to release of
chemicals that stimulate nerve endings; and loss of function is due to a combination of factors. These signs are
manifested when acute inflammation occurs on the surface of the body, but not all of them will be apparent in
acute inflammation of internal organs. Pain occurs only when there are appropriate sensory nerve endings in the
inflamed sitefor example, acute inflammation of the lung (pneumonia) does not cause pain unless the
inflammation involves the parietal pleura, where there are pain-sensitive nerve endings. The increased heat of
inflamed skin is due to the entry of a large amount of blood at body core temperature into the normally cooler
skin. When inflammation occurs internallywhere tissue is normally at body core temperatureno increase in
heat is apparent
2. Etiology
The causes
Inflammation n occur in response to anything that damages the tissues: such as
. Toxic chemical agents
b. Physical factors (e.g., heat, cold, electricity, radiation, and trauma)
. Biological (Microorganisms and their metabolic by-products, immune responses -hypersensitivity,
immune complex, or autoimmune reactions)
The Conditions
1. Force and duration of action of the factors
2. Presence of vessels in the region of damage
3. Presence of local damage of tissue or the same amount of the microorganisms which have got in tissues
4. The state of individual reactivity of the organism (factors of a nutrition, a sensitization to the damaging
factor, quantity of leukocytes of the blood, age, state of the basic metabolism, etc.)
5. The state of endocrine and nervous systems (stress, a narcosis), the state of immunity.
 Every organ and tissue type is susceptible to inflammation; the degree and nature of the inflammatory
response are governed by a prsn's state of health, nutrition, and immunity as well as by the nature and
severity of the noxious stimuli.
The inflammatory response involves vascular and cellular events that are mediated by the various chemical
substances
3. Cells involved in inflammation
Neutrophils (also known as polymorphonuclear neutrophils (PMNs), granulocytes, polys, and pus cell)
are the predominant cells in acute inflammation as well as in abscess formation, flocculation and empyema.
They are the white blood cells (WBCs) most responsible for the leukocytosis that occurs in response to an
inflammatory or infectious crisis. In the inflammatory response, neutrophils are the first cells to arise at the
injured area. They leave the vascular system by diapedesis and are directed to the tissue site by chemotaxis.
Neutrophils arriving on the scene begin phagocytizing cells and debris immediately. They also release
chemicals that attract other white blood cells to the area, in a process called chemotaxis. Neutrophils initiate the
inflammatory responses of vasodilation and increased capillary permeability. Intracellular granules (lysosomes)
within neutrophils contain several active enzymes. There are myeloperoxidase (MPO), acid hydrolases,
Lysozyme (muramidase), cationic proteins.
Myeloperoxidase (MPO), the major active component of granulocytes is the main antibacterial enzyme. It
operates by combining with hydrogen peroxide and a halide ion.
Acid hydrolases act on organic matter, including bacteria.
Proteases cause degradation of proteins, including elastin, collage and the proteins found in basement
membranes. Neutrophilic proteases destroy proteins and cell membranes and are responsible for proteolytic
activation of the complement, coagulation, and kinin cascade.
Lysozyme (muramidase) acts on microorganisms through hydrolysis; it is found in monocytes
(macrophages, histiocytes) as well as neutrophils.
Cationic proteins inhibit bacterial growth, cause monocyte chemotaxis and increase vascular permeability.
The extracellular release of the highly irritating lysosomal enzymes into tissues contributes to the local
inflammation.
Basophiles The Basophilic granules then release histamine and other bradykinin, and serotonin. These
substances increase capillary permeability and blood flow to the area, bringing to the area other mediators
required to eliminate infection and promote healing. Basophils secrete the natural anti-clotting substance
heparin, which ensures that clotting and coagulation pathways do not continue unchecked. Basophils are also
involved in producing allergic responses. They are similar in function to important initiators of tissue
inflammation, the mast cells, but unlike mast cells, basophils circulate in the blood.
Eosinophils have several functions. First, they are involved in the allergic response. Second, they are
important in the defense against parasitic (helminthic) infections. They also appear to perform a protective role
for the host by helping to end the inflammatory reaction. The eosinophils phagocytize cell debris, although to a
lesser degree than do neutrophils (minor phagocyts). The level of eosinophils may increase during an allergic
response or in response to helminthic infection.
Mast cells resemble basophils in both structure and function. Whereas basophils are present mainly in the
peripheral blood and at sites of inflammation, mast cells are connective tissue cells found close to small blood
vessels.
Mast cells contain numerous granules that stain metachromatically with basic dyes. Like basophilic granules,
mast cell granules release histamine, heparin, and SRS-A during type I reactions. In addition, mast cell granules
release ECF. Agents that cause inflammation (e.g., physical factors, drugs, immunoglobulins, complement
components and 5, cationic proteins) may cause histamine release from mast cells.
Monocytes circulate in the blood and enter injured tissue across capillary membranes that become permeable
as part of the inflammatory reaction. Monocytes are not phagocytic, but after several hours in the tissue area,
they mature into macrophages.
Macrophages. Some macrophage cells colonize tissues such as skin, lymph nodes, and lungs for months or
years. The mononuclear phagocyte system (also known as the monocyte-macrophage system and
reticuloendothelial system) is an extensive network of macrophages that exists throughout the body.
Cellular components of the system include: pulmonary alveolar macrophages, pleural and peritoneal
macrophages, Kupffer cells of the liver, histiocytes of mesenchymal and connective tissue, mesangial cells of
the kidney, both fixed and mobile macrophages in the lymph nodes, spleen, and bone marrow. These cells are
readily available to scavenge microorganisms that may enter the body through those routes. The monocyte-
macrophage cell system is called the reticuloendothelial system
 Macrophages in the body tissues develop from monocytes that have left the peripheral blood. The monocytes
originally derive from bone marrow precursors. Monocytes in the bone marrow and the peripheral blood n
are converted rapidly into additional macrophages when needed.
Macrophages dispose of noxious matter within tissues, for example, microorganisms and necrotic tissue or
other debris dispose by phagocytosis. Macrophages also appear to serve in tumor cell killing. Endocytosis is the
first step in the process. In phagocytosis, the cytoplasmic membrane extends around particles and engulfs them,
forming an intracellular vacuole. In pinocytosis, the cell membrane engulfs extracellular fluid along with the
particles. Digestion of the engulfed matter within the vacuole is the next step. The lysosomes of macrophages
contain degradative substances similar to those in neutrophils (e.g., proteinases, acid hydrolase, lysozyme, and
MPO).
In their microbicidal function, macrophages are most effective against intracellular or encapsulated
organisms, such as Mycoplasma, salmonella, Listeria, and Cryptococcus.
Opsonization. Macrophages have surface receptors for the Fc segment of the immunoglobulin G (IgG)
molecule and for complement component C3b. These aid the macrophage in phagocycosis of opsonized
microorganisms (i.e., organisms coated with IgG or C3b).
Macrophages are important components of the immune system. Their involvement begins with the initiation
of the immune response, and they interact closely with lymphocytes ( cells).
Macrophages release interleukin-1 (IL-1), substance that stimulates sensitized cells to release
interleukin-2 (IL-2).
Macrophages release substances other than IL-1, such as:
- Colony-stimulating factor (F) and tumor necrosis factor (TNF), which serve in the immune response
- Alpha interferon (IFN-a), which aids in blocking viral replication
- Precursors of prostaglandins, which, in conjunction with IL-1 ( pyrogen), induce acute-phase signs of
inflammation, sach as fever and peripheral blood leukocytosis (i.e., shift to the left with an increase in
immature neutrophils).
Macrophages aid in healing after inflammation subsides by: cellular debridement through phagocytosis,
release of fibroblast proliferating factor
Lymphocytes and their derivatives (more detalaised see Immunity) are participant as adaptive immune
response such innate immune response by releasing mediators and as effector cells. They found in the tissues in
all types of inflammation, especially after the acute ingress of neutrophils.
Platelets
Platelets are not cells, but cytoplasmic fragments that develop from specialized cells in the bone marrow
called megakaryocytes. Like white blood cells, platelets are drawn to an area of inflammation. Once the
platelets arrive at the site of injury, they adhere to the vessel wall, forming aggregates or plugs. Adhering to the
vessel wall activates the platelets, causing them to release several biochemical mediators, including serotonin
and histamine, which temporarily decrease blood flow and bleeding. This vasoconstriction is short lived,
however, and soon blood flow increases to deliver other white blood cells to the area. If the injury is small, the
platelet plug is usually sufficient to allow for healing. Platelets circulate in the blood for about 10 days before
they become non-functioning and are phagocytized by neutrophils and monocytes.
Endothelial Cells
Endothelial cells, a monolayer of cells lining blood vessels, help to separate intra- and extravascular spaces.
They produce antiplatelet and antithrombotic agents that maintain blood vessel patency and also vasodilators
and vasoconstrictors that regulate vascular tone. Injury to a vessel wall interrupts the endothelial barrier and
exposes a local procoagulant signal (Fig. 2-18B).
Endothelial cells are gatekeepers in inflammatory cell recruitment: they can promote or inhibit tissue
perfusion and inflammatory cell influx. Inflammatory agents such as bradykinin and histamine, endotoxin, and
cytokines induce endothelial cells to reveal adhesion molecules that anchor and activate leukocytes, present
major histocompatibility complex (MHC) class I and II molecules, and generate cytokines and important
vasoactive and inflammatory mediators. These mediators include:
Nitric oxide (NO-).
Endothelins: Endothelins-1, -2, and -3 are low molecular-weight peptides produced by endothelial
cells. They are potent vasoconstrictor and pressor agents, which induce prolonged vasoconstriction of vascular
smooth muscle.
Arachidonic acid-derived contraction factors: Oxygen radicals generated by the hydroperoxidase
activity of cyclooxygenase and prostanoids such as TXA2 and PGH2 induce smooth muscle contraction.
Arachidonic acid-derived relaxing factors: PGI2 inhibits platelet aggregation and causes vasodilation.
 Cytokines: IL-1, IL-6, TNF and other inflammatory cytokines are generated by activated endothelial
cells.
Anticoagulants which inactivate the coagulation cascade.
Fibrinolytic factors: Tissue-type plasminogen activator (t-PA) promotes fibrinolytic activity.
Prothrombotic agents activate the extrinsic clotting cascade.
4. Chemical mediators of inflammation
variety of chemical substances are synthesized and emitted during the inflammatory process. These
substances are responsible for controlling the response. The actions of these chemicals also produce the
observable signs (edema, erythema) and the symptoms (pain, fever) of inflammation. Most mediators perform
their biologic activity by initially binding to specific receptors on target cells. Some, however, have direct
enzymatic activity (e.g., lysosomal proteases) or mediate oxidative damage (e.g., reactive oxygen and nitrogen
intermediates).
In an uncomplicated inflammation, these substances mutually activate each other so that individual steps in
an inflammation combine to form a coordinated defensive reaction.
They may be derived from dead tissue (as are kinins) or be formed by living tissue. The following classes of
mediators are differentiate according to their origin:
cell-derived mediators;
plasma mediators including necrosis- derived mediators (see kinins)
Cell-Derived Mediators
These are either mediators stored in certain cells that release them in activated form, or mediators
synthesized de novo by cells.
Preformed Mediators - Vasoactive amines (e.g., histamine and serotonin), Lisosomal enzyme.
Newly synthesized Prostaglandins, Leukotrienes, ytokines ILs, Chemotactic factors, migration-
inhibiting factor (MIF), Macrophage-activating factor (MAF), lnterferon, Platele activating ating factor or
(PAF).
Vasoactive amines (e.g., histamine and serotonin) are responsible for hemodynamic and vascular changes.
-Histamine Most of the body's histamine is stored in the granules of mast cells. It is also found in basophils
and platelets. Histamine is released by degranulation in response to various stimuli, such as physical factors
(heat, cold, trauma, radiation), type 1 hypersensitivity reactions, and 5 (referred to as anaphylatoxins),
and cationic lysosomal proteins. Once released, histamine causes direct vascular effects. Some degree of
vasoconstriction (which varies according to animal species) almost always occurs, followed vasodilation
(which is the stage of observable hyperemia). Histamine also causes an increase in the vascular permeability of
small veins and venules and pruritus (itching); Histamine has also been shown to be chemotactic for
eosinophils.
-Serotonin. Most of the body's serotonin is stored in the gastrointestinal tract and central nervous system
(CNS); much smaller proportion exists in the dense granules of platelets. Although serotonin is known to have
the same vascular effects as histamine in rodents, its role in inflammation in humans is not well understood.
Leukocyte substances, such as proteases, hydrolytic enzymes, and cationic proteins, are activators of
inflammation and are discussed above.
Arachidonic acid derivatives: Every cell njury activates phospholipase A2, resulting in the formation of
arachidonic acid. This acid is metabolized in two ways.
Lipoxygenase breaks it to do down into leukotrienes (LLT).
Cyclooxygenase breaks it do down into prostaglandins
Prostaglandins are group of compounds derived from arachidonic acid via the cyclooxigenase pathway.
Most mammalian cells, including endothelial and inflammatory cells, have the potential to produce
prostaglandins. Nonsteroidal anti-inflammation agents (e.g., aspirin, indomethacin) inhibit cyclooxygenase and,
therefore, interrupt the synthesis of prostaglandins. Prostaglandins are involved in variety of biologic and
physiologic activities.
Prostaglandin 2 (PDE) and PGI2 (also called prostacyclin) are potent vasodilator and, although they do not
directly affect vascular permeability, are involved in edema formation by potentiating the effects of histamine.
In addition, PGE2 produces pain as well as potentiating this effect of bradykinin and it acts on the hypothalamic
mechanism of fever production. PCI2 also inhibits platelet aggregation.
Other prostaglandins are vasodilators (e.g., PGD, F2') as well as vasoconstrictors and agents of platelet
aggregation (e.g., PGG, PGH, thromboxane ).
Leukotrienes, like prostaglandins, are derived from arachidonic acid, but by the lipoxygenase pathway.
They have the following actions.
 -Chemotaxis. Leukotriene B4 (LTB4) is potent chemotactic agent for neutrophils and monocytes-
macrophages. The 5-hydroperoxy derivative of arachidonic acid, referred to as 5-, has similar, although
less powerful, chemotactic activity.
-Vascular effects. LTC4, LTD4, and LTE4 are powerful stimulators of vascular permeability, with 1000 times
the potency of histamine. They also cause vasoconstriction and bronchoconstriction.
SRS-A is low-molecular-weight lipid found in mast cells and is now known to be composed by LTC4,
LTD4, and LTE. It also may be produced by neutrophils and macrophages. SRS-A accounts for many of the
clinically dramatic (and potentially lethal) reactions that occur during anaphylaxis because of vasoconstrictive
and bronchoconstrictive effects. SRS-A also causes edema because of its powerful effect on vascular
permeability.
ytokines Secreted proteins that function as mediators of immune and inflammatory reactions. In innate
immune responses, cytokines are produced by macrophages and NK cells and, in adaptive immune responses,
mainly by T lymphocytes. Lymphokine. is an old name for cytokines produced by T lymphocytes. It is now
known that the same cytokines may be produced by other cell types
Chemotactic factors. Sensitized lymphocytes produce factors that attract specific leukocytes to inflamed
tissues. There are lymphokines that are selective for monocytes-macrophages (macrophage chemotactic factor
(MCF)], neutrophils (NCE), eosinophils (ECF), and basophils (BCF).
Migration-inhibiting factor (MIF) arrests the intrinsic mobility of macrophages, serving to keep them in the
area of inflammation where they are needed.
Macrophage-activating factor (MAF) promotes the bactericidal and tumoricidal activities of macrophages by
stimulating macrophage growth; an increase in mitochondria, lysosomes, and hydrolytic enzymes accompanies
the increase in cell size.
Interleukin-1 (IL-1) from macrophages activates the arachidonate cascade, forms platelet activating factor
(PAF), and activates the kinin system.
Interleukin-2 (IL-2), formerly referred to as T-cell growth factor, is produced by cells that have been
stimulated by antigen in the presence of IL-1. IL-2 causes nonspecific amplification of activated T-cell
production (i.e., both helper cells and cytotoxic cells proliferate).
Tumor necrosis factor (TNF- a) from macrophages activates granulocytes. This triggers generation of
cytotoxic antimicrobial O2 and N2 compounds and generation of prostaglandins and leuko leukotrie trienes.
lnterferons are glycoproteins that have widely varied antiviral and antitumor cell activities.
Plasma factors.
Some of these mediators are synthesized as inactive precursors. Before they go intoaction in the
inflammation process, they must be activated ated by enzymes or combined to form active complexes. Kinin
system activated by necrosis.
The kinin system, when activated, leads to the formation of bradykinin. When plasma comes in contact with
collagen, endotoxin, r basement membrane proteins, clotting factor II (Hagemen factor) is activated. This
step is followed sequentially by kallikrein formation, which then converts high-molecular weight kininogen
(HMWK) to bradykinin. Although bradykinin is not chemotactic, its actions are much like those of histamine. It
causes increased vascular permeability, vasoconstriction, smooth muscle ntraction, and pain.
The complement system, an important mediator of the inflammatory process, contains nine major plasma
proteins, termed complement components.
Critical to the biologic actions of the complement system is the activation, or cleavage, of complement
component , which forms . This cleavage can occur in two ways. In the classic pathway, circulating
antigen-antibody complexes activate the system and, by successive steps of cleavage and combination, generate
complement components and 5. In the alternative pathway, nonimmunologic stimuli (e.g., bacterial
endotoxin activate the system and lead to the cleavage of 3. Both and 5 are chemotactic for neutrophils
and play an important role in increased vascular permeability caused by histamine release from mast cells.
Following complement cascade activation (by either pathway), 5, 6, and C7 in combination also become
chemotactic. C5b and 9 (termed the membrane attack sequence;) appear to be involved in injury to
parenchymal cells.
5. Stages and pathogenesis
Three stages of inflammtion
I. Alteration;
II. Changes of microcirculation with exudation and emigration of leukocytes;
III. Proliferation.
The first stage - Alteration
 The acute inflammatory response begins with direct injury or stimulation of cellular or structural
components of a tissue.
Alteration is damage of cells and tissues.
Alteration divides into Primary and Secondary.
Primary alteration result from direct action of etiological factors. There are changes at all levels (molecular,
subcellular and cellular), that result in damage of structure and function of the cells. The most impotente point
is desraption of lysosoms and releasing of lysosomic enzymes, what result in secondary alteration - autolysis
of the cells.
Secondary alteration is a damage of a functional element of body or a tissue under influence active
lysosomic enzymes.
Alterations in the blood vessels and capillary beds of the injured site begin almost immediately within the
site of primary injury and variably within the peripheral tissue adjacent to the site.
There are physical and chemical changes in the site of an inflammation.
- Increased amount of + because of damage and destruction of cells.
- Increased amount of + (acidosis) because of accumulation of acidy products of metabolism and
disintegration of substances under influence of lysosomic enzymes.
- Hyperosmium (increase of osmotic pressure) because of disintegration of cells, tissues and some
substances.
- Increased oncotic pressure because of disintegration cells, tissues and various protein substances
Under influence of disorders of the homeostasis tissue macrophages are activated.
Activation of macrophages leads to liberation of early cytokines (lnterleukin-1 (1L-1), lnterleukin-6 (1L-6),
lnterleukin-8 (1L-8), etc.).
One mediator can stimulate the release of other mediators by target cells themselves (secondary mediators)
Many mediators have been identified, and how they function in a coordinated manner is still not fully
understood. Plasma-derived mediators (e.g., complement proteins, kinins) are present in plasma in precursor
forms that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties.
Cell-derived mediators are normally sequestered in intracellular granules that need to be secreted (e.g.,
histamine in mast cell granules) or are synthesized de novo (e.g., prostaglandins, cytokines) in response to a
stimulus. The major cellular sources are platelets, neutrophils, monocytes macrophages, and mast cells, but
mesenchymal cells (endothelium, smooth muscle, fibroblasts) and most epithelia can also be induced to
elaborate some of the mediators.
Most mediators have the potential to cause harmful effects.
The interplay of these factors and substances causes a typical pattern of changes in the capillary structures
and changes of the hemodynamics in syte of inflammation.
The second stage of inflammation
Change in microcirculation with the exudation and the emigration of leukocytes
hanges of the hemodynamics in site of inflammation
First phase of changes in microcirculation is vasoconstriction.
Second phase of changes in microcirculation is arterial (active) hyperemia
Third phase of changes in microcirculation is venous hyperemia with increasing vascular permeability
First phase of changes in microcirculation: This involves transient arteriolar vasoconstriction lasting from a
few seconds to a few minutes. The noxious agent enters the tissue. The faucet is turned off by means of
arteriolar vasoconstriction, preventing further spread of the noxious agent. Result: Brief paling of the inflamed
area. Mechanism of vasoconstriction is neurogenic, it is activation of symphatetic nervus system.
Second phase of changes in microcirculation: Arterial (active) hyperemia (Vasodilation). This begins a few
minutes after the first phase. The initial vasoconstriction phase is followed by massive vasodilation in the
arterioles, capillaries, and postcapillary venules in the injured area. Massive vasodilatation is mediated by
histamine, bradykinin, and prostaglandins and neurogenic mechanisms (neurotonic and neuroparalytic - see last
class). This vasodilatation leads to increased blood flow to the site of inflammation (hyperemia). This causes
exudation of blood serum that leads to inflammatory tissue swelling with stimulation of the nociceptive nerves
(pain nerves).
The noxious agent is in the tissue. All faucets are turned on by means of vasodilatation of the arterioles,
capillaries, and venules to thoroughly flush out the noxious agent.
Result: Erythema, swelling, and pain in the inflamed area.
Third phase of changes in microcirculation: venous hyperemia. This lasts for a period of several hours. It is
brought about by vasodilatation of the capillaries and arterioles and is accompanied by vasoconstriction of the
venules. This results in slow rate of circulation of blood and elevated filtration pressure.
In the inflamed area vascular permeability for fluid is increased.
This increased permeability of postcapillary venules results from
Mechanisms of increased vascular permeability in inflammation for fluid.
Endothelial cell contraction: The cytoskeleton of the endothelial cells of the postcapillary venules
contains actin. These cells can contract under the influence of most inflammation mediators, such as vasoactive
amines(secreted from mast cells, basophils, and platelets), bradykinin, complement components (C3a and C5a),
and leukotrienes (C4, D4, and E4), and pores in the walls of the vessels open.
Endothelial necrosis: The noxious agent that triggers inflammation damages the endothelium and causes
endothelial swelling. This later leads to irreversible endothelial damage in the form of endothelial necrosis, with
formation of holes in the capillary. Result: Unregulated, excessive fluid exudation
Result of this increased vascular permeability is that large amounts of fluid and cells from the blood can leak
into the interstitial tissue.
Slower rate of venous blood outflow and the loss of plasma due to increased vascular permeability leads to
vascular stasis and sluggish movement of red cells through the microcirculation. Laminar aggregations of
erythrocytes change into what appear under light microscopy to be homogeneous cylindrical vascular castings
(red sludge). This causes endothelial damage, making the endothelium wettable. This causes thrombocytes
to aggregate, leading to thrombosis. This seals off the leaking vascular structures in the inflamed area.
Eventually, blood clots form in the small capillaries that supply the inflamed area, helping to localize the effects
of the injury. The noxious agent remains in the tissue. The area damaged by the noxious agent is sealed off,
paving the way for the strike force of leukocytes. Leukocytes migrate out of the microvasculature and into the
inflamed area.
The exudation and the emigration of leukocytes
In the earliest phase of inflammation, arteriolar vasodilation and augmented blood flow increase
intravascular hydrostatic pressure and the movement of fluid from capillaries. This fluid, called a transudate, is
essentially an ultrafiltrate of blood plasma and contains little protein. However, transudation is soon eclipsed by
increasing vascular permeability that allows the movement of protein-rich fluid and even cells into the
interstitium (called an exudate).
The loss of protein-rich fluid into the perivascular space reduces the intravascular osmotic pressure and
increases the osmotic pressure of the interstitial fluid. The net result is outflow of water and ions into the
extravascular tissues; this fluid accumulation is called edema
The biologic purpose of exudation is the result of the interplay of a trio of factors:
Contaminants are diluted by the protein-rich exudate.
Contaminants are neutralized by the rapid introduction of counteractive substances such as antibodies.
Contaminants are fixed and damage is controlled.
Exudate is composed of water, fibrinogen and other coagulating proteins, immunoglobulins, complement
factors and cleavage products, and macroglobulins and microglobulins.
Emigration of the leukocytes (Cellular phase of the inflammatory response).
Leukocytes have four specific actions in inflamation.
1. Margination and pavementing. During the vascular stasis stage of hyperemia, leukocytes (principally
neutrophils and monocytes) begin to line the endothelia1 surfaces of the affected vessels (margination).
Leukocytes adhere to the vascular endothelium (pavementing) in preparation for migration into the
extravascular space. Adhesion is mediated by complementary molecules on the surface of neutrophils and
endothelium. Chemotactic factors probably influence the attraction of leukocytes to the vessel periphery and
microcirculatory stasis aids in the margination of leukocytes along the endothelial suface. Cell membrane
electronegativity and divalent calcium probably play role in leukocyte adherence to the endothelial surfaces.
2. Diapedesis (also called transmigration) refers to the process by which leukocytes migrate from blood
vessels. Leukocytes develop pseudopods and emigrate, without accompanying loss of fluid through gaps
between the endothelial ce11s. The emigration is purposeful, directed, and ameboid and it occurs without
endothelial cell contraction. Neutrophils are the first t emigrate outside the vascular compartments. They are
short-lived, with life span of 24 to 48 hours, and they contain chemotactic factor for monocytes (MCF).
Monocytes follow neutrophils into the site of inflammation, apparently on due from the chemotactic factor
elaborated by neutrophils (NCF). Monocytes are referred to as macrophages or histiocytes after emigrating.
ll leukocytes-neutrophils, basophils, eosinophils, lymphocytes, and monocvtes - emigrate in the same
manner. Occasionally, passive emigration of red cells may accompany leukocyte diapedesis.
3. Chemotaxis is the process by which leukocytes are directed to the site of injury. Leukocvte appear to have
cell-surface binding receptors for peptides of chemotactic factors. Follow no exposure to chemotactic agent,
random motion of the leukocyte begins. The microtubular system and contractile proteins are involved in cell
locomotion.
Chemotactic factors for neutrophils primarily include:
- Bacterial proteases, which are soluble, low-molecular-weight factors that are elaborated from both
gram-positive and gram-negative organisms
- Complement component 5, which is activated by the complement cascade
- LTB, and other products of the lipoxygenase pathway of arachidonic acid metabolism
Chemotactic factors for monocytes-macrophages include:
- Complement components 5 and
- LTB 4
- Bacteria-related substances
- Neutrophil components
- Lymphokines generated in response to exposure of sensitized lymphocytes t antigens
- Fibronectin fragments
Chemotactic factors for eosinophils (ECF) is emitted by mast cells, basophils, and sensitized lymphokines.
Eosinophils are attracted to sites of immediate hypersensitivity reactions (anaphylaxis), some immune complex
reactions, and parasitic infestation.
4. Phagocytosis is the process by which phagocytic cells-mainly neutrophils and monocytes-macrophages-
recognize and then engulf and dispose of foreign particles (e.g., bacteria)
Recognition The first step in phagocytosis is recognition of the injurious agent by the phagocytic cell, either
directly (as occurs with large, inert particles) or after the agent has been coated with immunoglobulin or
complement factor 3b (C3b) (opsonization). The coating agents are opsonins. Op sonin-mediated phagocytosis
is the mechanism operating in the immune phagocytosis of microorganisms. Both IgG and C3b are effective
opsonins. Immunoglobulin that is specifically reactive with antigens on the injurious agent (specific antibody)
is the most effective opsonin. C3b is generated locally by activation of the complement cascade. Early in acute
inflammationbefore the immune response has developednonimmune factors dominate, but as immunity
develops, they are superseded by the more efficient immune phagocytosis.
Engulfment. phagolysosome is formed when the cytoplasmic membrane of the phagocyte extends around
the attached particle, forming vacuole that connects with lysosome.
Phagolysosome formation is accompanied by the release of peroxides and hydrolytic enzymes into the
extracellu1ar space, which may result in some injury to surrounding tissue. Acid hydrolases, then, are released
into the phagolysosomes. Both divalent calcium and divalent magnesium are required for engulfment of
particles.
Degradation is caused by oxygen-dependent mechanism and oxygen-independent mechanism
Oxygen-dependent mechanism
Oxidase-mediated bactericidal activity, which is initiated by cell membrane oxidase, converts oxygen to
hydrogen peroxide. Hydrogen peroxide then combines with MPO (present in neutrophil granules) and chloride
ion in the phagolysosome. This chemical combination is the most important and powerful bactericidal agent of
leukocytes. Superoxide free radicals are formed in other reactions, being stimulated during oxidative
metabolism following phagocytosis. They are independent of MPO and have bactericidal activity.
Oxygen-independent mechanism
Leukocyte bactericidal activity that is independent of oxygen involves certain proteins, including:
- Lysozyme, which hydrolyzes bacterial wall gycopeptides in powerful bactericidal activity
- Cationic proteins, which also have deleterious effect on bacterial cell walls
- Lactoferrin, an iron-binding protein with bactericidal activity
Hydrogen ions are released into the phagolysosome, creating an acid pH to suppress bacterial growth.
The acute inflammatory response is characterized by the formation of an exudate (i.e., mixture of fluid,
cells, and proteins exuded from damaged cells). The exudate contains protein in excess of 3 g/dl and has
specific gravity exceeding 1.015. There are four major types of acute inflammatory exudate.
Purulent (suppurative, pyogenic) exudate consists of large amounts of neutrophils, often accumulated in
response to bacterial infection, which may lead to abscess formation
Fibrinous exudate is characterized by large amount of protein (albumin, fibrinogen) from plasma, with
visible deposits of fibrin coagulum,; it often is bloody (sanguineous). Examples of fibrinous exudate include
tuberculous pleuritis and rheumatic pericarditis. The coagulum exudate may become organized by
neovascularity and fibroblast formation, with consequent scarring.
 Serous exudate occurs with mild inflammation. Characteristically, it involves fewer cells and less protein
than the other types of exudates contain. Serous exudates generally form in body cavities (pleural, pericardial,
peritoneal) and in the spinal fluid. Examples are the fluids in second-degree thermal burns, viral meningitis, and
joint and pleural effusions.
Catarrhal exudate refers to the type of exudate that forms on mucous membranes and is characterized by
high mucus content. An example is the exudate that occurs in allergic rhinitis (coryza) and bronchitis.
The third stage - Proliferation
Proliferation (duplication) of the cells results in repair.
Eventual healing is the goal of ll inflammatory Tissue restoration begins almost at the onset of
inflammation itself processes.
Dissolution of the exudate: In the absence of complications or defects in the immune system, the
inflammatory exudate is eliminated by macrophages. The dissolved components of the inflammatory exudate
are transported via the lymph vessels to the regional lymph nodes, resulting in regional lymphadenitis.
Once the exudate has been dissolved, the tissue may either regenerate completely, or replacement tissue may
form to fill the defect.
After about 3 days granulation tissue rich in capillaries with numerous fibroblasts develops under the
influence of thrombocytic and macrophagic growth factors (GF). These factors act as a road building crew.
The capillaries and fibroblasts of this tissue extend into the wound area. Fibroblasts proliferate under the
influence of thrombocytic and macrophagic growth factors until the defect has been covered. These cells act as
a tarpaulin cover to close the wound.
Healing of tissue injury or loss caused by inflammation depends on the type of cells that comprise the organ.
Complete restoration of injured tissue requires the removal or destruction of the injurious agent. Repair by
regeneration of cells n occur only in injured tissues that have retained their cell division capability.
Restoration occurs by regeneration of cells and tissue specific for the damaged site. The regenerative ability of
cells is described in three ways.
Labile cells possess constant capacity for regeneration, multiplying continuously t replace old cells that
are lost in normal physiologic activities, organs derived from these cells heal completely. Lymphoid and
hematopoietic cells as well as epithelial cells in the gastrointestinal tract, respiratory tract, urinary bladder, male
and female genital tracts, and skin are all labile cells.
Stable (facultative mitotic) cells have limited regrowth capacity; they n undergo cell division in order to
replace dead cells but normally are not actively multiplying. Stable cells are replaced by regeneration from
remaining cells, which are stimulated to enter the mitotic cycle. The liver, pancreas, kidney, endocrine glands,
and blood vessels are composed of stable cells. For normal structural restoration to occur in these organs,
basement membrane zones must be in contact with the supporting stroma of the organs.
Permanent cells (post-mitotic) d not have the ability to reproduce and, once destroyed, cannot be replaced.
Neurons and cardiac muscle cell are examples of permanent cells. Scar tissue is laid down in their stead.
6. Consequences of inflamation
Four Outcomes of Acute Inflammation
1. Complete resolution with regeneration
2. Complete resolution with scarring
3. Abscess formation
4. Transition to chronic inflammation
Untoward effects of inflammation and repair
Perforation. Expanding masses of inflamed tissue in the acute inflammatory phase may lead to viscus wall
weakening and potential rupture. ruptured appendix with spillage of the contents into the abdominal cavity
results inpurulent peritonitis.
Exudative perihepatitis n occur secondary to luboovarian pyogenic infections e.g. pelvic inflammatory
disease (PID) due to gonorrhea. Chemical peritonitis n occur as complication of perforated gastric ulcer.
Advancing planes of inflammatory tissue (fistulous tracts) also may result. bronchopleural fistula can form
from pulmonary staphylococcal abscess, with consequent purulent pleuritis (empyema). Acute mediastinitis
n result from an eroding inflammatory tracheoesophageai fistula. Perirectal and ischiorectal fossa fistulas can
form from expanding perineal abscesses.
Extensive fibrosis. The following are problems related to fibrosis and scar formation after healing. Keloids
are excessive accumulations of collagen, which form in susceptible persons during the healing process. This
excess collagen results in protuberant scar that extends beyond the region of the original injury. Bowel
obstruction n occur if adhesive fibrous bands form after repair of abdominail trauma (e.g., surgery, knife
wounds). Sterility n result from fibrous obliteration of the fallopian tubes after healing of sa1pingitis.
Complications may result from sequelae t an inflammatory process. Ascending pyelophlebitis of the portal
vein system and cholangitis n be caused by ruptured appendix. large abscess may form in the liver, brain,
or body cavities, with thickened fibrous capsule on the exterior that prevents resolution and healing. Infection
may occur and spread through the draining lymphatics, with regional lymphadenilis. The lymphangilis appears
as reddish streaking, which is visible through the skin.