Celsus,

• listed the four cardinal signs of inflammation: rubor, tumor, calor, and dolor (redness, swelling, heat, and pain).

• A fifth clinical sign, loss of function (functio laesa), was later added by Virchow.

Scottish surgeon John Hunter

• inflammation is not a disease but a nonspecific response

• Julius Cohnheim (1839-1884) first used the microscope to observe inflamed blood vessels in thin, transparent membranes, such as in the mesentery and tongue of the frog.

• Noted the initial changes in blood flow, the subsequent edema caused by increased vascular permeability, and the characteristic leukocyte emigration,

the Russian biologist Elie Metchnikoff 1880s,

• discovered the process of phagocytosis by observing eating bacteria by mammalian leukocytes.

• concluded the purpose of inflammation was to bring phagocytic cells to the injured area to engulf invading bacteria.

• both cells (phagocytes) and serum factors (antibodies) were critical for defense against microorganisms,

Sir Thomas Lewis,

• that chemical substances, such as histamine locally induced by injury, mediate the vascular changes of inflammation.

Definition

• inflammatory process is the reaction of blood vessels, leading to the accumulation of fluid and leukocytes in extravascular tissues.

• Inflammation is a complex reaction to injurious agents such as microbes and damaged, usually necrotic, cells that consists of vascular responses, migration and activation of leukocytes, and systemic reactions.

Definition

• a host response of vascularized tissues to exogenous and endogenous stimuli is called inflammation.

The inflammatory response is closely intertwined with the process

of repair.

• Inflammation serves to destroy, dilute, or wall off the injurious agent, and it sets into motion a series of events that try to heal and reconstitute the damaged tissue.

Repair

• Repair begins during the early phases of inflammation but reaches completion usually after the injurious influence has been neutralized.

• During repair, the injured tissue is replaced• regeneration of native parenchymal cells,• by filling of the defect with fibrous tissue

(scarring) or,• by a combination of these two processes.

Inflammation

• a protective response, the ultimate goal of which is to rid the organism of both the initial cause of cell injury (e.g., microbes, toxins) and the consequences of such injury (e.g., necrotic cells and tissues).

• Inflammation and repair may be potentially harmful, • Inflammatory reactions, for example, underlie common

chronic diseases, such as rheumatoid arthritis, atherosclerosis, and lung fibrosis,

• . Repair by fibrosis may lead to disfiguring scars or fibrous bands that cause intestinal obstruction or limit the mobility of joints.

•

The components of acute and chronic inflammatory responses: circulating cells and proteins, cells of blood vessels, and cells and proteins of the extracellular matrix.

Compnents

• The inflammatory response consists of two main components,

• a vascular reaction and a cellular reaction.

Components

• The circulating cells include neutrophils, monocytes, eosinophils, lymphocytes, basophils, and platelets.

Components• The connective tissue cells • mast cells, which intimately surround blood vessels;

• fibroblasts; • resident macrophages; • lymphocytes. • The extracellular matrix, • structural fibrous proteins (collagen, elastin), • adhesive glycoproteins (fibronectin, laminin, nonfibrillar collagen,

tenascin, and others), • proteoglycans. • The basement membrane is a specialized component of the

extracellular matrix consisting of adhesive glycoproteins and proteoglycans.

Patterns

• Acute inflammation is rapid in onset (seconds or minutes) and is of relatively short duration, lasting for minutes, several hours, or a few days;

• characteristics are the – exudation of fluid and plasma proteins

(edema) – emigration of leukocytes, predominantly

neutrophils.

Patterns

• Chronic inflammation is of longer duration Chronic inflammation is associated with

• the presence of lymphocytes and macrophages,

• the proliferation of blood vessels,

• fibrosis,

• tissue necrosis.

PLEASE NOTE

• The vascular and cellular reactions of both acute and chronic inflammation are mediated by chemical factors

Chemical mediators

• chemical mediators are derived from – plasma proteins or cells

• are produced in response to or activated by the inflammatory stimulus.

• mediators, acting singly, in combinations, or in sequence,

• amplify the inflammatory response and influence its evolution.

• Necrotic cells or tissues themselves-whatever the cause of cell death-can also trigger the elaboration of inflammatory mediators. – acute inflammation after myocardial infarction

Inflammation is terminated

• offending agent is eliminated

• the secreted mediators are broken down

• dissipated.

• there are active anti-inflammatory mechanisms

• control the response

– prevent it from causing excessive damage to the host.

Acute inflammation has three major components:

• . (1) alterations in vascular caliber that lead to an increase in blood flow;

• (2) structural changes in the microvasculature that permit plasma proteins and leukocytes to leave the circulation

• (3) eukocytes– emigration of the leukocytes from the microcirculation– Accumulation of the leukocytes in the focus of injury, – activation of the leukocytes to eliminate the offending

agent

exudation

• The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities is known as exudation.

exudate

• An exudate is an inflammatory extravascular fluid that has a high protein concentration, cellular debris, and a specific gravity above 1.020.

• It implies significant alteration in the normal permeability of small blood vessels in the area of injury.

transudate

• a transudate is a fluid with low protein content (most of which is albumin) and a specific gravity of less than 1.012.

• It is essentially an ultrafiltrate of blood plasma that results from osmotic or hydrostatic imbalance across the vessel wall without an increase in vascular permeability.

• Edema denotes an excess of fluid in the interstitial or serous cavities; it can be either an exudate or a transudate.

Pus

• Pus, a purulent exudate, is an inflammatory exudate rich in leukocytes (mostly neutrophils), the debris of dead cells and, in many cases, microbes.

STIMULI FOR ACUTE INFLAMMATION

• Infections (bacterial, viral, parasitic) and microbial toxins

• Trauma (blunt and penetrating) • Physical and chemical agents (thermal injury,

e.g., burns or frostbite; irradiation; some environmental chemicals)

• Tissue necrosis (from any cause) • Foreign bodies (splinters, dirt, sutures) • Immune reactions (also called hypersensitivity

reactions)

The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (causing erythema and warmth), (2) extravasation and deposition of plasma fluid and proteins (edema), and (3) leukocyte emigration and accumulation in the site of injury.

VASCULAR CHANGES

• Changes in Vascular Flow and Caliber– vasodilatation

• increased permeability of the microvasculature

• Effects on the endothelial cells

Changes in Vascular Flow and Caliber

• Vasodilation– Vasodilation first involves the arterioles and

then results in opening of new capillary beds in the area.

– Thus comes about increased blood flow, which is the cause of the heat and the redness

increased permeability of the microvasculature,

• outpouring of protein-rich fluid into the extravascular tissues;

• The loss of fluid results in concentration of red cells in small vessels and increased viscosity of the blood,

• dilated small vessels packed with red cells and slower blood flow, a condition termed stasis.

• stasis, leukocytes, principally neutrophils, accumulate along the vascular endothelium.

• Leukocytes then stick to the endothelium, and soon afterward they migrate through the vascular wall into the interstitial tissue,

increased permeability of the microvasculature,

• The loss of protein from the plasma reduces the intravascular osmotic pressure

• The loss of protein from the plasma increases the osmotic pressure of the interstitial fluid.

• increased blood flow through the dilated vessels increases hydrostatic pressure

• a marked outflow of fluid and its accumulation in the interstitial tissue

• The net increase of extravascular fluid results in edema.

Blood pressure and plasma colloid osmotic forces in normal and

inflamed microcirculation.

Blood pressure and plasma colloid osmotic forces in normal and inflamed microcirculation.

• A, Normal hydrostatic pressure (red arrows) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure. Although fluid tends to leave the precapillary arteriole, it is returned in equal amounts via the postcapillary venule, so that the net flow (black arrows) in or out is zero. B, Acute inflammation. Arteriole pressure is increased to 50 mm Hg, the mean capillary pressure is increased because of arteriolar dilation, and the venous pressure increases to approximately 30 mm Hg. At the same time, osmotic pressure is reduced (averaging 20 mm Hg) because of protein leakage across the venule. The net result is an excess of extravasated fluid.

Diagrammatic representation of five mechanisms of increased vascular permeability in inflammation

Diagrammatic representation of five mechanisms of increased vascular permeability in inflammation

Effects on the endothelial cells

• Formation of endothelial gaps in venules due to contraction of the endothelial cells and separation of intercellular junctions

• Direct endothelial injury, resulting in endothelial cell necrosis and detachment.

• Leukocyte-mediated endothelial injury

• Leakage from new blood vessels.

in acute inflammation, fluid loss from vessels with increased

permeability occurs in distinct phases:

• (1) an immediate transient response lasting for 30 minutes or less, mediated mainly by the actions of histamine and leukotrienes on endothelium;

• (2) a delayed response starting at about 2 hours and lasting for about 8 hours, mediated by kinins, complement products, and other factors; and

• (3) a prolonged response that is most noticeable after direct endothelial injury, for example, after burns.

• CELLULAR EVENTS: LEUKOCYTE EXTRAVASATION AND PHAGOCYTOSIS

A critical function of inflammation is to

• deliver leukocytes to the site of injury and to activate the leukocytes to perform their normal functions in host defense.

• Leukocytes ingest offending agents, kill bacteria and other microbes, and get rid of necrotic tissue and foreign substances.

• A price that is paid for the defensive potency of leukocytes is that they may induce tissue damage and prolong inflammation, since the leukocyte products that destroy microbes and necrotic tissues can also injure normal host tissues.

The multistep process of leukocyte migration through blood vessels

• The leukocytes first roll, then become activated and adhere to endothelium,

• then transmigrate across the endothelium, pierce the basement membrane,

• and migrate toward chemoattractants emanating from the source of injury.

• Different molecules play predominant roles in different steps of this process-selectins in rolling; chemokines in activating the neutrophils to increase avidity of integrins (in green);

• integrins in firm adhesion

• The sequence of events in the journey of leukocytes from the vessel lumen to the interstitial tissue, called extravasation, can be divided into the following In the lumen: margination, rolling, and adhesion to endothelium.

• Vascular endothelium normally does not bind circulating cells or impede their passage.

• In inflammation, the endothelium has to be activated to permit it to bind leukocytes, as a prelude to their exit from the blood vessels.

• Transmigration across the endothelium (also called diapedesis)

• Migration in interstitial tissues toward a chemotactic stimulus

• Because blood flow slows early in inflammation (stasis), hemodynamic conditions change (wall shear stress decreases), and more white cells assume a peripheral position along the endothelial surface. This process of leukocyte accumulation is called margination.

• Subsequently, individual and then rows of leukocytes tumble slowly along the endothelium and adhere transiently (a process called rolling), finally coming to rest at some point where they adhere firmly (resembling pebbles over which a stream runs without disturbing them).

• In time, the endothelium can be virtually lined by white cells, an appearance called pavementing. After firm adhesion, leukocytes insert pseudopods into the junctions between the endothelial cells, squeeze through interendothelial junctions, and assume a position between the endothelial cell and the basement membrane.

• Eventually, they traverse the basement membrane and escape into the extravascular space. Neutrophils, monocytes, lymphocytes, eosinophils, and basophils all use the same pathway to migrate from the blood into tissues.

• The next step in the process is migration of the leukocytes through the endothelium, called transmigration or diapedesis. Chemokines act on the adherent leukocytes and stimulate the cells to migrate through interendothelial spaces toward the chemical After traversing the endothelium, leukocytes are transiently retarded in their journey by the continuous basement membrane of the venules, but eventually the cells pierce the basement membrane, probably by secreting collagenases. The net result of this process is that leukocytes rapidly accumulate where they are needed.

• Once leukocytes enter the extravascular connective tissue, they are able to adhere to the extracellular matrix by virtue of β1 integrins and CD44 binding to matrix proteins. Thus, the leukocytes are retained at the site where they are needed.

Chemotaxis

• After extravasation, leukocytes emigrate in tissues toward the site of injury by a process called chemotaxis, defined most simply as locomotion oriented along a chemical gradient.

• All granulocytes, monocytes and, to a lesser extent, lymphocytes respond to chemotactic stimuli with varying rates of speed. Both exogenous and endogenous substances can act as chemoattractants. The most common exogenous agents are bacterial products.

• Endogenous chemoattractants, which are detailed later, include several chemical mediators: (1) components of the complement system, particularly C5a;

• (2) products of the lipoxygenase pathway, mainly leukotriene B4 (LTB4); and

• (3) cytokines, particularly those of the chemokine family (e.g., IL-8).

histologic sequence of events following acute injury. The photomicrographs are representative of the early (neutrophilic) (left) and later (mononuclear) cellular infiltrates (right) of infarcted myocardium.

Leukocyte Activation

• Microbes, products of necrotic cells, antigen-antibody complexes, and cytokines, including chemotactic factors, induce a number of responses in leukocytes

Phagocytosis

• Phagocytosis and the release of enzymes by neutrophils and macrophages are responsible for eliminating the injurious agents and thus constitute two of the major benefits derived from the accumulation of leukocytes at the inflammatory focus.

• Phagocytosis involves three distinct but interrelated steps (

• (1) recognition and attachment of the particle to be ingested by the leukocyte;

• (2) its engulfment, with subsequent formation of a phagocytic vacuole; and

• (3) killing or degradation of the ingested material

CONTROLS OF ACUTE INFLAMMATION

• inherent capacity to cause tissue damage, • needs tight controls to minimize the damage. • inflammation declines simply because the

mediators of inflammation have short half-lives• , are degraded after their release, • and are produced in quick bursts, only as long

as the stimulus persists. • In addition as inflammation develops, the

process also triggers a variety of stop signals that serve to actively terminate the reaction.42

CONTROLS OF ACUTE INFLAMMATION

• switch in the production of pro-inflammatory leukotrienes to anti-inflammatory lipoxins

• the liberation of an anti-inflammatory cytokine,

• transforming growth factor-β (TGF-β), from macrophages and other cells;

• {\B Neutrophils are the main effector cells in acute inflammation}

• The neutrophil is the main cell to mediate the effects of acute inflammation. If tissue damage is slight, an adequate supply is derived from normal numbers circulating in blood. If tissue damage is extensive, stores of neutrophils, including some immature forms, are released from bone marrow to increase the absolute count of neutrophils in the blood. To maintain the supply of neutrophils, growth factors derived from the inflammatory process stimulate division of myeloid precursors in the bone marrow, thereby increasing the number of developing neutrophils.

• {\B Neutrophils adhere to endothelial cells prior to emigration}• The adhesion of neutrophils to endothelium causes them to

aggregate along the vessel walls in a process termed margination. Following margination, neutrophils migrate through the wall of the vessel into the surrounding tissue in a process termed emigration, as shown in {\I Fig. 5.3.}

• ¶{\B Activation of endothelium is a key process in acute inflammation}

• Endothelium in local vessels is activated both by products of tissue damage and by cytokines. This induces the expression of surface cell adhesion molecules, which interact with complementary molecules in the neutrophil cell membrane.

• Some of the factors involved in the activation of endothelial cells, together with its role in neutrophil margination,

• are summarized in the pink box opposite. The endothelium is modified to become sticky for neutrophils, to secrete factors mediating vasodilation and to promote platelet adhesion and aggregation

• {\B Neutrophils are attracted to the area of tissue damage by chemical mediators}

• The movement of neutrophils from the vessel lumen into a damaged area is mediated by substances known as chemotactic factors, which diffuse from the area of tissue damage. The main neutrophil {\B chemotactic factors} are listed in the Key Facts on mediators (see {\L page 67}). These factors bind to receptors on the surface of neutrophils and activate secondary messenger systems, stimulating increased cytosolic calcium, with resulting assembly of cytoskeletal specializations involved in motility.

• +}• FIGLEGEND {+• {\B Fig. 5.3 Neutrophil emigration in acute} • {\B inflammation.}• +}

The acute inflammatory exudate is derived from local vessels}

• The acute inflammatory exudate is composed of: • • {\B Fluid} containing salts and a high concentration of • proteins including immunoglobulins.• • • {\B Fibrin,} a high molecular weight filamentous insoluble • protein.• • • Many {\B neutrophil polymorphs,} from the blood white• cell population.• • • A few {\B macrophages,} phagocytic cells derived from• blood monocytes.• • • A few {\B lymphocytes.}

• All of these components are derived from the blood as a result of changes that occur in blood vessels in the surviving tissue around the area of damage. These changes, the vascular and cellular responses of acute inflammation, are illustrated diagrammatically in {\I Fig. 5.2.} Briefly, the steps are :

• {\B 1} Small blood vessels adjacent to the area of tissue • damage initially become dilated with increased blood • flow, then flow along them slows down.• {\B 2} Endothelial cells swell and partially retract so that they • no longer form a completely intact internal lining.• {\B 3} The vessels become leaky, permitting the passage of • water, salts, and some small, molecular-sized protein • from the plasma into the damaged area (exudation). • One of the main proteins to leak out is the small • soluble molecule, fibrinogen.•

• {\B 4} Circulating neutrophil polymorphs initially adhere to

• the swollen endothelial cells (margination), then • actively migrate through the vessel basement • membrane (emigration), passing into the area of

tissue • damage.• {\B 5} Later, small numbers of blood monocytes • (macrophages) migrate in a similar way, as do • lymphocytes.• +}

• FIGLEGEND {+• Death of tissue leads to release of substances (chemical mediators)

which act on nearby blood vessels.• Mediators produce:• • Persistent vasodilatation and loss of axial flow• • Endothelial cell swelling and separation• • Increased permeability, with exudation of water, salts • and small proteins, including fibrinogen. Fibrinogen is • converted to fibrin.• Mediators cause neutrophils to adhere to endothelium

(margination), and move through vessel walls into damaged tissue (emigration). Blood monocytes/macrophages also emigrate by a similar mechanism slightly later. The damaged area becomes progressively replaced by the components

Acute inflammation is the most common early tissue response

to tissue damage and destruction

The acute inflammatory response has three main functions:

• The affected area is occupied by a transient material called the acute inflammatory exudate. The exudate carries proteins, fluid, and cells from local blood vessels into the damaged area to mediate local defences.

• If an infective causative agent (e.g. bacteria) is present in the damaged area, it can be destroyed and eliminated by components of the exudate.

• The damaged tissue can be broken down and partly liquefied, and the debris removed from the site of damage.

• The acute inflammatory response is controlled by the production and diffusion of chemical messengers derived both from damaged tissues and from the acute inflammatory exudate.

Overview of outcome

When tissue is damaged and cells die, more than one

outcome is possible

restitution• The damaged area may be replaced by

tissue identical in structure and function to that originally present.

• this is the ideal outcome

It can take place only if

• The damaging agent is removed

• The cell debris is cleared from the site

• The specialized cells which have been destroyed have the capacity to re-grow or regenerate.

most frequent outcome of substantial tissue damage.

• If damaged cells cannot re-grow, or local damage is so severe that tissue architecture is entirely destroyed, complete restitution of a damaged area is not always possible.

• In this case, the tissue response is to heal the damaged area by replacing it by non-specialized scar tissue a process termed fibrous repair.

If the damaging agent persists

• If the damaging agent persists (particularly if it involves infection), continuing tissue destruction, attempts to heal by fibrous repair and immune responses occur concurrently, a process known as {\B chronic inflammation.}

• ¶Irrespective of the ultimate outcome of tissue damage, the initial response of the tissue is termed acute inflammation or the acute inflammatory reaction. This response is relatively non-specific, its main roles being to clear away dead tissues, protect against local infection, and allow the immune system access to the damaged area.

• +}

Vascular and exudative changes in} acute inflammation.

• {\B Local vascular flow and permeability alter in acute inflammation}

• The main vascular changes that arise in acute inflammation are slowing of flow and dilatation of vessels, and increase in the permeability of their walls, allowing diffusion of large proteins and fluid.

• {\B Fibrin in the acute inflammatory exudate may have roles in allowing cell movement}

• Fibrin is a long, insoluble, filamentous protein, formed by the polymerization of numerous molecules of the smaller, soluble, precursor plasma protein fibrinogen. The fibrinogen passes out from vessels with the fluid and salts, polymerizing into insoluble fibrin threads once outside the vessel lumen by activation of the blood coagulation cascade.

• ¶It is widely speculated that the network of fibrin threads prevents migration of micro-organisms and produces a scaffold which might assist the migration of neutrophils and macro-phages through the damaged area. However, there is no real proof that these are the precise functions of the network.

• {\B Fluid in the acute inflammatory exudate carries nutrients, mediators and immunoglobulins}

• It is logical to assume that the presence of fluids and salts may dilute or buffer any locally produced toxins in an area of tissue damage, but little more is known about their precise functions in the acute inflammatory reaction. Glucose and oxygen can diffuse into the area of inflammation to support macrophages. Fluid also allows diffusion of mediators of the inflammatory process, particularly plasma-derived precursors (see {\L page 66}).

• If immunity to an invading organism already exists, immuno-globulins in the exudate act as opsonins for neutrophil phagocytosis.

• The fluid in the exudate is not static but is constantly circulating from local vessels, through the extracellular space of the damaged tissue, to be re-absorbed by lymphatics. This increased flow of lymph takes antigens to the local nodes and assists in later development of a specific immune response.

• ¶{\B Cellular reactions are also needed in acute inflammation}• The main cellular events in acute inflammation, all of which• are caused by chemical mediators, are as follows:• • The normally inactive endothelium has to be activated to• allow adhesion of neutrophils.• • Normally inactive neutrophils have to be activated to• enhance their capacity for phagocytosis, bacterial killing,• and generation of inflammatory mediators.• • Neutrophils have to develop the ability to move actively, • in a directional fashion, from vessels towards the area of• tissue damage.

LFA

ELA2

• Endothelial activation in acute inflammation}• The endothelium plays a vital role as a physical

barrier against diffusion of plasma outside vessels, as well as being the source of many regulatory molecules. Because of its extent and its constant secretion of messenger substances, the endothelium has been called the largest endocrine organ in the body.

• The main factors secreted by the endothelium are:

• • Nitric oxide and prostacyclin, which induce vascular

• relaxation and inhibit platelet aggregation.• • Endothelin, thromboxane A2, and angiotensin

II, which• cause vascular constriction.• • Growth factor PDGF promotes inhibitors, e.g.

heparin-like • substances.

• In the normal state the endothelium provides a surface that prevents platelet aggregation and degranulation. The balance of secreted factors is a major determinant in control of regional blood flow. In acute inflammation this balance is changed and there is increased synthesis of a lipid-derived molecule known as platelet activating factor (PAF), which increases vascular permeability; increased synthesis of nitric oxide, which promotes vascular dilatation; and more cell adhesion molecules are expressed, which allows neutrophil adhesion.

• ¶In addition to modulation of secreted factors, the surface properties of the endothelium are altered in acute inflammation (Fig. 5.4).

• • IL-1 and TNF increase the expression of adhesion • molecules on the endothelium, especially P-selectin.• • Endothelial leukocyte adhesion molecule 1 (ELAM-1 or • E-selectin ) promotes adhesion of neutrophils.• • Intercellular adhesion molecule 1 (ICAM-1) promotes • adhesion of neutrophils and lymphoid cells.• • Vascular cell adhesion molecule 1 (VCAM-1) • promotes adhesion of lymphoid and monocyte cells.• At the same time, other mediators of inflammation, particularly the

C5a fragment of complement, induce increased

• expression of complementary cell adhesion molecules on neutrophils (CD11/CD18 complex).

• The endothelium in acute inflammation is therefore meta-bolically altered to produce vasoactive factors (particularly PAF and nitric oxide) as well as to be sticky for neutrophils.

• +}• FIGLEGEND {+• {\B Fig. 5.4 Cell adhesion molecules involved in }• {\B neutrophil adhesion.}• {\B IL-I interleukin-I, TNF tumour necrosis factor, }• {\B LTB4 leukotriene B4}• +}