figura 13.1 - glifo egizio che indicherebbe infiammazione...

Figura 13.1 - Glifo egizio che indicherebbe “infiammazione”.

Dal volume: Pontieri “Patologia Generale” Piccin Nuova Libraria S.p.A.

INFIAMMAZIONE

Ippocrate: individua fenomeni quali rossore e gonfiore Celso: definisce i 4 punti cardinali della infiammazione Galeno introduce il concetto della “funzione lesa” Hunter: non si tratta di una malattia ma di una risposta agli stimoli E. Metchnicoff: scopre i macrofagi Lewis: scopre il ruolo dell’Istamina Definizione generale L’Infiammazione è il più importante processo morboso reattivo locale che forma la base patologica delle malattie

INFIAMMAZIONE

Infiammazione (sintesi) •  Che cosa è: processo reattivo (morboso) locale, base delle malattie

•  Sede: vascolo-connettivale

•  Nomenclatura: suffisso “ITE” con il nome dell’organo interessato, polmonite, pancreatite, gastrite….

•  Andamento stereotipato. Per effetto dei mediatori e nonostante la diversità degli stimoli.

•  Fenomeni elementari costanti: vasodilatazione, variazione permeabiltà, migrazione cellulare.

•  Decorso: variabile per quantità e diversità stimoli, e delle reattività dell’ospite ( danno variabile).

Cosa è l’infiammazione? Rubor Tumor Calor Dolor (rossore) (gonfiore) (calore) (dolore)

Quattro segni chiave (noti già a Greci e Romani)

INFIAMMAZIONE: generalità •  L'infiammazioneèunareazionecomplessaadagentinocivi,comeimicrobiecelluledanneggiate,disolitonecrotiche. Si compone di molteplici meccanismi di risposta: vascolare, migrazione e attivazione deileucociti,edireazionisistemiche

•  Lacaratteristicaunicadelprocessoinfiammatorioèlareazionedeivasisanguigni,provocandol'accumulodiliquidieleucocitineitessutiextra-vascolare.

•  Larispostainfiammatoriaèstrettamenteconnessaconilprocessodiriparazione.

•  L'infiammazione è fondamentalmente una risposta protettiva, il cui fine ultimo è quello diliberarel'organismodallacausainizialedidannocellulare(peresempio,imicrobi,tossine)edalle conseguenze di tale danno (ad esempio, cellule e tessuti necrotici). Senzainfiammazione,leinfezionisarebberononcontrollate,leferitenonguarirebbero.

•  Comunque, l'infiammazioneelariparazionepossonoesserepotenzialmentedannosi:–  Reazioni infiammatorie, sonoalla basedi comunimalattie croniche, come l'artrite reumatoide, l'arteriosclerosi, e lafibrosipolmonare,

–  lereazionidiipersensibilitàapunturediinsetti,drogheetossine.

–  Riparazionechecomportanofibrosipossonoportareacicatricideturpantioformazionidibandefibrosechecausanoostruzioneintestinaleodilimitarelamobilitàdellearticolazioni

•  The inflammatory response consists of two main components, a vascular reaction and acellularreaction.

Prodotti leucocitari e lesione tissutale indotta da leucociti

•  Durante l’attivazione e la fagocitosi i leucociti liberano prodotti microbicidi e di altra natura non solo all’interno dei fagolisosomi ma anche nello spazio extracellulare

–  Enzimi lisosomiali –  Metaboliti reattivi dell’ossigeno –  Prodotti dell’acido arachidonico (prostaglandine e leucotrieni)

•  Possono causare lesioni endoteliali e danno tissutale e possono amplificare gli effetti dell’agente lesivo iniziale.

•  Se persistente e non controllato lo stesso infiltrato leucocitario diviene l’agente lesivo, e il danno tissutale dipendente dai leucociti è alla base di patologie umane acute e croniche

Reazioni infiammatorie acute sono attivate da una varietà di stimoli

•  Infezioni (batteriche, virali, parassitarie) e le tossine microbiche

•  Trauma

•  Agenti fisici e chimici (lesione termica, ad esempio, ustioni o congelamento, irradiazione, alcuni prodotti chimici ambientali)

•  Necrosi dei tessuti

•  Corpi estranei (schegge, sporcizia, suture)

•  Reazioni immunitarie (chiamate anche reazioni di ipersensibilità)

Inflammation is divided into acute and chronic 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; its main characteristics are the EDEMA (exudation of fluid and plasma proteins) and the emigration of leukocytes, predominantly neutrophils.

Chronic inflammation is of longer duration and is associated histologically with the presence of lymphocytes and macrophages, the proliferation of blood vessels, fibrosis, and tissue necrosis. Many factors modify the course and morphologic appearance of both acute and chronic inflammation.

The vascular and cellular reactions of both acute and chronic inflammation are mediated by chemical factors that are derived from plasma proteins or cells and are produced in response to or activated by the inflammatory stimulus. Such mediators, acting singly, in combinations, or in sequence, then 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. Such is the case with the acute inflammation after myocardial infarction. Inflammation is terminated when the offending agent is eliminated and the secreted mediators are broken down or dissipated. In addition, there are active anti-inflammatory mechanisms that serve to control the response and prevent it from causing excessive damage to the host.

Consequences of Defective or Excessive Inflammation

•  Defective inflammation typically results in increased susceptibility to infections (progression) and delayed healing of wounds and tissue damage.

–  reflects the fundamental role of the inflammatory response in host defense,

–  Delayed repair is because the inflammatory response is essential for clearing damaged tissues and debris, and provides the necessary stimulus to get the repair process started.

•  Excessive inflammation is the basis of many categories of human disease. –  allergies, in which individuals mount unregulated immune responses against commonly

encountered environmental antigens,

–  autoimmune diseases, in which immune responses develop against normally tolerated self-antigens, are disorders in which the fundamental cause of tissue injury is inflammation.

–  cancer, atherosclerosis and ischemic heart disease, and some neurodegenerative diseases such as Alzheimer disease (not primarily disorders of the immune system).

–  prolonged inflammation and the fibrosis that accompanies it are responsible for much of the pathology in many chronic infectious, metabolic and other diseases.

The components of acute and chronic inflammatory responses

Many tissues and cells are involved in these reactions, including the fluid and proteins of plasma, circulating cells, blood vessels, and cellular and extracellular constituents of connective tissue

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

•  The connective tissue cells: the mast cells, which intimately surround blood vessels, fibroblasts, resident macrophages and lymphocytes.

•  The extracellular matrix, consists of the structural fibrous proteins (collagen, elastin), adhesive glycoproteins (fibronectin, laminin, nonfibrillar collagen, tenascin, and others), and proteoglycans.

The basement membrane is a specialized component of the extracellular matrix consisting of adhesive glycoproteins and proteoglycans.

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

matrix

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2-1

Acute inflammation •  Acute inflammation is a rapid response to an injurious agent

that serves to deliver mediators of host defense-leukocytes and plasma proteins-to the site of injury.

•  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) emigration of the leukocytes from the microcirculation, their

accumulation in the focus of injury, and their activation to eliminate the

offending agent.

The major local manifestations of acute inflammation


1. dilatazione vascolare ed a u m e n t o d e l f l u s s o sanguigno (che causa rossore e calore)

2. Extravasazione e deposizione di fluido e proteine plasmatiche (edema)

3. migrazione dei leucociti e accumulo nel sito del “danno” 2 3

1

1

3 2

I 4 segni cardinali

•  Rubor •  Calor •  Tumor •  Dolor •  Functio lesa

Cellulitis. The skin over the lateral part of the foot is red (erythema) due to vascular

dilatation associated with acute inflammation.

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Early acute appendicitis. The appendix is swollen due to oedema, the surface is covered by fibrinous

exudate, and there is vascular dilatation.


Acute inflammation

•  Infiammazione acuta ha tre componenti principali:

–  (1) alterazione del calibro vascolare che porta a un aumento del flusso sanguigno;

–  (2) modifiche strutturali del microcircolo che permettono alle proteine plasmatiche e ai leucociti di lasciare il circolo s.

–  (3) migrazione dei leucociti dal microcircolo e loro accumulo

Changes in Vascular Flow and Caliber •  Changes in vascular flow and caliber begin early after injury and develop at varying ratesdependingontheseverityoftheinjury.Thechangesoccurinthefollowingorder:

•  VASODILATION is one of the earliestmanifestations of acute inflammation; sometimes, itfollowsatransientconstrictionofarterioles,lastingafewseconds.Vasodilationfirstinvolvesthe arterioles and then results in opening of new capillary beds in the area. Thus comesabout increasedbloodflow,whichisthecauseoftheheatandtheredness.Vasodilationisinducedby theactionofseveralmediators,notablyhistamineandnitricoxide,onvascularsmoothmuscle.

•  Vasodilation is quickly followed by INCREASED PERMEABILITY of the microvasculature,withtheoutpouringofprotein-richfluidintotheextravasculartissues.

•  The LOSSOF FLUID results in concentration of red cells in small vessels and increasedviscosityoftheblood,reflectedbythepresenceofdilatedsmallvesselspackedwithredcellsandslowerbloodflow,aconditiontermedstasis.

•  As stasis develops, leukocytes, principally neutrophils, accumulate along the vascularendothelium. Leukocytes then stick to the endothelium, and soon afterward they migratethroughthevascularwallintotheinterstitialtissue,inprocessesthataredescribedlater.

Vascular dilatation in acute inflammation


Normally, most of the capillary bed is closed down by precapillary sphincters

In acute inflammation, the sphincters open, causing blood to flow through all capillaries.

Acute inflammation





Increased Vascular Permeability

•  A hallmark of acute inflammation is increased vascular permeability leading to the escape of a protein-rich fluid (exudate) into the extravascular tissue.

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

•  Together with the increased hydrostatic pressure owing to increased blood flow through the dilated vessels, this leads to a marked outflow of fluid and its accumulation in the interstitial tissue.

•  The net increase of extravascular fluid results in edema.

B, Acute inflammation •  Arteriole pressure is increased to 50 mm Hg, the mean capillary pressure is increased because of arteriolar dilation, •  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.


Increased Vascular Permeability pressure and plasma colloid osmotic forces in normal and inflamed microcirculation

A, Normal 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.


Mechanisms of increased vascular permeability in inflammation

Legame dell’istamina ai propri recettori sulle HEV attiva il segnale intracellulare che porta a fosforilazione delle proteine del citoscheletro e proteine contrattili (miosina). IL-1, TNF-alfa, IFN-gamma (late and longer)


Mechanisms of increased vascular permeability in inflammation

2-5 Vascular leakage induced by chemical mediators. A, This is a fixed and cleared preparation of a rat cremaster muscle examined unstained by transillumination. One hour before sacrifice, bradykinin was injected over this muscle, and colloidal carbon was given intravenously. Plasma, loaded with carbon, escaped, but most of the carbon particles were retained by the basement membrane of the leaking vessels, with the result that these became "labeled" black. Note that not all the vessels leak-only the venules. In B, a higher power, the capillary network is faintly visible in the background. (Courtesy of Dr. Guido Majno, University of Massachusetts Medical School, Worcester, MA.)


B Inflammatory oedema. Gaps between endothelial cells (mostly at venular level) allow water and albumin (and other plasma constituents) to escape. There is increased lymphatic drainage, but this cannot cope with all the water released into the tissues and oedema results.


Pathogenesis of oedema

A Normal. Hydrostatic blood pressure forces water out of capillaries at the arterial end, but the plasma oncotic pressure attributable to albumin sucks water back into capillary beds at the venous end. A small amount of water drains from the tissues through lymphatic channels.



C Venous oedema. Increased venous pressure (e.g. from heart failure, venous obstruction due to thrombus) causes passive dilatation and congestion of the capillary bed. Increased venous pressure exceeds that of plasma oncotic pressure and so water remains in the tissues.

D Lymphatic oedema. Lymphatic obstruction (e.g. by tumour deposits, filarial parasites) prevents drainage of water from tissues.

E Hypoalbuminaemic oedema. Low plasma albumin concentration reduces the plasma oncotic pressure so that water cannot be sucked back into the capillary bed at the venous end.



Perdita di liquidi nell’infiammazione acuta:

•  Nell’infiammazione acuta, la perdita di liquidi dai vasi con aumentata permeabilità avviene in 3 fasi distinte:

–  (1) una risposta immediata transitoria della durata di 30 minuti o meno, mediata principalmente dalle azioni di istamina e di leucotrieni sull’endotelio;

–  (2) una risposta ritardata a partire da circa 2 ore e della durata di circa 8 ore, mediata dalla chinine, prodotti del complemento e altri fattori, e

–  (3) una risposta prolungata che è più evidente in seguito a lesioni dell’endotelio come per esempio, dopo le ustioni.

riassumendo

Acute inflammation





CELLULAR EVENTS: LEUKOCYTE EXTRAVASATION AND PHAGOCYTOSIS

•  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 steps:

•  In the lumen: margination, rolling, and adhesion to endothelium. –  Vascular endothelium normally does not bind circulating cells and block 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

Adhesion Molecules Selectins, characterized by an extracellular N-terminal domain related to sugarbinding mammalian lectins, E-selectin (CD62E, endothelium), P-selectin (CD62P, endothelium and platelets), and L-selectin (CD62L, leukocytes)

Immunoglobulin family molecules include two endothelial adhesion molecules: ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1), CD31. Both these molecules serve as ligands for integrins found on leukocytes

Integrins transmembrane heterodimeric glycoproteins expressed on many cell types, bind to ligands on endothelial cells, other leukocytes, and the extracellular matrix (CD11a/CD18 and CD11b/CD18

Mucin-like glycoproteins, such as heparan sulfate, serve as ligands for the leukocyte adhesion molecule called CD44. These glycoproteins are found in the extracellular matrix and on cell surfaces.

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; and CD31 (PECAM-1) in transmigration.


2.6

The multistep process of leukocyte migration through blood vessels


Regulation of endothelial and leukocyte adhesion molecules

Redistribution of P-selectin Cytokine activation of endothelium

Increased binding avidity of integrins 2.7

Leukocyte Margination and Diapedesis

Neutrophil Pavementing (lining the venule)

Neutrophil Transendothelial Migration (Diapedesis)

Schematic and 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. The kinetics of edema and cellular infiltration are approximations. For sake of simplicity, edema is shown as an acute transient response, although secondary waves of delayed edema and neutrophil infiltration can also occur.


2.8

Schematic and histologic sequence of events following acute injury

Adhesion Molecules

Selectins, characterized by an extracellular N-terminal domain related to sugarbinding mammalian lectins, E-selectin (CD62E, endothelium), P-selectin (CD62P, endothelium and platelets), and L-selectin (CD62L, leukocytes)

immunoglobulin family molecules include two endothelial adhesion molecules: ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1), CD31. Both these molecules serve as ligands for integrins found on leukocytes

Integrins transmembrane heterodimeric glycoproteins expressed on many cell types, bind to ligands on endothelial cells, other leukocytes, and the extracellular matrix (CD11a/CD18 and CD11b/CD18

Mucin-like glycoproteins, such as heparan sulfate, serve as ligands for the leukocyte adhesion molecule called CD44. These glycoproteins are found in the extracellular matrix and on cell surfaces.

The multistep process of leukocyte migration through blood vessels, shown here for neutrophils. 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; and CD31 (PECAM-1) in transmigration.


2.6

The multistep process of leukocyte migration through blood vessels

Cinetica di espressione di molecole adesive da parte di cellule endoteliali attivate con citochine infiammatorie

Dal volume: Pontieri “Patologia Generale” Piccin Nuova Libraria S.p.A.

Leukocyte activation •  Microbes, products of necrotic cells, antigen-antibody

complexes, and cytokines, including chemotactic factors, induce a number of responses in leukocytes that are part of the defensive functions of the l eukocy tes (neu t roph i l s and monocy tes /macrophages) and are referred to under the rubric of leukocyte activation

•  Activation results from several signaling that are triggered in leukocytes, resulting in increases in cytosolic Ca2+ and activation of enzymes such as protein kinase C and phospholipase A2.

The functional responses that are induced on leukocyte activation include the following:

•  Production of arachidonic acid metabolites from phospholipids, as a result

of activation of phospholipase A2 by increased intracellular calcium and other signals.

•  Degranulation and secretion of lysosomal enzymes and activation of the oxidative burst.

•  Secretion of cytokines, which amplify and regulate inflammatory reactions. Activated macrophages are the chief source of the cytokines that are involved in inflammation, but mast cells and other leukocytes may contribute.

•  Modulation of leukocyte adhesion molecules. Different cytokines cause increased endothelial expression of adhesion molecules and increased avidity of leukocyte integrins, allowing firm adhesion of activated neutrophils to endothelium.

Leukocytes express a number of surface receptors that are involved in their activation

•  Toll-like receptors (TLRs),

•  Different seven-transmembrane G-protein-coupled receptors

•  Receptors for cytokines

•  Receptors for opsonin: FcγRI (antibodies IgG), type 1 complement receptor, CR1 (complement proteins, C3b), C1q receptor (mannose-binding lectin MBL, fibronectin, fibrinogen, and C-reactive protein)

Different classes of cell surface receptors of leukocytes recognize different stimuli. The receptors initiate responses that mediate the functions of the leukocytes.


2.10

Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation


Chemical mediators of inflammation


2-12

AMINE VASOATTIVE

ISTAMINA SEROTONINA

A flat spread of omentum showing mast cells around blood vessels and in the interstitial tissue. Stained with metachromatic stain to identify the mast cell granules (dark blue or purple). The red structures are fat globules stained with fat stain. (Courtesy of Dr. G. Majno, University of Massachusetts Medical School, Worcester, MA.)


2.13

Istamina principal mediator of the immediate transient phase of increased

vascular permeability, causing venular gaps •  Histamine is widely distributed in tissues, the

richest source being the mast cells that are normally present in the connective tissue adjacent to blood vessels

•  It is also found in blood basophils and platelets.

•  Preformed histamine is present in mast cell granules and is released by mast cell degranulation in response to a variety of stimuli:

–  (1) physical injury such as trauma, cold, or heat;

–  (2) immune reactions involving binding of antibodies to mast cells;

–  (3 ) f ragments o f complement ca l led anaphylatoxins (C3a and C5a);

–  (4) histamine-releasing proteins derived from leukocytes;

–  (5) neuropeptides (e.g., substance P); and –  (6) cytokines (IL-1, IL-8).

•  histamine causes dilation of the arterioles and increases the permeability of venules (it, however, constricts large arteries)


2.13

Serotonina •  Preformed vasoactive mediator with actions similar to

those of histamine.

•  Present in platelets and enterochromaffin cells, and in mast cells in rodents but not humans.

•  Release of serotonin (and histamine) from platelets is stimulated when platelets aggregate after contact with collagen, thrombin, adenosine diphosphate (ADP), and antigen-antibody complexes.

•  Platelet aggregation and release are also stimulated by Platelet Activating Factors (PAF) derived from mast cells during IgE-mediated reactions. In this way, the platelet release reaction results in increased permeability during immunologic reactions.

Platelet Activating Factors (PAF) Fattore attivante piastrine

• A variety of cell types, including platelets, basophils (and mast cells), neutrophils, monocytes/macrophages, and endothelial cells, can elaborate PAF, in both secreted and cell-bound forms

• PAF causes platelet aggregation, but it is now known to have multiple inflammatory effects

• P A F c a u s e s v a s o c o n s t r i c t i o n a n d bronchoconstriction, and at extremely low concentrations it induces vasodilation and increased venular permeability with a potency 100 to 10,000 times greater than that of histamine.

• PAF also causes increased leukocyte adhesion to endothelium (by enhancing integrin-mediated leukocyte binding), chemotaxis, degranulation, and the oxidative burst

PROTEINE PLASMATICHE

Sistema del Complemento Sistema delle chinine

Sistema della coagulazione

Complemento •  Increased vascular permeability,

chemotaxis, and opsonization.

•  Complement proteins are present as INACTIVE forms in plasma and are numbered C1 through C9

•  Many of these proteins are activated to become proteolytic enzymes that degrade other complement proteins

•  The critical step is the activation of the third and most abundant component, C3.

•  Cleavage of C3 can occur by one of three pathways: –  the classical pathway, –  the alternative pathway, –  the lectin pathway.

Complement has a central role in inflammation causing chemotaxis of phagocytes, activation of mast cells and phagocytes, opsonization and lysis of pathogens, and

clearance of immune complexes.


Each of the activation pathways generates a C3 convertase, which converts C3 to C3b, the central event of the complement pathway.

C3b in turn activates the terminal lytic membrane attack pathway.


The first stage in the classical pathway is the binding of antigen to antibody.

The alternative pathway does not require antibody and is initiated by the covalent binding of C3b to hydroxyl and amine groups on the surface of various microorganisms

The lectin pathway is also triggered by microorganisms in the absence of antibody, with sugar residues on the pathogen surface providing the binding sites.

The alternative and lectin pathways provide non-specific 'innate' immunity, whereas the classical pathway represents a more recently evolved link to the adaptive immune system.

Complemento

lectin pathway

in which plasma mannose-binding lectin binds to carbohydrates on microbes and directly activates C1

alternative pathway which can be triggered by microbial surface molecules (e.g., endotoxin, or LPS), complex

polysaccharides, cobra venom, and other substances, in the absence of antibody

classical pathway

which is triggered by fixation of C1 to antibody (IgM or IgG) combined with antigen

Il risultato è sempre l’attivazione della C3 convertasi che cliva il C3 in C3a e C3b

Complemento

Il risultato è sempre l’attivazione della C3 convertasi che cliva il C3 in C3a e C3b

C5 convertasi


2.14

The biologic functions of the complement system fall into two general categories: 1.  cell lysis by the MAC, and

2.  the effects of proteolytic fragments of complement. Complement-derived factors mediate a variety of phenomena in acute inflammation:

Leukocyte adhesion, chemotaxis, and activation. C5a is a powerful chemotactic agent for neutrophils, monocytes, eosinophils, and basophils.

Vascular phenomena. C3a, C5a, and, to a lesser extent, C4a are split products of the corresponding complement components that stimulate histamine release from mast cells and thereby increase vascular permeability and cause vasodilation. They are called anaphylatoxins because they have effects similar to those of mast cell mediators that are involved in the reaction called anaphylaxis. C5a also activates the lipoxygenase pathway of arachidonic acid (AA) metabolism in neutrophils and monocytes, causing further release of inflammatory mediators.

Anafilotossine C3a, C5a (e C4a)

•  Vascular phenomena. C3a, C5a, and, to a lesser extent, C4a are split products of the corresponding complement components that stimulate histamine release from mast cells and thereby increase vascular permeability and cause vasodilation.

•  They are called anaphylatoxins because they have effects similar to those of mast cell mediators that are involved in the reaction called anaphylaxis.

•  C5a also activates the lipoxygenase pathway of arachidonic acid (AA) metabolism in neutrophils and monocytes, causing further release of inflammatory mediators.

•  C3 e C5 possono essere attivati da diversi enzimi proteolitici presenti nell’essudato infiammatorio: plasmina ed enzimi lisosomiali rilasciati dai neutrofili.

Ruolo multiplo del fattore di Hageman (XIIa) attivato dal contatto con una superficie caricata negativamente

Note that thrombin induces inflammation by binding to protease-activated receptors (principally PAR-1) on platelets, endothelium, smooth muscle cells, and other cells.


Aumenta la permeabilità vascolare Contrazione del muscolo liscio, Dilatazione dei vasi sanguigni Dolore

Chininogeno ad alto peso molecolare

Legame a diversi recettori Che stimolano infiammazione: Mobilizzazione di selectina P Produzione di chemochine Espressione di molecole di adesione endoteliali per le integrine leucocitarie Produzione prostaglandine Produzione di PAF Produzione di NO

Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor).

CITOCHINE E CHEMOCHINE

Fattore di necrosi tumorale, TNF-alfa Interleuchina-1, IL-1

2-18 Major effects of interleukin-1 (IL-1) and tumor necrosis factor (TNF) in inflammation.


Macrophage ingests and degrades bacteria and is activated

to secrete monokines

Activates vascular endothelium

Activates lymphocytes Local tissue destruction

increased access of effector cells

Chemotactic factor for leukocytes

increases access of effector cells

Activates binding by β2 integrins

Activates vascular endothelium and increases vascular permeability which leads to increased entry of IgG complement and cells and increased fluid drainage to lymph nodes

Lymphocyte activation increased

antibody production Activates NK cells

induces the differentiation of CD4 T cells into

TH1 cells

Fever Production of IL-6

Local effects

Systemic effects Fver

Mobilisation of metabolites Shock

Fever Induces acute phase

protein production

IL-1 IL-8 TNF-α IL-6 IL-12

Macrophage Pro-inflammatory Mediators

Cytokines from activated macrophages coordinate the body’s response to infection.

FEVER

What are acute phase proteins?

The acute phase response increases the supply of recognition molecules of innate immunity.

Acute-phase proteins (CRP and MBP) produced by the liver can each bind structural features of bacterial cells. Upon binding they act as opsonins and also activate complement (lysis – dotted bacterial margin).

CRP MBP

(found as far back as invertebrates)

Encapsulated bacteria are more efficiently engulfed by phagocytosis when the bacteria are coated with antibody, C3b, CRP or MBP.

Cytokines from activated macrophages coordinate the body’s response to infection.

FEVER

Has fever any benefits?

FEVER IL-1, IL-6 and TNFα (endogenous pyrogens) released by macrophages act on the hypothalamus and on muscle and fat cells to raise body temperature (induce fever). Fever helps the immune system fight infection because: 1.  Most bacterial and viral pathogens grow better at temperatures

lower than human body temperature (37oC). 2. Human cells become more resistant to the deleterious effects of

TNFα at raised temperatures. 3. Adaptive immunity becomes more potent at higher temperatures

(antigen processing is enhanced). How else do macrophages promote T lymphocytes in the inflamed region?

Macrophage cytokines influencing T cells: IL-1 A general activator of all T cells IL-6 T cell growth and differentiation IL-12 Preferentially activates TH1 cells TH1 cytokines released in response to macrophage (MØ) cytokines: Interferon-γ (IFN- γ) expression of MHC on MØs and other local cells MØ antigen processing induces MØ maturation NK cell activity inhibits TH2 cells causes antiviral effects Tumour necrosis factor (TNF) several roles in inflammation but high local levels can cause tissue destruction and has potent systemic effect of causing weight loss.

Th1 cell cytokine effects on MØs

2-19 Functions of nitric oxide (NO) in blood vessels and macrophages, produced by two NO synthase enzymes. NO causes vasodilation, and NO free radicals are toxic to microbial and mammalian cells. NOS, nitric oxide synthase.


NITRIC OXIDE (NO) factor released from endothelial cells that caused vasodilation by relaxing vascular smooth muscle and was therefore called

endothelium-derived relaxing factor Sintetizzatp dalla ossido nitrico sintetasi (NOS) a partire da L-arginina

NO induce vasodilatazione agendo sulla muscolatura liscia, Riduce l’aggregazione e l’adesione delle cellula inibendo alcune caratteristiche dell’infiammazione e risultando per questo un regolatore endogeno del reclutamento leucocitario.

Effetti locali e sistemici delle citochine infiammatorie

Figure 2-20 Ultrastructure and contents of neutrophil granules, stained for peroxidase activity. The large peroxidase-containing granules are the azurophil granules; the smaller peroxidase-negative ones are the

specific granules (SG). N, portion of nucleus; BPI, bactericidal permeability increasing protein.


Metaboliti dell’acido arachidonico

Prostaglandine Leucotrieni Lipossine

Metaboliti dell’acido arachidonico

•  Acido grasso poli-insaturo derivante da fonti alimentari o per conversione dell’acido linoleico.

•  Non si trova libero nella cellula ma nei fosfolipidi di membrana informa esterificata.

•  Rilasciato attaverso l’azione di fosfolipasi (fosfolipasi A2) attivate da diversi stimoli di natura chimica, fisica meccanica o da mediatori come il C5a,

•  Avviene per attivazione della fosfolipasi A2 attivata a sua volta dall’aumento del calcio intracellulare e altri segnali

Metaboliti dell’acido arachidonico I metaboliti dell’AA (eicosanoidi) sono sintetizzati da due classi di enzimi: •  Ciclossigenasi prostaglandine e trombossani •  Lipossigenasi leucotrieni e lipossine

•  Gli eicosanoidi si legano a recettori accoppiati alle proteine G presenti su molti tipi cellulari e mediano “ogni” fase dell’infiammazione.

Trombossano A2, leucotrieni C4, D4, E4 VASOCOSTRIZIONE

Prostaglandine VASODILATAZIONE

leucotrieni C4, D4, E4 AUMENTO PERMEABILITA’ VASCOLARE

Leucotrine B4, HETE, lipossine CHEMIOTASSI E ADESIONE LEUCOCITARIA

METABOLITA AZIONE

2-16 Generation of arachidonic acid metabolites and their roles in inflammation. The molecular targets of action of some anti-inflammatory drugs are indicated by a red X. COX, cyclooxygenase; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid.


Figure 2-17 Biosynthesis of leukotrienes and lipoxins by cell-cell interaction. Activated neutrophils generate LTB4 from arachidonic acid-derived LTA4 by the action of 5-lipoxygenase, but they do not possess LTC4-synthase activity and consequently do not produce LTC4. In contrast, platelets cannot form LTC4 from endogenous substrates, but they can generate LTC4 and lipoxins from neutrophil-derived LTA4. (Courtesy of Dr. C. Serhan, Brigham and Women's Hospital, Boston, MA.)


(1) return to normal vascular permeability; (2) drainage of edema fluid and proteins into lymphatics or (3) by pinocytosis into macrophages; (4) phagocytosis of apoptotic neutrophils and (5) phagocytosis of necrotic debris; and (6) disposal of

macrophages. Macrophages also produce growth factors that initiate the subsequent process of repair. Note the central role of macrophages in resolution. (Modified from Haslett C, Henson PM: In Clark R, Henson PM (eds): The Molecular and

Cellular Biology of Wound Repair. New York, Plenum Press, 1996.) Downloaded from: StudentConsult (on 15 November 2009 11:35 AM)

© 2005 Elsevier

Events in the resolution of inflammation

figura 13.1 - glifo egizio che indicherebbe infiammazione...

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