INFIAMMAZIONE
Dr C. Montesano
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 (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
(rossore)
Tumor
(gonfiore)
Calor
(calore)
Quattro segni chiave
(noti già a Greci e Romani)
Dolor
(dolore)
INFIAMMAZIONE: generalità
•
L'infiammazione è una reazione complessa ad agenti nocivi, come i microbi e cellule danneggiate, di solito
necrotiche. Si compone di molteplici meccanismi di risposta: vascolare, migrazione e attivazione dei
leucociti, e di reazioni sistemiche
•
La caratteristica unica del processo infiammatorio è la reazione dei vasi sanguigni, provocando l'accumulo
di liquidi e leucociti nei tessuti extra-vascolare.
•
La risposta infiammatoria è strettamente connessa con il processo di riparazione.
•
L'infiammazione è fondamentalmente una risposta protettiva, il cui fine ultimo è quello di liberare
l'organismo dalla causa iniziale di danno cellulare (per esempio, i microbi, tossine) e dalle conseguenze di
tale danno (ad esempio, cellule e tessuti necrotici). Senza infiammazione, le infezioni sarebbero non
controllate, le ferite non guarirebbero.
•
Comunque, l'infiammazione e la riparazione possono essere potenzialmente dannosi: Reazioni
infiammatorie, per esempio, sono alla base di comuni malattie croniche, come l'artrite reumatoide,
l'arteriosclerosi, e la fibrosi polmonare, così come le reazioni di ipersensibilità a punture di insetti, droghe e
tossine. Riparazione che comportano fibrosi possono portare a cicatrici deturpanti o formazioni di bande
fibrose che causano ostruzione intestinale o di limitare la mobilità delle articolazioni
•
The inflammatory response consists of two main components, a vascular reaction and a cellular reaction.
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)
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
Difetti funzionali dei leucociti
• Difetti di adesione dei leucociti.
• Difetti in funzione phagolysosome
• Difetti di attività microbicida
Estinzione della risposta
infiammatoria acuta
ACUTE INFLAMMATION: STIMULI
Acute inflammatory reactions are triggered by a variety of
stimuli:
• 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)
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
exudation of fluid and plasma proteins (edema) 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.
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
circulating cells include neutrophils,
lymphocytes, basophils, and “platelets”.
• The
monocytes,
eosinophils,
• The connective tissue cells are the mast cells, which intimately surround
blood vessels; the connective tissue 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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Consequences of Defective or Excessive Inflammation
•
Defective inflammation typically results in increased susceptibility to infections 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 selfantigens, 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.
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
3
3. migrazione dei leucociti e
accumulo nel sito del “danno”
1.1 dilatazione vascolare ed
aumento
del
flusso
sanguigno
(che
causa
rossore e calore)
3
2
2
2.
Extravasazione
e
deposizione di fluido e
proteine
plasmatiche
(edema)
1
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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 rates
depending on the severity of the injury. The changes occur in the following order:
•
Vasodilation is one of the earliest manifestations of acute inflammation; sometimes, it follows
a transient constriction of arterioles, lasting a few seconds. 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. Vasodilation is induced
by the action of several mediators, notably histamine and nitric oxide, on vascular smooth
muscle.
•
Vasodilation is quickly followed by increased permeability of the microvasculature, with the
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, reflected by the presence of dilated small vessels packed with red cells and
slower blood flow, a condition termed stasis.
•
As stasis develops, 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, in processes that are described later.
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
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.
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.
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.
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2-4 Diagrammatic representation of five mechanisms of increased vascular permeability in inflammation
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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.)
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Perdita di liquidi nell’infiammazione acuta:
riassumendo
• 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.
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
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 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
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; and CD31 (PECAM-1) in transmigration.
2.6
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Leukocyte Margination and Diapedesis
Neutrophil Pavementing (lining the venule)
2.9
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
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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
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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.
Regulation of
endothelial and leukocyte adhesion molecules
Redistribution of P-selectin
2.7
Cytokine activation of endothelium
Increased binding avidity of integrins
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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
leukocytes (neutrophils and monocytes/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 (discussed below under phagocytosis).
• 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
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Outcomes of acute inflammation:
resolution, healing by fibrosis, or chronic inflammation
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Chemical mediators of inflammation
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AMINE VASOATTIVE
ISTAMINA
SEROTONINA
Istamina
principal mediator of the immediate transient phase of increased vascular
permeability, causing venular gaps
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.)
•
Histamine is widely distributed in tissues, the
•
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:
•
richest source being the mast cells that are
normally present in the connective tissue
adjacent to blood vessels
–
(1) physical injury such as trauma, cold, or heat;
–
(2) immune reactions
antibodies to mast cells;
–
(3) fragments of complement called anaphylatoxins
(C3a and C5a);
–
(4) histamine-releasing
leukocytes;
–
(5) neuropeptides (e.g., substance P); and
–
(6) cytokines (IL-1, IL-8).
involving
proteins
binding
derived
of
from
histamine causes dilation of the arterioles and
increases the permeability of venules (it,
however, constricts large arteries)
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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.
2.13
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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
•PAF
causes
vasoconstriction
and
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.
Complemento
classical pathway
which is triggered by fixation of C1 to antibody (IgM or IgG) combined with antigen
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
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
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.
2.14
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.
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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
Chininogeno ad alto
peso molecolare
Aumenta la permeabilità vascolare
Contrazione del muscolo liscio,
Dilatazione dei vasi sanguigni
Dolore
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
2-15 Interrelationships between the four plasma mediator systems triggered by activation of factor XII (Hageman factor). Note that thrombin induces
inflammation by binding to protease-activated receptors (principally PAR-1) on platelets, endothelium, smooth muscle cells, and other cells.
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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.
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Macrophage Pro-inflammatory Mediators
Macrophage ingests and degrades
bacteria and is activated
to secrete monokines
IL-1
IL-8
TNF-a
IL-6
IL-12
Local effects
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 b2 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
Systemic effects
Fever
Production of IL-6
Fver
Mobilisation of metabolites
Shock
Fever
Induces acute phase
protein production
Activates NK cells
induces the
differentiation of
CD4 T cells into
TH1 cells
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
(found as far back as invertebrates)
MBP
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
NITRIC OXIDE (NO)
factor released from endothelial cells that caused vasodilation by relaxing vascular smooth muscle and was therefore called
endothelium-derived relaxing factor
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.
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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.
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Metaboliti dell’acido
arachidonico
Prostaglandine
Leucotrieni
Lipossine
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.
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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.)
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Figure 2-22 Events in the resolution of inflammation: (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.)
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Figure 2-27 Maturation of mononuclear phagocytes. (From Abbas AK, et al: Cellular and Molecular Immunology, 5th ed. Philadelphia, Saunders, 2003.)
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Figure 2-28 The roles of activated macrophages in chronic inflammation. Macrophages are activated by
cytokines from immune-activated T cells (particularly IFN-γ) or by nonimmunologic stimuli such as
endotoxin. The products made by activated macrophages that cause tissue injury and fibrosis are
indicated. AA, arachidonic acid; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor;
TGFβ, transforming growth factor β.
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Figure 2-29 A, Chronic inflammation in the lung, showing all three characteristic histologic
features: (1) collection of chronic inflammatory cells (*), (2) destruction of parenchyma
(normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3)
replacement by connective tissue (fibrosis, arrows). B, By contrast, in acute inflammation of
the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels
are congested.
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Figure 2-30 Mechanisms of macrophage accumulation in tissues. The most important is continued recruitment from the microcirculation. (Adapted from Ryan G, Majno G: Inflammation.
Kalamazoo, MI, Upjohn, 1977.)
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Figure 2-31 Macrophage-lymphocyte interactions in chronic inflammation. Activated lymphocytes and macrophages influence each other and also release inflammatory mediators that
affect other cells.
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Figure 2-32 A focus of inflammation showing numerous eosinophils.
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Figure 2-33 Typical tuberculous granuloma showing an area of central necrosis, epithelioid
cells, multiple Langhans-type giant cells, and lymphocytes.
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