Kelompok 4

 Identification of microorganisms in host + In-

flammatory response  Infection
 Systemic inflammatory manifestations +
absence of infection  SIRS
 SIRS + Infection  SEPSIS
 Sepsis + Organ disfunction  Severe Sepsis
 Cardinal signs : heat (calor), redness (rubor), and
swelling (tumor)  due to the vascular changes
and cell recruitment. Pain (dolor) and loss of func-
tion (functio laesa)  consequences of mediator
elaboration and leukocyte-mediated damage.
 Several types of cells and molecules play impor-
tant roles in inflammation.
Blood leukocytes and plasma proteins,
Cells of vascular walls
Cells and (ECM) of the surrounding connective tissue
The components of acute and chronic inflammatory re-
sponses and their principal functions
 Steps of the Inflammatory Response
(1) Recognition of the injurious agent
(2) Recruitment of leukocytes
(3) Removal of the agent
(4) Regulation (control) of the response
(5) Resolution (repair)

 Can be Acute or Chronic

 Rapid in onset and of short duration
 Lasting from a few minutes to as long as a few
days
 Characterized by fluid and plasma protein exu-
dation and a predominantly neutrophilic leuko-
cyte accumulation
1) Alterations in vascular caliber → (Vasodilation) caus-
ing erythema and warmth
2) Extravasation and deposition of plasma fluid and pro-
teins (edema) (Increased vascular permeability)
3) Emigration of the leukocytes from the microcircula-
tion and their accumulation in the focus of injury
(Cellular recruitment and activation).
 Transient arteriolar vasoconstriction fol-
lowed by vasodilation
 Induced by mediators (eg. Histamines)
 Warmth and redness at the inflammatory
site
 Opens microvascular beds
 Increased intravascular hydrostatic pressure
causes an early transudate (protein-poor fil-
trate of plasma) into interstitium.
 Vascular Permeability Increase
• Allows the movement of protein-rich fluid
and even cells (exudate) into the interstitium
• The loss of protein-rich fluid into the
perivascular space reduces the intravascular
osmotic pressure and increases the osmotic
pressure of the interstitial fluid  Edema
(water and ions)
• Histamines, bradykinins, leukotrienes cause an
early, brief (15 – 30 min.), immediate transient re-
sponse in the form of endothelial cell contraction
that leads to intercellular gaps in postcapillary
venules
• Cytokine mediators (TNF, IL-1) induce endothe-
lial cell junction retraction through cytoskeleton
reorganization (4 – 6 hrs post injury, lasting 24 hrs
or more)
• Endothelial injury results in vascular leakage by
causing endothelial cell necrosis and detachment.
Severe injuries may cause immediate direct en-
dothelial cell damage (necrosis, detachment) mak-
ing them leaky until they are repaired (immediate
sustained response), or may cause delayed dam-
age as in thermal or UV injury.
• Accumulation of activated leukocytes along the
vessel wall may pile-up and damage the endothe-
lium through activation and release of toxic oxy-
gen radicals and proteolytic enzymes (leukocyte-
dependent endothelial cell injury) making the ves-
sel leaky.
• Certain mediators (VEGF) may cause increased
transcytosis of proteins via intracellular vesicles
which lead to venular permeability.

Although these mechanisms are separable,

all of them may participate in the response
to a particular stimulus
 Leukocytes leave the vasculature routinely
through the following sequence of events:
 Margination and rolling
 Adhesion and transmigration
 Chemotaxis and activation
 They are then free to participate in:
 Phagocytosis and degranulation
 Leukocyte-induced tissue injury
Margination
 Leukocyte accumulation at the periphery of vessels
Rolling
 Leukocytes tumble on the endothelial surface, tran-
siently sticking along the way
Adhesions
 Leukocytes firm adhesion to endothelial surfaces, me-
diated by integrins (transmembrane heterodimeric gly-
coproteins, function as cell receptors for ECM)
Transmigration
 leukocytes migrate through the vessel wall primarily
by squeezing between cells at intercellular junctions
(diapedesis)
Chemotaxis
 Leukocytes follow chemical gradient (chemotactic
substances) to site of injury
 Bacterial products
 Complement components (C5a)
 Cytokines (chemokine family e.g., IL-8)
 LTB4 (AA metabolite)
Produced in response to infections and tissue damage
and during immunologic reactions

Leukocyte Activation
 Stimuli for activation include microbes, products of
necrotic cells, and several mediators
 Consists of three distinct but interrelated
steps :
1. Recognition and Attachment of the particle to
the ingesting leukocyte
2. Engulfment, with subsequent formation of a
phagocytic vacuole
3. Killing and degradation of the ingested mate-
rial
Recognition and Attachment
Opsonins
 Specific surface receptors, which recognize either components
of the microbes and dead cells, or host proteins
 Coat microbes and target them for phagocytosis (opsonization)
 examples : antibodies of the IgG, breakdown products of the
complement protein C3, and collectins.
 Corresponding receptors : Fc receptor (FcγRI), complement re-
ceptors 1 and 3 (CR1 and 3), and C1q.

Engulfment
 Pseudopods are extended, forming a phagocytic vacuole.
Fusion of vacuole membrane with the membrane of a lysosomal
granule phagolysosome.
Killing and Degradation
 Production of microbicidal substances
(ROS & Lysosomal Enzymes)
 Stimulates an oxidative burst :
o Oxygen consumption
o Glycogenolysis
o Glucose oxidation
o Production of ROS
 phagocyte oxidase  oxidizes NADPH  converts
oxygen to superoxide ion  Superoxide converted 
hydrogen peroxide (O2 + 2H+  H2O2 ).
 Lysosomes of neutrophils (azurophilic
granules) contain enzyme myeloperoxi-
dase (MPO)  MPO converts H2O2 to
HOCl• (hypochlorous radical).  Power-
ful oxidant and antimicrobial agent
 After Oxygen burst, H2O2 broken down
to water and O2 by catalase
 Dead microorganisms degraded by lyso-
somal acid hydrolases
 Cytokines
• Protein cell products that act as a message to other cells,
telling them how to behave.
• Ex. IL-1, TNF- and -, IFN-
• Increase endothelial cell adhesion molecule expression, activa-
tion and aggregation of PMNs, etc.
 Nitric Oxide
• Short-acting soluble free-radical gas with many functions
• Produced by endothelial cells, macrophages, causes:
 Vascular smooth muscle relaxation and vasodilation
 Kills microbes in activated macrophages
 Counteracts platelet adhesion, aggregation, and degranula-
tion
 Components C1-C9 present in inactive form
• Activated via classic (C1) or alternative (C3) pathways to
generate MAC (C5 – C9) that punch holes in microbe
membranes
• In acute inflammation
 Vasodilation, vascular permeability, mast cell degranulation (C3a,
C5a)
 Leukocyte chemotaxin, increases integrin avidity (C5a)
 As an opsonin, increases phagocytosis (C3b, C3bi)
 Severe Septic
SIRS Sepsis Sepsis Shock

 A clinical response arising from

a nonspecific insult, with 2 of
the following: SIRS with a Sepsis with Refractory
 T >38oC or <36oC
presumed organ failure hypotension
 HR >90 beats/min
 RR >20/min or confirmed
 WBC >12,000/mm3 or infectious
<4,000/mm3 or >10% bands
process

SIRS = systemic inflammatory

response syndrome
Chest 1992;101:1644.
 In sepsis, the inflammatory response breaks
free from the anti-inflammatory checks and
becomes wide-spread, causing systemic dam-
age.
 Sepsis  Acute DIC with low platelets,
 Prolonged clotting times
 hypofibrinogenaemia  haemorrhagic and
thrombotic complications.
 Widespread microvascular thrombosis  due to impairment
of the anticoagulant systems (antithrombin III and thrombo-
modulin)
 Cytokine induction of the extrinsic coagulation systems 
exaggerates the deficiency in cellular oxygen delivery/utili-
sation.
 SEPSIS  ↓↓ Endogenous activated protein C, (which
promotes fibrinolysis and inhibits thrombosis and inflamma-
tion)
 Endothelial injury in the pulmonary vascula-
ture leads to disturbed capillary blood flow and
enhanced microvascular permeability
 Alveolar edema. The acute respiratory distress
syndrome is a frequent manifestation of these
effects.
 The circulatory abnormalities typical of sepsis
may depress the gut's normal barrier function,
allowing translocation of bacteria and endo-
toxin into the systemic circulation (possibly via
lymphatics, rather than the portal vein) and ex-
tending the septic response.
 Liver dysfunction can contribute to both the initiation
and progression of sepsis.
 Liver dysfunction can prevent the elimination of en-
teric-derived endotoxin and bacteria-derived products.
 The mechanisms to acute renal failure in Sepsis are
incompletely understood.
 Systemic hypotension, direct renal vasoconstriction,
release of cytokines such as tumor necrosis factor, and
activation of neutrophils by endotoxin and by FMLP,
a three amino acid (fMet-Leu-Phe) chemotactic pep-
tide in bacterial cell walls, all may contribute to renal
injury.
 Clinically, involvement of the central nervous
system in sepsis can produce an altered senso-
rium (encephalopathy) and a peripheral neu-
ropathy.
 The pathogenesis of the encephalopathy is
poorly defined.
 Impairment of vasomotor control
•  wide-spread vasodilatation and loss of reactivity to cate-
cholamines.
• Normal Condition
Endothelial cells  release NO  diffuses to the underlying
smooth muscle cells  NO activates guanylate cyclase  lead to
elevation of guanosine 3′,5′-cyclicmonophosphate (cGMP). 
triggers an intracellular cascade culminating in falls in free cal-
cium concentrations and muscle relaxation.
• During sepsis
NO prod. extensive systemic vasodilatation, which may be
detrimental to regional oxygen delivery  causing regional
blood flow mismatching.
 Cardiac dysfunction
• Sepsis  reduction in the rate of cardiac contraction and re-
laxation.
• hypodynamic phase of sepsis  ↓↓ voltage-gated
Ca2+channels (ryanodine receptor)in the sarcolemma re-
duces the rate of Ca2+release from the sarcoplasmic reticu-
lum,  ↓↓ interaction with the myocardial contractile pro-
teins during systole + decrease in the rate of reuptake  de-
lays the onset of relaxation and hence diastole.
• TNF-α and NO  can interfere Ca2+release via the ryan-
odine receptor.