ACUTE INFLAMMATION

&
SYSTEMIC INFLAMMATORY
RESPONSE SYNDROME
Jeppri
Priandana
Nivedita
Yurnita

OVERVIEW OF
INFLAMMATION
INFLAMMATION
Protective response intended to eliminate
the initial cause of cell injury as well as the
necrotic cells and tissues resulting from the
original insult.
to heal and reconstitute the damaged
tissue.
Main components :
Vascular Reaction and Cellular Response
(activated by mediators that are derived from plasma
proteins and various cells)

OVERVIEW OF
INFLAMMATION
Cardinal signs : heat (calor), redness
(rubor), and swelling (tumor) due to
the vascular changes and cell recruitment.
Pain (dolor) and loss of function (functio
laesa) consequences of mediator
elaboration and leukocyte-mediated
damage.
Several types of cells and molecules
play important 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

responses and their principal functions

OVERVIEW OF
INFLAMMATION
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

Acute Inflammation
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 exudation and a
predominantly neutrophilic
leukocyte accumulation

Major Components in Acute

Inflammation
1) Alterations in vascular caliber (Vasodilation)

causing erythema and warmth

2) Extravasation and deposition of plasma fluid and
proteins (edema) (Increased vascular
permeability)
3) Emigration of the leukocytes from the
microcirculation and their accumulation in the focus
of injury (Cellular recruitment and activation).

Vasodilatation
Transient arteriolar
vasoconstriction followed 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
filtrate of plasma) into interstitium.

Vascular Leakage
Vascular Permeability Increase
Allows the movement of proteinrich 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)

Mechanisms Causing Vascular

Leakiness
Histamines, bradykinins,
leukotrienes cause an early, brief (15
30 min.), immediate transient
response in the form of endothelial
cell contraction that leads to
intercellular gaps in postcapillary
venules
Cytokine mediators (TNF, IL-1)
induce endothelial 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 endothelial
cell damage (necrosis, detachment)
making them leaky until they are repaired
(immediate sustained response), or may
cause delayed damage as in thermal or
UV injury.
Accumulation of activated leukocytes
along the vessel wall may pile-up and
damage the endothelium through
activation and release of toxic oxygen
radicals and proteolytic enzymes
(leukocyte-dependent endothelial cell
injury) making the vessel 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

Cellular Recruitment and

Activation
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,
transiently sticking along the way
Adhesions
Leukocytes firm adhesion to endothelial
surfaces, mediated by integrins (transmembrane
heterodimeric glycoproteins, function as cell
receptors for ECM)
Transmigration
leukocytes migrate through the vessel wall
primarily by squeezing between cells at
intercellular junctions (diapedesis)

THE COMPLEX PROCESS OF LEUKOCYTE

MIGRATION

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

Leukocyte Activation

PHAGOCYTOSIS
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 material

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 (FcRI),
complement receptors 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
o
o
o

Oxygen consumption
Glycogenolysis
Glucose oxidation
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 myeloperoxidase (MPO)
MPO converts H2O2 to HOCl
(hypochlorous radical).
Powerful oxidant and
antimicrobial agent
After Oxygen burst, H2O2 broken
down to water and O2 by catalase
Dead microorganisms degraded
by lysosomal acid hydrolases

PHAGOCYTOSIS OF A PARTICLE (eg. bacteria)

Leukocyte-induced
tissue injury

Destructive enzymes may enter

extracellular space in event of:
regurgitation during
feeding/premature degranulation
Frustrated phagocytosis (large,
flat)
Membranolytic substances (urate
crystals)
Persistent leukocyte activation

CHEMICAL MEDIATORS OF
INFLAMMATION

AA METABOLITES AND THEIR ROLES IN

INFLAMMATION

More Specific Mediators

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, activation 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
degranulation

Kinin & Clotting Cascade

Complement System
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)

Complement System

Outcomes of Acute
Inflammation

Systemic Inflammatory
Response
Syndrome
(SIRS)

SEPSIS and Its Disease

spectrum
Various stages of disease

Bacteremia
SIRS
Sepsis syndrome
Sepsis shock : early and refractory

Definition
Infection

Presence of microorganisms in a normally

sterile site.

Bacteremia

Cultivatable bacteria in the blood stream.

Sepsis

The systemic response to infection.

If associated with proven or
clinically suspected infection, SIRS is
called sepsis.

American College of Chest Physicians/Society of Critical Care Medicine Consensus

Conference Committee. Crit Care Med. 1992;20:864-874.

SIRS
(Systemic Inflammatory Response
Syndrome)
The systemic response to a wide range of stresses.
Temperature >38C (100.4) or <36C (96.8F).
Heart rate >90 beats/min.
Respiratory rate >20 breaths/min or
PaCO2 <32 mmHg.
White blood cells > 12,000 cells/ml or < 4,000
cells/ml or >10% immature (band) forms.
Note
Two or more of the following must be present.
These changes should be represent acute alterations
from baseline in the absence of other known cause for
the abnormalities.
American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference Committee. Crit Care Med. 1992;20:864-874.

Severe Sepsis
Sepsis with organ hypoperfusion
one of the followings :
SBP < 90 mmHg
Acute mental status change
PaO2 < 60 mmHg on RA (PaO2 /FiO2 < 250)
Increased lactic acid/acidosis
Oliguria
DIC or Platelet < 80,000 /mm3
Liver enzymes > 2 x normal
American College of Chest Physicians/Society of Critical Care Medicine Consensus
Conference Committee. Crit Care Med. 1992;20:864-874.

MODS
(Multiple Organ Dysfunction Syndrome)
Sepsis with multiorgan hypoperfusion
Two or more of the followings:
SBP < 90 mmHg
Acute mental status change
PaO2 < 60 mmHg on RA (PaO2 /FiO2 < 250)
Increased lactic acid/acidosis
Oliguria
DIC or Platelet < 80,000 /mm3
Liver enzymes > 2 x normal

American College of Chest Physicians/Society of Critical Care Medicine Consensus

Conference Committee. Crit Care Med. 1992;20:864-874.

Relationship between SIRS

and Sepsis

Bone RC et al, Chest1992;101:164-55.

The Sepsis Continuum

SIRS

A clinical response arising

from a nonspecific insult,
with 2 of the following:
T >38oC or <36oC
HR >90 beats/min
RR >20/min
WBC >12,000/mm3 or
<4,000/mm3 or >10%
bands

Sepsis

SIRS with a
presumed
or confirmed
infectious
process

Severe
Sepsis

Septic
Shock

Sepsis with
organ failure

Refractory
hypotension

SIRS = systemic inflammatory

response syndrome
Chest 1992;101:1644.

Mortality rate in SIRS

Rangel-Frausto, et al. JAMA 273:117-123, 1995.

Normal Systemic Response

to Infection and Injury (1)
Leukocytosis
circulation
Tachycardia
to
Fever

Mobilizes neutrophils into the

Increases cardiac output, blood flow

injuried tissue
Raises core temperature; peripheral
vasoconstriction shunts
blood flow to
injuried
tissue. Occurs much more often
when infection is the trigger for systemic
responses

Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

Normal Systemic Response

to Infection and Injury (2)
Acute-Phase Responses
Anti-infective
Increases synthesis of complement factors,
microbe pattern-recognition molecules(mannosebinding lectin, LBP, CRP, CD14, Others)
Sequesters iron (lactoferrin) and zinc
(metallothionein)

Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

Normal Systemic Response

to Infection and Injury (3)
Anti-inflammatory
Releases anti-inflammatory neuroendocrine
hormones (cortisol, ACTH, epinephrine, -MSH)
Increases synthesis of proteins that help
prevent inflammation within the systemic
compartment
Cytokine antagonists (IL-1Ra, sTNF-Rs)
Anti-inflammatory mediators (e.g.,IL-4, IL-6, IL6R, IL-10, IL-13, TGF-)
Protease inhibitors (e.g.,1-antiprotease)
Antioxidants (haptoglobin)
Reprograms circulating leukocytes (epinephrine,
cortisol, PGE2, ?other)
Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

Normal Systemic
Response to Infection
and
Injury
(4)
Procoagulant

Walls off infection, prevents systemic spread

Increases synthesis or release of fibrinogen, PAI-1, C4b
Decreases synthesis of protein C, anti-thrombin III
Metabolic
Preserves euglycemia, mobilizes fatty acids, amino
acids
Epinephrine, cortisol, glucagon, cytokines
Thermoregulatory
Inhibits microbial growth
Fever

Mandell et al. Principals and Practice of Infectious Diseases6th ed;906:906-926.

Risk factors of sepsis

aggressive oncological chemotherapy and radiation therapy
use of corticosteroid and immunosuppressive therapies for
organ transplants and inflammatory diseases
longer lives of patients predisposed to sepsis, the elderly, diabetics,
cancer patients, patients with major organ failure, and with granulocyop
enia.
Neonates are more likely to develop sepsis (ex. group B
Streptococcal infections).
increased use of invasive devices such as surgical protheses, inhalation
equipment, and intravenous and urinary catheters.
indiscriminate use of antimicrobial drugs that create
conditions of overgrowth, colonization, and subsequent
infection by aggressive, antimicrobial-resistant organisms.

Angus DC, et al. Crit Care Med 2001, 29:1303-1310.