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Acute Inflammation

WWAMI lecture
Nicole Meissner-Pearson
• provoked response to tissue injury
• chemical agents
• cold, heat
• trauma
• invasion of microbes
• serves to destroy, dilute or wall off the injurious agent

• induces repair

• protective response

• can be potentially harmful


Acute Chronic

Acute versus chronic inflammation are distinguished

by the duration and the type of infiltrating inflammatory cells
Cardinal signs of (acute)

• Rubor = redness
• Tumor = swelling
• Calor = heat
• Dolor = pain
(described by Celsus 1st. Century AD)

• Functio laesa = loss of function

(added by R. Virchow)

Cellulits = acute skin infection commonly

caused by Streptococcus pyogenes or
Staphylococcus aureus
The nomenclature used to describe
inflammation in different tissues employs
the tissue name and the suffix “-itis”
The inflammatory response consists of
a vascular and a cellular reaction

Intensive Care Med. (2004)

30: 1702-1714
Acute inflammation involves:
alteration of vascular caliber
following very brief
vasoconstriction (seconds),
vasodilation leads to increased
blood flow and blood pooling
creating redness and warmth (rubor
and calor)
changes of microvasculature
increased permeability for plasma
proteins and cells creating swelling
(tumor). Fluid loss leads to
concentration of red blood cells and
slowed blood flow (stasis)
emigration of leukocytes from
due to stasis and activation leads
migration towards offending agent
Vascular changes and fluid leakage during acute inflammation lead to
Edema in a process called Exudation

•result of hydrostatic
or osmotic imbalance
•ultrafiltrate of plasma
•Low protein content
•specific gravity < 1.015

•result of inflammation
•vascular permeability
•high protein content

•specific gravity >1.020

Increased vascular permeability and edema:
a hallmark of acute inflammation
• Leakage is restricted to venules of
20-60µ m in diameter
• caused by endothelial gaps
• usually an immediate and transient
response (30 min.)

• Gaps occur due to contraction of

e.g myosin and shortening of the
individual endothelia cell

• loss of protein from plasma leads to

• due to reduced osmotic pressure in the
• and increased osmotic pressure in the
• direct endothelial injury
causing necrotic cell death
will result in leakage from all
levels of microcirculation
(venules, capillaries and
• This reaction is
immediate and

• Delayed prolonged leakage

begins after 2-12 hours and
can last several days due to
thermal-, x-ray radiation or
ultraviolet radiation (sunburn)
and involves venules and

• Leakage from new blood

vessels during tissue repair
(angiogenesis) due to
immature endothelial layer

All these described mechanisms may occur in one

wound (e.g burns) and can be life threatening
Different morphological patterns of acute inflammation can be found
depending on the cause and extend of injury and site of inflammation

Serous inflammation Purulent inflammation

Fibrinous inflammation ulcers

A critical function of the vascular inflammatory response (stasis
and vascular permeability) is to deliver leukocytes to the site of
injury in order to clear injurious agents

Neutrophils are commonly the first inflammatory cells (first 6-24 hours) recruited to a
site of inflammation.
Extravasation of leukocytes is a coordinated event of:
transmigration (diapedesis)
In order for leukocytes to leave the vessel lumen, endothelial cells need to be
activated and upregulate adhesion molecules that can interact with
complementary adhesion molecules on leukocytes
Selectins Integrins

Up-regulation of adhesion molecules on endothelial cells is induced by

an array of inflammatory mediators such as TNF, IL-1, histamine and
others produced by tissue resident inflammatory cells.
Four families of adhesion molecules are involved in leukocyte migration
Integrins (α + β chain)
E-selectin (on endothelium)
Heterodimeric molecules
P-selectin (on endothelium &
platelets; is preformed and stored in VLA-4 (β 1 integrin) binds to
Weible Palade bodies) VCAM-1

L-selectin (leukocytes) LFA1 and MAC1

(CD11/CD18) = β 2 integrin
Ligands for E-and P-Selectins are bind to ICAM
sialylated glycoproteins (e.g
Sialylated Lewis X) Expressed on leukocytes

Ligands for L-Selectin are Glycan-

bearing molecules such as
Immunoglobulin family
GlyCam-1, CD34, MadCam-1
ICAM-1 (intercellular
adhesion molecule 1)
Mucin-like glycoproteins
VCAM-1 (vascular adhesion
Heparan sulfate (endothelium) molecule 1)
Ligands for CD44 on Are expressed on activated
leukocytes endothelium
Bind chemokines Ligands are integrins on
Specific targeting of adhesion molecules may be a
promising tool in drug development against some
chronic inflammatory diseases

• e.g Natalizumab, a monoclonal antibody to α 4 integrin

chain, blocks the binding of VLA-4 to VCAM-1 on brain-
infiltrating TH-1 cells and the binding of α 4β 7 integrin to
MadCAM on gut-infiltrating TH-1 cells and has been
successfully used in the treatment of MS and Crohn’s
( the drug was transiently taken off the market because of safety
concerns, but has recently been re-approved)

• Odulimomab and Efaluzimab are antibodies inhibiting

LFA-1 and have shown promising results in the treatment
of Psoriasis and Graft versus Host disease
Leukocytes follow towards the site of injury
in the tissue along a chemical gradient of
chemo-attractants in a process called
Exogenous and endogenous stimuli can act
as chemoattractants
Exogenous: bacterial product (e.g N-
formyl-methionyl peptides

Endogenous: anaphylatoxins (C5a),

leukotrienes (LTB4),
chemokines (e.g IL-8)

Most chemotactic agents signal via G-protein-coupled 7 transmembrane

receptors leading to the activation of phospholipase C resulting in
intracellular Ca2+ release and activation of small GTPases (Rac,Rho,
cdc42). This leads to actin/myosin polymerization and a morphological
response with directional filopodia formation
Wiskott-Aldrich Syndrome:
a defect in the morphological response and
trafficking defect of antigen presenting cells
Normal leukocytes responding to WAS patient leukocyte unable to
chemoattractant respond to chemoattractant

WAS – Syndrome
Recurrent infections Eczema Thrombocytopenia
While signaling of chemo-attractants induces a morphological
response and locomotion of neutrophils, pattern recognition
receptors or opsonin receptors induce neutrophil and macrophage
effector functions
Pattern recognition receptors recognize
Toll-like receptor endotoxins, CpG, dsRNA,
bacterial proteoglycans
Mannose receptor bacterial carbohydrates
Scavenger receptors lipids

Opsonin-receptors recognize
CR1 complement product C3b
Fcγ receptor IgG coated pathogens
C1q collectins
Neutrophil and macrophage effector functions
serve to eliminate pathogens and noxious

• Phagocytosis of pathogens and noxious


• Release of bactericidal and cytoxic

Neutrophils are highly motile cells that constitute
the first line of defense of the
innate immune system

Normal neutrophil Phagocytosing neutrophil

They are characterized by a high content of granules in their cytoplasm

which gave them the name granulocytes
Phagocytosis and its outcome involves
three distinct steps
• Recognition and attachment

• Engulfment and fusion of phagosome and


• Killing and degradation of ingested material

Neutrophils have oxidative and non-oxidative mechanisms of killing

NADPH oxidase system, a membrane bound enzyme complex, reduces O2 to

superoxide anion (02-), hydrogen peroxide (H2O2), and hydroxyl radical (OH) =
Oxidative burst
H2O-MPO-halide system is thought to be the most efficient bactericidal system (in
vitro!!) by catalyzing the formation of bleach (hypochlorous radical = HOCL.) from
H2O2 and Cl- which kills bacteria by halogenation or protein and lipid
Bacteriocidal and cell degrading enzyme contents of lysosomal granules
(azurophil- and specific granules) fuse with phagosome to form phago-lysosome
Oxidative burst and co-lateral damage


Oxidative burst
The NADPH oxidase system is only active when the cytosolic subunits are
assembled with the membrane bound subunits in response to leukocyte
Inflammatory products may be released into the extracellular space causing
tissue damage and additional disease.
Release occurs transiently during “engulfing” = regurgitation during feeding
If material is deposited on flat membranes and can not be removed (e.g immune
complexes on basement membrane) = frustrated phagocytosis
Ingestion of membranolytic material (urate crystals)
Immunodeficiency Diseases caused by deficiencies or
defects in phagocytes (neutrophils and macrophages)

Lack of neutrophil/macrophage numbers or defect of their

function can lead to live threatening infectious diseases,
particularly with bacterial and fungal pathogens

Clinically most common:

bone marrow suppression with decreased cell numbers
(leukopenia) due to tumor infiltrate or chemotherapy resulting in
myelosuppression (>500 neutrophils /µ l is considered very

However, inherited defects of adhesion, phago-lysosome- and

microbicidal functions have been found
Leukocyte adhesion deficiency 1 and 2

LAD 1 is a result of a lack of β 2 intergrin expression

due to defect of CD18 (LFA-1 and MAC-1). Interaction
with ICAM and VCAM on endothelium is impaired

LAD 2 results from a lack of sialyl LewisX (defect of

carbohydrate fucosylation). Interaction with endothelial
E-and P-selectins is impaired
Leukocyte adhesion deficiencies (LAD 1 and 2)
Neutrophils unable to aggregate
Leukocytes unable to leave the circulatory
Neutrophil counts are commonly twice
NEJM: Vol. 343: No 23, pp1703-1714

the normal level even without

an ongoing infection
Clinical findings:
History of delayed separation of umbilical cord
Severe peridontitis
Recurrent bacterial and fungal infections of oral
and genital mucosa (enteric bacteria, staph,
candida, aspergillus)
Infected foci contain few neutrophils (no pus) and
heal poorly
LAD 2 immunodeficiency is less severe, however the defect is associated with
growth retardation, dysmorphy and neurological deficits
Chronic granulomatous disease
(a defect of NADPH oxidase system and therefore inability to
undergo oxidative burst and production of hydrogen peroxide)

• CGD is a heterogeneous
disorder caused by defects
of any of the four subunits
of NADPH oxidase.

• 70% are due to X-linked

defect of gp91 phox (more
severe form)

• Second most due to

autosomal recessive
defect of p47 phox

NEJM: Vol. 343: No 23, pp1703-1714

Chronic granulomatous disease = defect of NADPH oxidase system

Clinical findings:
Recurrent infections with catalse-
positve microorganisms
(S. aureus, Burgholderia cepacia,
Aspergillus spec., Nocardia spec., and
Serratia marrcescens)

Recurrent infections of lungs, soft

tissue and other organs (typical is
infection of nares, and gingivitis)

Fever and other clinical signs of

infection may be delayed

Excessive formation of granuloma in

all tissues
NEJM: Vol. 343: No 23, pp1703-1714
Chediak-Higashi Syndrome
Defect of the formation and function of neutrophil

CHS is an autosomal recessive disorder of all lysosomal granule

containing cells with clinical features involving the hematological and
neurological system

• All cells containing lysosomes have giant granules.

• In neutrophils large granules result from abnormal fusion of azurophilic

and specific granules and delayed fusion with phagosomes.

• Neutrophils of CHS patients fail to orient themselves during chemotaxis

resulting in delayed diapedesis

• Mutated gene: LYST = protein involved in vacuolar formation and

transport of proteins
Defect of the formation and function of neutrophil granules
Chediak-Higashi Syndrome
Clinical features:
Normal PMN Abnormal PMN recurrent bacterial infections
with S. aureus and beta hemolytic

Peripheral nerve defects

(nystagmus and neuropathy)

NEJM: Vol. 343: No 23, pp1703-1714

Mild mental retardation and partial
ocular and cutaneous albinism

Platelet dysfunction and severe

periodontal disease

Mild neutropenia and normal

Myeloperoxidase deficiency

• Most common inherited

disorder of neutrophils

• Catalyzes the generation of

hypochlorous acid (HOCL)

• A deficiency is not generally

associated with disease(!!!!)

• Except in patients with

diabetes mellitus, who are
susceptible to disseminated
Acute Inflammation 2
chemical mediators, outcome and termination

Nicole Meissner-Pearson
The inflammatory response consists of two main components:
a vascular and a cellular reaction

Intensive Care Med. (2004)

30: 1702-1714
Mediators of acute inflammation
Effector-cell-derived factors
preformed in secretory granules:

Mast cell Neutrophil/Macrophage Platelet

Histamine Lysosomal enzymes Serotonin

Newly synthesized

Platelet activating factor
Oxygen radicals
Mediators of acute inflammation

Plasma factors synthesized mainly in liver

Kinin system
Factor XII =
coagulation system
(Hageman factor) Coagulation
activation system
Plasma proteins

C3a anaphylatoxins
Complement C3b opsonin
C5b-C9 MAC
Histamine and Serotonin
induce vasodilation and increased vascular
Mast cell :
• richest source of histamine
• located in connective tissue
• adjacent to blood vessels
• Degranulation through receptors for IgE-,
IgG, histamine, bacterial products and
anaphylatoxin C5a, physical injury, cold,
• release of PAF (platelet activating factor)
leads to serotonin and histamine release
from activated platelets
• Mastcells are very important effector cells
in hypersensitivity reactions (anaphylactic
Further mediator release by mast cells perpetuates acute
inflammation at the site of release
Histamine receptors
H1 blockers are used to treat H2 blockers more relevant
allergic and inflammatory in gastric ulcer treatment

H1 receptors are found on smooth muscles of intestines, blood vessels and bronchi
H2 receptors are found in gastric parietal cells, vasculature and central nervous system
H3 receptors are found in brain
Metabolites of Arachidonic Acid (eicosanoids)

•Membrane lipids of activated cells can be transformed

into biological active lipid mediators
•All mammalian cells except erythrocytes can produce
•They are autocoids = short-range hormones (very
short range and half-life)
• Arachidonic acid is derived from conversion of
linoleic acid
Numerous stimuli (e.g. thrombin, bradykinin, epinephrine) activate
phospoholipase A2

Cox-1 = constitutively expressed

Cox-2 = inducible -1 , COX-2
Distinct Prostaglandins and Leukotrienes are derived by the
action of specific enzymes on an intermediate in the pathway and
some of these enzymes have restricted tissue distribution

*5-hydroxyperoxyeicosatetraenoic acids
(+) refers to vasoconstriction, (-) refers to vasodilation
Eicosanoids can mediate virtually every step of
Action Metabolite

Vasoconstriction Thromboxane A2,

Leukotrien C4, D4, E4

Vasodilation PGI2, PGE1, PGE2,


Increased vascul. permeab. LTC4, LTD4, LTE4

Chemotaxis, Leuko. adhesion LTB4, 5-HETE

Bronchospasm Leukotrien C4, D4, E4

Platelet aggregation Thromboxane A2

Pain mediation, Fever induction PGE2

Therapeutic intervention in arachidonic acid
metabolism and mediator action

X Steroids
Aspirin suppresses Cox-1 10-100 X more than Cox-2
Lipoxigenase inhibitors
Coxibs = selective Cox-2 inhibitors

Predominantly Predominantly
Cox-1 Cox-2

*5-hydroxyperoxyeicosatetraenoic acids
(+) refers to vasoconstriction, (-) refers to vasodilation
Nitric Oxide (NO)
a pleitropic mediator of inflammation
NO was initially discovered as
endothelium derived
relaxing factor
NO is a soluble gas
NO is produce by many cells
1. endothelial cells
2. some neurons
3. phagocytes
* synthesized from L-arginine by:
nitric oxide synthase (NOS)
Three different NOS:
endothelial eNOS Constitutive
neuronal nNOS
inducible iNOS
* peroxynitrate (phagocytes)
NO modulates the inflammatory

• NO is a potent vasodilator

• Reduces platelet aggregation

• Reduces leukocyte recruitment

• Is antimicrobial
Inhaled Nitric Oxide in the treatment of Persistent
Pulmonary Hypertension of the Newborn (PPHN)

PPHN is caused by the persistence of fetal circulation after birth with right to left
shunting of blood through fetal channels (foramen ovale and ductus ateriosus)
secondary to elevated pulmonary vascular resistance and consequently reduction of
pulmonary blood flow
Inhaled Nitric Oxide in the treatment of Persistent
Pulmonary Hypertension of the Newborn
• Inhaled NO relaxes
pulmonary vessels
and thereby decreases
pulmonary vascular
• This selectivity is the
result of rapid
• Pulmonary blood flow
is increased and right
ventricular afterload is
Kinin-Bradykinin System


Bradykinin increases vascular permeability, contraction of smooth

muscles, vasodilation and pain
Kallikrein is a potent activator of factor XII, is chemotactic and can
directly convert C5 to C5a
Coagulation system
a cascade of serine proteases
Thrombin provides the main link between
Intrinsic pathway a c t. coagulation and inflammation by binding
a nf
gem to protease activated receptors (PARs) on
Extrinsic pathway platelets, endothelium and smooth muscle
and leukocytes

plasminogen PAR-signaling induces:

Thrombin Fact. IIa Endothelial adhesion
plasmin molecules (ICAM, VCAM)
P selectin mobilization
from Weibel Palade bodies
Fibrin split products PAF
Bi-directional relationship between coagulation and
Complement System

Immune complex Mannose on microbe Microbes

C1 ,P
, D

,C B

Interaction of Kinin-, Coagulation- and
Complement system during acute inflammation
Factor XII (Hageman)
Collagen, basement membrane,
platelets and microbial surfaces

Kinin cascade Clotting cascade

in sic
Int hway
Kallikrein Prekallikrein pa
PAR* Acute
Prothrombin Thrombin Inflammation

HMWK Bradykinin
Plasminogen Plasmin Fibrin Fibrinogen


C3a * Protease activated receptors

Acute Inflammation 3
Systemic effects, outcome and termination

Nicole Meissner Pearson

TNF and IL-1 (and IL-6)
two macrophage derived cytokines mediating

•Activation of endothelium
•Priming of neutrophils
•Stimulation of
inflammatory mediator
•Induction of systemic
acute phase response
Systemic effects of acute inflammation
acute phase response
• Fever (temperature > 37.8oC or >100 F)
• Increased pulse, blood pressure
• Chills
• Anorexia
• Leukocytosis
• Neutrophilia and left shift of neutrophils points to bacterial
• Lymphocytosis points to viral infection
• Eosinophilia point to allergy or parasitic infection
• Acute phase protein production in liver
• fibrinogen, CRP,SAA leads to increased ESR
TNF, IL-1 and

Adrenal gland
Increased Erythrocyte Sedimentation Rate as a
result of the presence of acute phase reactants
ESR = rate at which erythrocytes settle
out of unclotted blood in one hour
Normally, Erythrocytes are very
buoyant and settle slowly
Erythrocytes are negatively charged
and repel each other (no aggregation
In presence of acute phase reactants
(fibrinogen) erythrocytes aggregate
due to loss of their negative charge
resulting in increased sedimentation

ESR is a widely performed test to detect occult processes and

monitor inflammatory conditions
Granulocytosis with “left shift” of neutrophil population are a
good indicator for a severe bacterial infection

Leukocyte release results from a direct effect of IL-1 and IL-6 on bone
marrow neutrophil stores.
Exaggeration of this can result in a “Leukemoid reaction” release of
very immature precursors and cell counts >25-30 x 106/µ l
Termination of acute inflammation
• Eradication of an offending agent should lead to discontinuation of the
inflammatory response

• Neutrophils have only a short life span (few hours -1 day)

• Most mediators are very short lived and are degraded immediately

• Anti-inflammatory cytokines (TGF-beta, and IL-10) can inhibit the production

of pro-inflammatory cytokines (TNF)

• In Arachidonic acid metabolism, lipoxin and resolvins are generated that have
anti-inflammatory activity

However, the exact mechanisms by which acute inflammation

resolves remain still somewhat elusive
Nature Immunology 2005

Lipoxins are generated from

Arachidonic acid (AA)-metabolites Once leukocytes enter tissue they gradually

Resolvins are generated from

Omega-3 poly unsaturated Switch their lipoxygenase-derived AA-mediators
fatty acids from proinflammatory to anti-inflammatory
Outcome of acute inflammation

• Complete restitution

• Abscess formation (encapsulation and


• Chronic inflammation

• Healing with scar formation

Examples of acute inflammatory diseases of
different origin

• Allergic reaction

• Bacterial pneumonia

• Peptic ulcer

• Sepsis
Allergic Reaction with swelling of the larynx

Or mucosa

Asthma symptoms
when affecting the lung
Pneumonia = infection of the lung
• Most community acquired
Pneumonias are bacterial of origin
• Often the infection follows a viral
upper respiratory tract infection
• Acute bacterial pneumonias present
as two anatomical patterns:
– Bronchopneumonia
– Lobar pneumonia
What causes the white consolidation of the
Normal lung
histology Pneumonia

Congested septal

Extensive erythrocyte,
neutrophil and
fibrin exudation

= red hepatization
Pathological Stages of Lobar Pneumonia
• Congestion
– Lung is heavy and red due to vascular engorgement and intra-
alveolar fluid with few neutrophils
• Red Hepatization
– Massive confluent exudation with red cells, neutrophils and fibrin
into alveolar spaces
– Lobes are distinctly red, firm and airless, with liver-like consistency
• Gray Hepatization
– Follows with progressive disintegration of red cells and
persistence of a fibrino-suppurative exudate resulting in grayish
dry appearance
• Resolution or scarring
– Resolution due to clearance of the infection and enzymatic digest
of exudate which can be reabosrbed, ingested by macrophages
cleared via muco-cilliary escalator
– Scarring due to organization of exudate, infiltration of fibroblasts
and deposition of collagen
Red hepatization Gray hepatization
Abscess formation
• is the result of a suppurative (purulent)
necrosis of the parechyma resulting in
the formation of one or more cavities
• it has a central necrosis, rimmed by
neutrophils and surrounded by

Occurs in the lung due to:

• Aspiration of infective material
• Aspiration of gastric content
• Complication of necrotizing bacterial
pneumonia (e.g Staphylococcus)
• Septic embolism
Peptic ulcer
An ulcer is a local defect of
mucosal lining produced by
shedding of necrotic tissue
Peptic ulcers are produced by an
imbalance between gastro-
duodenal defense mechanisms
and the damaging force
70% of all ulcers are due to H.
pyolri infection which initiates a
strong inflammatory response
Septicemia with disseminated intravascular
coagulation due to Meningococcal Infection

Invasion of the bloodstream by Neisseria meningitides leads to

widespread vascular injury with endothelial necrosis, thrombosis
and peri-vascular hemorrhage.
Hemorrhage as it is seen in the skin can occur in all organs