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WWAMI lecture
Nicole Meissner-Pearson
Inflammation
• 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
Acute Chronic
• Rubor = redness
• Tumor = swelling
• Calor = heat
• Dolor = pain
(described by Celsus 1st. Century AD)
Transudate
•result of hydrostatic
or osmotic imbalance
•ultrafiltrate of plasma
•Low protein content
•specific gravity < 1.015
Exudate
•result of inflammation
•vascular permeability
•high protein content
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:
margination
rolling,
adhesion,
transmigration (diapedesis)
migration.
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
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
CD14 LPS
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
substances
phagocytosis
Oxidative burst
The NADPH oxidase system is only active when the cytosolic subunits are
assembled with the membrane bound subunits in response to leukocyte
activation.
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)
• CGD is a heterogeneous
disorder caused by defects
of any of the four subunits
of NADPH oxidase.
Clinical findings:
Recurrent infections with catalse-
positve microorganisms
(S. aureus, Burgholderia cepacia,
Aspergillus spec., Nocardia spec., and
Serratia marrcescens)
Nicole Meissner-Pearson
The inflammatory response consists of two main components:
a vascular and a cellular reaction
Newly synthesized
Prostaglandins
Leukotrienes
Platelet activating factor
Oxygen radicals
NO
cytokines
Mediators of acute inflammation
Kinin system
Factor XII =
coagulation system
(Hageman factor) Coagulation
activation system
Plasma proteins
C3a anaphylatoxins
C5a
Complement C3b opsonin
activation
C5b-C9 MAC
Histamine and Serotonin
induce vasodilation and increased vascular
permeability
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,
heat
• 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
reactions)
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
reactions
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)
*5-hydroxyperoxyeicosatetraenoic acids
(+) refers to vasoconstriction, (-) refers to vasodilation
Eicosanoids can mediate virtually every step of
inflammation
Action Metabolite
X Steroids
Aspirin suppresses Cox-1 10-100 X more than Cox-2
Lipoxigenase inhibitors
Coxibs = selective Cox-2 inhibitors
X
Leukotriene
X
receptor
antagonists
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
including:
1. endothelial cells
2. some neurons
3. phagocytes
* synthesized from L-arginine by:
nitric oxide synthase (NOS)
Three different NOS:
endothelial eNOS Constitutive
expression
neuronal nNOS
inducible iNOS
* peroxynitrate (phagocytes)
NO modulates the inflammatory
response
• NO is a potent vasodilator
• 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
resistance
• This selectivity is the
result of rapid
hemoglobin-mediated
inactivation
• Pulmonary blood flow
is increased and right
ventricular afterload is
reduced
Kinin-Bradykinin System
(HMWK)
C1 ,P
, D
BL
,C B
2,
M
C4
Interaction of Kinin-, Coagulation- and
Complement system during acute inflammation
Factor XII (Hageman)
Collagen, basement membrane,
platelets and microbial surfaces
XIIa
HMWK Bradykinin
Fibrinolysis
Plasminogen Plasmin Fibrin Fibrinogen
Complement
Action:
•Activation of endothelium
•Priming of neutrophils
•Stimulation of
inflammatory mediator
release
•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
infection
• 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
IL6
TH
AC
PGE2
Adrenal gland
releases
Glucocorticoids
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
occurs)
In presence of acute phase reactants
(fibrinogen) erythrocytes aggregate
due to loss of their negative charge
resulting in increased sedimentation
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
• Most mediators are very short lived and are degraded immediately
• In Arachidonic acid metabolism, lipoxin and resolvins are generated that have
anti-inflammatory activity
• Complete restitution
• Chronic inflammation
• 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
Chest-X-ray?
Normal lung
histology Pneumonia
Congested septal
capillaries
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
fibroblasts