Acute and Chronic Inflammation

Dra. Mari Karr Esguerra

Blood leukocytes, principally neutrophils, accumulate along the

vascular endothelium

Overview of Inflammation
Protective response: host response to get rid of necrotic tissues
and microbes
Inflammation is terminated when the offending agent is
eliminated
Inflammatory response is closely intertwined with the process of
repair
o
Regeneration
o
Scarring
Mechanisms designed to destroy foreign invaders and necrotic
tissues have an intrinsic ability to injure normal tissues
Inflammation my contribute to a variety of diseases that are not
thought to be primarily due to abnormal host responses
o
Atherosclerosis
o
Type 2 Diabetes
o
Alzheimers disease

Acute Inflammation: Mechanisms of Increased Vascular Permeability

Endothelial injury, resulting in endothelial cell necrosis and
detachment
Increased transport of fluids and proteins, called transcytosis
o
Vesiculovacuolar organelle
o
VEGF

Inflammation
Complex reaction in tissues that consists mainly of responses of
blood vessels and leucocytes
Cardinal signs of inflammation:
o
Redness (rubor)
o
Swelling (tumor)
o
Heat / warmth (calor)
o
Pain (dolor)
o
Loss of function (functio laesa)

Extravasation
In the lumen margination, rolling and adhesion to endothelium
o
The adhesion of leucocytes to endothelial cells is
mediated by complementary adhesion molecules on
the two cell types whose expression is enhanced by
secreted proteins called cytokines
Migration across the endothelium and vessel wall
Migration into the tissues toward a chemotactic stimulus

Acute Inflammation
Rapid in onset (typically minutes)
Short duration
Lasting for hours or few days
3 Major Components of Acute Inflammation
Vascular dilation and increased blood flow (causing erythema and
warmth)
Extravasation and extravascular deposition of plasma fluid and
proteins (edema)
Leukocyte emigration and accumulation in the site of injury
Stimuli for Acute Inflammation
Infections
Most importantly receptors for microbial products are
(bacteria, fungi,
the family of Toll-like receptors (TLRs)
parasite, virus)
Tissue necrosis
Molecules are released from necrotic cells mediated
from any cause,
largely by a protein called HIF-1 (hypoxia-induced
including ischemia, factor-1).
trauma, and
Activates the transcription of many genes involved in
physical and
inflammation, including vascular endothelial growth
chemical injury
factor (VEGF), which increases vascular permeability
Foreign bodies
Splinters, dirt, sutures typically elicit inflammation
because they cause traumatic tissue injury or carry
microbes
Immune reactions
May be directed against self antigens, causing
(hypersensitivity
autoimmune diseases may be excessive reactions
reactions)
against environmental substances or microbes
Edema
-

Transudate
Exudate

Acute Inflammation: Changes in Vascular Flow and Caliber

Vasodilatation increased blood flow, erythema, induced by
mediators notably histamine and nitric oxide
This leads to increased permeability of vasculature with
outpouring of protein-rich fluid into the extravascular tissues
Stasis dilation of small vessels that are packed with slowly moving
red cells congestion

Acute Inflammation: Responses of Lymphatic Vessels

Lymph flow is increased and helps drain edema fluid
Lymphatic vessels proliferate
Lymphangitis reactive/inflammatory lymphadenitis
Reaction of Leucocytes in Inflammation
Recruitment from the blood into the extravascular tissues
Recognition of microbes and necrotic tissues
Removal of the offending agent

Endothelial-Leucocyte Adhesion Molecules

Endothelial molecule
Leucocyte molecule
P-selectin
Sialyl-Lewis X-modified
proteins
E-selectin
Sialyl-Lewis X-modified
proteins
GlyCam-1, CD-34
L-selectin
ICAM-1
CD11/CD18 (B2)
integrins (LFA-1, Mac1)
VCAM-1
VLA-4 (B1) integrin

Major role
Rolling
Rolling and adhesion
Rolling
Adhesion, arrest,
transmigration
Adhesion

Diapedesis or Transmigration
Through the endothelium into the extravascular tissue mainly in
post capillary venules
Adhesion molecules are involved like PECAM-1 or CD31
Migrate toward a chemotactic gradient
Accumulate in the extravascular site
Adhere to ECM using integrin and CD44

Chemotaxis of Leucocytes
Chemoattractant exogenous (bacterial products) or endogenous
(chemokine, c5a, LTB4) which binds to specific seventransmembrane G-protein coupled receptors
Signals result in activation of second messengers increased
cytosolic calcium and activate guanosine triphosphatase of the
Rac/Rho/cdc42 family
The nature of leucocyte infiltrate varies with the age of the
inflammatory response and the type of stimulus
In most forms of acute inflammation, neutrophils predominate in
the inflammatory infiltrate during the first 6-24 hours and are
replaced by monocytes in 24-48 hours
Recognition of Microbes and Dead Tissue
Once leukocytes (neutrophils and monocytes) have been
recruited to a site of infection or cell death, they must be
activated to perform their functions
o
(1) Recognition of the offending agents, which deliver
signals that (2) Activate the leukocytes to ingest and
destroy the offending agents and amplify the
inflammatory reaction
Leucocytes Express Receptors to Recognize Stimuli and Deliver Signals
Toll-like receptors (TLRs) microbial products
G-protein coupled receptors recognize N-formylmethionyl
residues, chemokines c5a, lipid mediators, PAF, prostaglandins, LT
Receptors for opsonins (Ab, complement proteins like C3,
mannan-binding lectin) to target for phagocytosis
Receptors for cytokines IFN-
Removal of Offending Agents
Increase cytosolic Calcium
Activation of enzymes like protein kinase-C and phospholipase-A2
Phagocytosis and intracellular killing
Phagocytosis
Recognition and attachment of the particle to be ingested by the
leukocyte
Engulfment with subsequent formation of phagocytic vacuole
Killing or degradation of the ingested material
Binding to receptors on leucocyte membrane
o
Mannose receptors bind to mannose and fucose
o
Scavenger receptors Mac-1 (CD11b/CD18)
o
Opsonin receptors IgG, c3b, mannan-binding lectin
Pseudopods phagosome phagolysosome resulting to
engulfment
Killing and Degradation
Microbial killing is accomplished largely by reactive oxygen
species (ROS), also called reactive oxygen intermediates and
reactive nitrogen species, mainly derived from NO
Generation of ROS: NADPH oxidase / phagocyte oxidase which
reduces oxygen to superoxide anion (respiratory burst)
The H2O2-MPO-Halide system is the most efficient bactericidal
system of neutrophils
Neutrophil granule contain enzymes (elastase), defensins,
cathelicidins, lysozyme, lactoferrin, major basic protein,
bactericidal / permeability increasing protein
Release of Leucocyte Products and Leucocyte-Mediated Injury
As part of a normal defense reaction against infectious microbes,
when adjacent tissues suffer collateral damage
When the inflammatory response is inappropriately directed
against host tissues, as in certain autoimmune diseases
When the host reacts excessively against usually harmless
environmental substances, as in allergic diseases including asthma

Defects in Leucocyte Adhesion

Type 1 defect in the biosynthesis of the beta-2 chain shared by
LFA-1 and Mac-1 integrins
Type 2 absence of Sialyl-Lewis X
Defects in Phagolysosome Function
Chediak-Higashi syndrome
o
Defective gene LYST
o
Defective fusion of phagosomes and lysosomes in
phagyocytes
o
Neutropenia, defective degranulation and delayed
microbial killing
o
Leucocytes contain giant granules (PBS)
o
Albinism, nerve defects, bleeding disorders
Inherited Defects in Microbicidal Activity
Chronic granulomatous disease
o
Inherited defects in genes encoding components of
phagocyte oxidase
o
X-linked: gp91phox
o
AR: p47phox and p67phox
Acquired Deficiency of Leucocyte Defects
Bone marrow suppression: tumors, radiation and chemotherapy
o
Production of leucocytes
Diabetes, malignancy, sepsis, chronic dialysis
o
Adhesion and chemotaxis
Leukemia, anemia, sepsis, diabetes, malnutrition
o
Phagocytosis and microbicidal activity
Termination of the Acute Inflammatory Response
Switch in the type of arachidonic acid metabolite produced, from
pro-inflammatory leukotrienes to anti-inflammatory lipoxins
The liberation of anti-inflammatory cytokines, including TGF-beta
and IL-10
The production of anti-inflammatory lipid mediators resolvins
and protectins
Neural impulses (cholinergic discharge) that inhibit the production
of TNF in macrophages
Cell-Derived Mediators
Histamine
o
Dilation of arterioles and increases the permeability of
venules
o
Principal mediator of the immediate transient phase of
increased vascular permeability, producing
interendothelial gaps in venules
Serotonin
o
Vasodilatation and increased vascular permeability

Lipoxins
-

Arachidonic-Cyclooxygenase Pathway

Principal actions: to inhibit leukocyte recruitment and the cellular

components of inflammation
Inhibit neutrophil chemotaxis and adhesion to endothelium
Inverse relationship between the production of lipoxin and
leukotrienes
o
Suggesting that the lipoxins may be endogenous
negative regulators of leukotrienes and may thus play
a role in the resolution of inflammation

Anti-Inflammatory Drugs
Cyclooxygenase inhibitors (NSAIDs like indomethacin, aspirin)
inhibit prostaglandin synthesis
Lipooxygenase inhibitors inhibit leukotriene production
(Zileuton) or block leukotriene receptors (Montelukast)
Broad spectrum inhibitors corticosteroids
Increase consumption of fish oil excellent substrates for
production of resolvin and protectin
Platelet Activating Factor
Platelet aggregation, vasoconstriction and bronchoconstriction
At extremely low concentrations it induces vasodilation and
increased venular permeability
Increased leukocyte adhesion to endothelium (by enhancing
integrin-mediated leukocyte binding), chemotaxis, degranulation,
and the oxidative burst
Reactive Oxygen Species

Arachidonic Acid Metabolites

Prostaglandins PGE2, PGD2, PGF2, PGI2, TXA2
o
TXA2 platelet-aggregating agent, vasoconstrictor
o
Prostacyclin vasodilator, inhibitor of platelet
aggregation, and also markedly potentiates the
permeability-increasing and chemotactic effects of
other mediators
o
PGD2 the major prostaglandin made by mast cells;
chemoattractant for PMN; along with PGE2, it causes
vasodilation and increases the permeability of postcapillary venules, thus potentiating edema formation
o
PGE2 pain and fever
o
PGF2 - stimulates the contraction of uterine and
bronchial smooth muscle and small arterioles, and
PGD2 is a chemoattractant for neutrophils
Lipooxygenases leukotrienes LTB4, LTC4, LTD4, LTE4
o
LTB4 chemotactic agent and activator of neutrophils,
causing aggregation and adhesion of the cells to
venular endothelium, generation of ROS, and release
of lysosomal enzymes
o
LTC4, LTD4, LTE4 cause intense vasoconstriction,
bronchospasm and increased vascular permeability
o
Leukotrienes are much more potent than is histamine
increasing vascular permeability and causing
bronchospasm

Superoxide anion, hydrogen peroxide, hydroxyl radical are the

MAJOR species and superoxide anion can combine with NO to
form ROS which may cause:
o
Endothelial cell damage, with resultant increased
vascular permeability
o
Injury to other cell types (parenchymal cells, red blood
cells)
o
Inactivation of antiproteases

Antioxidant Mechanisms that Protect Against Oxygen

Superoxide dismutase
Catalase
Glutathione peroxidase
Ceruloplasmin
The iron-free fraction of serum transferrin
Nitric Oxide (EDRF)
Synthesidzed from L-arginine by NOS
Types: eNOS, nNOS, and iNOS
Dual actions in inflammation: relaxes vascular smooth muscle and
promotes vasodilation, but it is also an inhibitor of the cellular
component of inflammatory responses
An endogenous mechanism for controlling inflammatory
responses
Microbicidal host defense against infection

Cytokines
TNF and IL-1 major cytokines that mediate inflammation
Their most important actions in inflammation are their effects on
endothelium, leukocytes, and fibroblasts (repair), and induction of
systemic acute-phase reactions

Fibrinolytic System
Plasmin
o
o
o

Chemokines
Act primarily as chemoattractants
o
C-X-C chemokines (alpha-chemokines) act primarily
on neutrophils, IL-8 is typical of this group
o
C-C chemokines (beta-chemokines) MCP-1, eotaxin,
MIP-1 and RANTES
o
C chemokines (gamma-chemokines) lymphotactin
o
CX3C chemokines fractalkine
Chemokines have 2 main functions:
o
Leukocyte recruitment in inflammation
o
Control of the normal migration of cells through
various tissues
Neutrophils
Specific (or secondary) granules lysozyme, collagenase,
gelatinase, lactoferrin, plasminogen activator, histaminases, and
alkaline phosphatase
Azurophil (or primary) granules myeloperoxidase, bactericidal
factors (lysozyme, defensins), acid hydrolases, and a variety of
neutral proteases (elastase, cathepsin G, nonspecific collagenases,
proteinase 3)
Neuropeptides
Secreted by sensory nerves and various leukocytes, and play a
role in the initiation and propagation of an inflammatory response
Substance P and neurokinin A
Complement System
Inflammation : anaphylatoxins c3a, c5a, and c4a histamine
release, increase vascular permeability and vasodilation
C3b and its cleavage product ic3b (inactive c3b)
o
Act as opsonins and promote phagocytosis
Cell lysis

Lyse fibrin clots

Cleaves the complement protein c3 to produce c3
fragments
Degrades fibrin to form fibrin split products, which
may have permeability-inducing properties
Also activate Hageman factor

Outcomes of Acute Inflammation

Complete resolution
Healing by connective tissue replacement (fibrosis)
o
Occurs after substantial tissue destruction
o
Involves tissues incapable of regeneration
o
Abundant fibrin exudation in tissue or serous cavities
(pleura, peritoneum) that cannot be adequately
cleared
Progression to chronic inflammation
Morphologic Hallmarks of Acute Inflammation
Dilation of small blood vessels
Slowing of blood flow
Accumulation of leukocytes and fluid in the extravascular tissue
Serous Inflammation
Outpouring of a thin fluid
Derived from the plasma or from the secretions of mesothelial
cells lining the peritoneal, pleural, and pericardial cavities
Fibrinous Inflammation
Vascular leaks are large or there is a local procoagulant stimulus
Fibrin appears as eosinophilic meshwork of threads
Suppurative or Purulent Inflammation
Neutrophils, liquefactive necrosis and edema
Ulcer
-

Coagulation and Kinin System

Bradykinin increases vascular permeability and causes
contraction of smooth muscle, dilation of blood vessels, and pain
when injected into the skin
Kallikrein potent activator of Hageman factor, chemotactic
activity, and it also directly converts c5 to the chemoattractant
product of c5a

Local defect or excavation, of the surface of an organ or tissue

that is produced by the sloughing (shedding) of inflamed necrotic
tissue

Chronic Inflammation
Inflammation of prolonged duration (weeks or months) in which
inflammation, tissue injury, and attempts at repair coexist, in
varying combinations
May follow acute inflammation
May begin insidiously, as a low-grade, smoldering response
without any manifestations of an acute reaction

Causes of Chronic Inflammation

Persistent infections by microorganisms that are difficult to
eradicate
o
Such as Mycobacteria, and certain viruses, fungi and
parasites
o
These organisms often evoke an immune reaction
called delayed-type hypersensitivity
o
Inflammatory response sometimes takes a specific
pattern called a granulomatous reaction
Immune-mediated inflammatory diseases
o
Excessive and inappropriate activation of the immune
system
o
Immune reactions develop against the individuals own
tissues, leading to autoimmune diseases
o
Unregulated immune responses against microbes, as in
inflammatory bowel disease
Prolonged exposure to potentially toxic agents, either exogenous
or endogenous
o
Silicosis
o
Atherosclerosis

Other Cells in Chronic Inflammation

Lymphocytes
Plasma cells
Eosinophils
Mast cells

Morphologic Features of Chronic Inflammation

Infiltration with mononuclear cells, which include macrophages,
lymphocytes, and plasma cells
Tissue destruction, induced by the persistent offending agent or
by the inflammatory cells
Attempts at healing by connective tissue replacement of damaged
tissue, accomplished by proliferation of small blood vessels
(angiogenesis) and, in particular, fibrosis

Other Manifestations
Increased pulse and blood pressure
Decreased sweating, mainly because of redirection of blood flow
from cutaneous to deep vascular beds, to minimize heat loss
through the skin
Rigors (shivering)
Chills (search for warmth)
Anorexia, somnolence, and malaise

Maturation of Mononuclear Macrophage

Consequences
Defective inflammation
o
Increased susceptibility to infections
o
Delayed wound healing
Excessive inflammation
o
Allergies
o
Autoimmune disease
o
Atherosclerosis and ischemic heart disease
o
Neurodegenerative disease like Alzheimers disease

Granulomatous Inflammation
A granuloma is a focus of chronic inflammation consisting of a
microscopic aggregation of macrophages that are transformed
into epithelium-like cells, surrounded by a collar of mononuclear
leukocytes, principally lymphocytes and occasionally plasma cells
Foreign body granuloma
Immune granuloma Mycobacterium tuberculosis
Systemic Effects of Inflammation
Fever pyrogens (LPS) that act by stimulating prostaglandin
synthesis (PGE2)
Increased acute phase proteins CRP, fibrinogen, and serum
amyloid A, hepcidin
Leukocytosis

It is because of the activities of these macrophages that tissue

destruction is one of the hallmarks of chronic inflammation
The products of activated macrophages serve to eliminate
injurious agents such as microbes and to initiate the process of
repair, and are responsible for much of the tissue injury in chronic
inflammation

Prepared by: Paolo Warren (Med-2E)