Chapter 2 Acute and Chronic Inflammation
circulation
Inflammation
This is fundamentally a protective
response
a complex reaction in tissues that
consists mainly of responses of blood
vessels and leukocytes.
The vascular and cellular reactions of
inflammation are triggered by soluble
factors that are produced by various cells
or derived from plasma proteins and are
generated or activated in response to the
inflammatory stimulus
The inflammatory response is closely
intertwined with the process of repair
Inflammation may be harmful in some
situations
Inflammation may contribute to a variety
of diseases that are not thought to be
primarily due to abnormal host
responses.
Patterns of Inflammation
Acute Inflammation
rapid in onset (typically minutes)
short duration, lasting for hours or a few
days
exudation of fluid and plasma proteins
(edema)
emigration of leukocytes, predominantly
neutrophils (also called
polymorphonuclear leukocytes)
Chronic Inflammation
longer duration
the proliferation of blood vessels,
fibrosis, and tissue destruction
presence of lymphocytes and
macrophages
Classic clinical signs
Heat (calor)
Redness (rubor)
Edema (tumor)
Pain (dolor)
Loss of function (functio laesa)
ACUTE INFLAMMATION
Immediate & early response to tissue injury
(physical, chemical, microbiologic, etc.)
Acute inflammation has three major
components:
1. alterations in vascular caliber that lead
to an increase in blood flow
2. structural changes in the
microvasculature that permit plasma
proteins and leukocytes to leave the
3. emigration of the leukocytes from the
microcirculation, their accumulation in
the focus of injury, and their activation to
eliminate the offending agent
STIMULI FOR ACUTE INFLAMMATION
Infections (bacterial, viral, fungal,
parasitic)
Tissue necrosis from any cause, including
ischemia (as in a myocardial infarct),
trauma, and physical and chemical injury
(e.g., thermal injury, as in burns or
frostbite; irradiation; exposure to some
environmental chemicals)
Foreign bodies (splinters, dirt, sutures)
Immune reactions (also called
hypersensitivity reactions)
Definitions
Exudation
- escape of fluid, proteins, & blood cells from the
vascular system into the interstitial tissue or
body cavities
Exudate
- inflammatory extravascular fluid high in
protein conc., much cellular debris, & sp.gr.
>1.020
Transudate
- low protein content, sp.gr. <1.020, ultrafiltrate
of blood plasma
Edema
excess of fluid in the interstitial tissue or
serous cavity
Pus
purulent inflammatory exudate rich in
leukocytes & parenchymal cell debris
Changes in Vascular Flow and Caliber
Vasodilation
one of the earliest manifestations of
acute inflammation
first involves the arterioles and then
leads to opening of new capillary beds in
the area
The result is increased blood flow, which
is the cause of heat and redness
(erythema) at the site of inflammation
induced by the action of several
mediators, notably histamine and nitric
oxide (NO), on vascular smooth muscle
Increased permeability of the microvasculature
Stasis
dilation of small vessels that are packed
with slowly moving red cells
vascular congestion
Increased Vascular Permeability (Vascular
Leakage)
 Contraction of endothelial cells resulting
in increased interendothelial spaces is
the most common mechanism of
vascular leakage and is elicited by
histamine, bradykinin, leukotrienes, the
neuropeptide substance P, and many
other chemical mediators
Endothelial injury, resulting in endothelial
cell necrosis and detachment
Increased transport of fluids and
proteins, called transcytosis, through the
endothelial cell. This process may involve
channels consisting of interconnected,
uncoated vesicles and vacuoles called
the vesiculovacuolar organelle
Responses of Lymphatic Vessels
The lymphatics may become secondarily
inflamed (lymphangitis), as may the
draining lymph nodes (lymphadenitis).
Inflamed lymph nodes are often enlarged
because of hyperplasia of the lymphoid
follicles and increased numbers of
lymphocytes and macrophages
2nd line of defense
REACTIONS OF LEUKOCYTES IN
INFLAMMATION
Recruitment of Leukocytes to Sites of
Infection and Injury
1. In the lumen: margination, rolling, and
adhesion to endothelium. Vascular endothelium
in its normal, unactivated state does not bind
circulating cells or impede their passage. In
inflammation the endothelium is activated and
can bind leukocytes, as a prelude to their exit
from the blood vessels.
2. Migration across the endothelium and vessel
wall
3. Migration in the tissues toward a chemotactic
stimulus
Margination & Rolling
With increased vascular permeability,
fluid leaves the vessel causing
leukocytes to settle-out of the central
flow column & marginate along the
endothelial surface
Endothelial cells & leukocytes have
complementary surface adhesion
molecules which briefly stick & release
causing the leukocyte to roll along the
endothelium until it eventually comes to
a stop as mutual adhesion reaches a
peak
Early rolling adhesion mediated by
selectin family:
E-selectin (endothelium), P-selectin
(platelets, endothelium), L-selectin
(leukocytes) bind other surface
molecules (i.e.,CD34, Sialyl-Lewis X-
modified GP) that are upregulated on
endothelium by cytokines (TNF, IL-1) at
injury sites
Adhesion
Rolling comes to a stop and adhesion
results
Other sets of adhesion molecules
participate:
Endothelial: ICAM-1, VCAM-1
Leukocyte: LFA-1, Mac-1, VLA-4
(ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds
VLA-4)
Ordinarily down-regulated or in an
inactive conformation
Transmigration (diapedesis)
Occurs after firm adhesion within the
systemic venules and pulmonary
capillaries via PECAM 1 (CD31)
Must then cross basement membrane
Collagenases
Integrins
Chemotaxis
- leukocytes emigrate in tissues toward the site
of injury
Endogenous chemoattractants include several
chemical mediators:
(1) cytokines, particularly those of the
chemokine family (e.g., IL-8)
(2) components of the complement system,
particularly C5a
(3) arachidonic acid (AA) metabolites, mainly
leukotriene B4 (LTB4)
In most forms of acute inflammation
neutrophils predominate in the
inflammatory infiltrate during the first 6
to 24 hours and are replaced by
monocytes in 24 to 48 hours
Leukocytes express several receptors that
recognize external stimuli and deliver activating
signals:
Receptors for microbial products:
Toll-like receptors (TLRs) recognize
components of different types of
microbes
G proteincoupled receptors found
on neutrophils, macrophages, and
most other types of leukocytes
recognize short bacterial peptides
containing N-formylmethionyl residues.
 Receptors for opsonins: Leukocytes
express receptors for proteins that coat
microbes
Receptors for cytokines: Leukocytes
express receptors for cytokines that are
produced in response to microbes. One
of the most important of these cytokines
is interferon- (IFN-)
Phagocytosis
(1) recognition and attachment of the
particle to be ingested by the leukocyte
(2) its engulfment, with subsequent formation
of a phagocytic vacuole
(3) killing or degradation of the ingested
material
Outcomes of Acute Inflammation
All acute inflammatory reactions may have one
of three outcomes:
Complete resolution
there has been little tissue destruction
and the damaged parenchymal cells can
regenerate
removal of cellular debris and microbes
by macrophages, and resorption of
edema fluid by lymphatics
Healing by connective tissue replacement
(fibrosis)
tissues that are incapable of
regeneration
when there is abundant fibrin exudation
in tissue or serous cavities (pleura,
peritoneum) that cannot be adequately
cleared
mass of fibrous tissue
Progression of the response to chronic
inflammation
Morphologic Patterns of Acute
Inflammation
SEROUS INFLAMMATION
marked by the outpouring of a thin fluid
that may be derived from the plasma or
from the secretions of mesothelial cells
lining the peritoneal, pleural, and
pericardial cavities
ex. skin blister resulting from a burn or
viral infection
effusion
FIBRINOUS INFLAMMATION
large molecules such as fibrinogen pass
the vascular barrier, and fibrin is formed
and deposited in the extracellular space
A fibrinous exudate develops when the
vascular leaks are large or there is a local
procoagulant stimulus
Ex. Conversion of the fibrinous exudate
to scar tissue (organization) within the
pericardial sac
SUPPURATIVE OR PURULENT
INFLAMMATION; ABSCESS
characterized by the production of large
amounts of pus or purulent exudate
consisting of neutrophils, liquefactive
necrosis, and edema fluid
pyogenic - pus-producing (ex.
Staphylococci)
Ex. Appendicitis
Abscess - localized collections of purulent
inflammatory tissue caused by
suppuration buried in a tissue, an organ,
or a confined space
ULCERS
a local defect, or excavation, of the
surface of an organ or tissue that is
produced by the sloughing (shedding) of
inflamed necrotic tissue
It is most commonly encountered in:
(1) the mucosa of the mouth, stomach,
intestines, or genitourinary tract; and
(2) the skin and subcutaneous tissue of
the lower extremities in older persons
who have circulatory disturbances that
predispose to extensive ischemic
necrosis
Chronic Inflammation
- Inflammation of prolonged duration (weeks or
months) in which inflammation, tissue injury,
and attempts at repair coexist, in varying
combinations
CAUSES OF CHRONIC INFLAMMATION
Persistent infections by microorganisms
that are difficult to eradicate, such as
mycobacteria, and certain viruses, fungi,
and parasites. These organisms often
evoke an immune reaction called
delayed-type hypersensitivity
Immune-mediated inflammatory
diseases. Chronic inflammation plays an
important role in a group of diseases that
are caused by excessive and
inappropriate activation of the immune
system. Under certain conditions
immune reactions develop against the
individual's own tissues, leading to
autoimmune diseases. In other cases,
chronic inflammation is the result of
unregulated immune responses against
 microbes, as in inflammatory bowel - A granuloma is a focus of chronic
disease. Immune responses against inflammation consisting of a microscopic
common environmental substances are aggregation of macrophages that are
the cause of allergic diseases, such as transformed into epithelium-like cells,
bronchial asthma surrounded by a collar of mononuclear
Prolonged exposure to potentially toxic leukocytes, principally lymphocytes and
agents, either exogenous or endogenous. occasionally plasma cells
An example of an exogenous agent is
particulate silica. Atherosclerosis is Two Types of Granulomas
thought to be a chronic inflammatory Foreign body granulomas - are incited by
process of the arterial wall induced, at relatively inert foreign bodies
least in part, by endogenous toxic Immune granulomas - are caused by a variety
plasma lipid components of agents that are capable of inducing a cell-
mediated immune response
MORPHOLOGIC FEATURES
Infiltration with mononuclear cells, which Systemic Effects of Inflammation
include macrophages, lymphocytes, and Fever
plasma cells Acute-phase proteins
Tissue destruction, induced by the Leukocytosis
persistent offending agent or by the increased pulse and blood pressure;
inflammatory cells decreased sweating
Attempts at healing by connective tissue Sepsis
replacement of damaged tissue,
accomplished by proliferation of small Consequences of Defective or Excessive
blood vessels (angiogenesis) and, in Inflammation
particular, fibrosis Defective inflammation typically results
in increased susceptibility to infections
ROLE OF MACROPHAGES IN CHRONIC Excessive inflammation is the basis of
INFLAMMATION many types of human disease
Macrophages - the dominant cellular player in
chronic inflammation; one component of the
mononuclear phagocyte system ex. liver
(Kupffer cells), spleen and lymph nodes (sinus
histiocytes), lungs (alveolar macrophages), and
central nervous system (microglia).
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
When a monocyte reaches the
extravascular tissue, it undergoes
transformation into a larger phagocytic
cell, the macrophage
The activities of these macrophages that
tissue destruction is one of the hallmarks
of chronic inflammation
OTHER CELLS IN CHRONIC INFLAMMATION
Lymphocytes
Plasma cells
Eosinophils
Mast cells

GRANULOMATOUS INFLAMMATION
- a distinctive pattern of chronic inflammation
that is encountered in a limited number of
infectious and some noninfectious conditions