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Chapter 2 Acute and Chronic Inflammation proteins and leukocytes to leave the

circulation
Inflammation 3. emigration of the leukocytes from the
This is fundamentally a protective microcirculation, their accumulation in
response the focus of injury, and their activation to
a complex reaction in tissues that eliminate the offending agent
consists mainly of responses of blood STIMULI FOR ACUTE INFLAMMATION
vessels and leukocytes. Infections (bacterial, viral, fungal,
The vascular and cellular reactions of parasitic)
inflammation are triggered by soluble Tissue necrosis from any cause, including
factors that are produced by various cells ischemia (as in a myocardial infarct),
or derived from plasma proteins and are trauma, and physical and chemical injury
generated or activated in response to the (e.g., thermal injury, as in burns or
inflammatory stimulus frostbite; irradiation; exposure to some
The inflammatory response is closely environmental chemicals)
intertwined with the process of repair Foreign bodies (splinters, dirt, sutures)
Inflammation may be harmful in some Immune reactions (also called
situations hypersensitivity reactions)
Inflammation may contribute to a variety
of diseases that are not thought to be Definitions
primarily due to abnormal host Exudation
responses. - escape of fluid, proteins, & blood cells from the
vascular system into the interstitial tissue or
Patterns of Inflammation body cavities
Exudate
Acute Inflammation - inflammatory extravascular fluid high in
rapid in onset (typically minutes) protein conc., much cellular debris, & sp.gr.
>1.020
short duration, lasting for hours or a few
Transudate
days
- low protein content, sp.gr. <1.020, ultrafiltrate
exudation of fluid and plasma proteins
of blood plasma
(edema) Edema
emigration of leukocytes, predominantly excess of fluid in the interstitial tissue or
neutrophils (also called serous cavity
polymorphonuclear leukocytes) Pus
Chronic Inflammation purulent inflammatory exudate rich in
longer duration leukocytes & parenchymal cell debris
the proliferation of blood vessels,
fibrosis, and tissue destruction Changes in Vascular Flow and Caliber
presence of lymphocytes and Vasodilation
macrophages one of the earliest manifestations of
acute inflammation
Classic clinical signs first involves the arterioles and then
Heat (calor) leads to opening of new capillary beds in
Redness (rubor) the area
Edema (tumor) The result is increased blood flow, which
Pain (dolor) is the cause of heat and redness
(erythema) at the site of inflammation
Loss of function (functio laesa)
induced by the action of several
mediators, notably histamine and nitric
ACUTE INFLAMMATION oxide (NO), on vascular smooth muscle
Immediate & early response to tissue injury Increased permeability of the microvasculature
(physical, chemical, microbiologic, etc.) Stasis
dilation of small vessels that are packed
Acute inflammation has three major
with slowly moving red cells
components:
vascular congestion
1. alterations in vascular caliber that lead
to an increase in blood flow Increased Vascular Permeability (Vascular
2. structural changes in the Leakage)
microvasculature that permit plasma
Contraction of endothelial cells resulting (leukocytes) bind other surface
in increased interendothelial spaces is molecules (i.e.,CD34, Sialyl-Lewis X-
the most common mechanism of modified GP) that are upregulated on
vascular leakage and is elicited by endothelium by cytokines (TNF, IL-1) at
histamine, bradykinin, leukotrienes, the injury sites
neuropeptide substance P, and many Adhesion
other chemical mediators Rolling comes to a stop and adhesion
Endothelial injury, resulting in endothelial results
cell necrosis and detachment Other sets of adhesion molecules
Increased transport of fluids and participate:
proteins, called transcytosis, through the Endothelial: ICAM-1, VCAM-1
endothelial cell. This process may involve Leukocyte: LFA-1, Mac-1, VLA-4
channels consisting of interconnected, (ICAM-1 binds LFA-1/Mac-1, VCAM-1 binds
uncoated vesicles and vacuoles called VLA-4)
the vesiculovacuolar organelle Ordinarily down-regulated or in an
Responses of Lymphatic Vessels inactive conformation
The lymphatics may become secondarily Transmigration (diapedesis)
inflamed (lymphangitis), as may the Occurs after firm adhesion within the
draining lymph nodes (lymphadenitis). systemic venules and pulmonary
Inflamed lymph nodes are often enlarged capillaries via PECAM 1 (CD31)
because of hyperplasia of the lymphoid Must then cross basement membrane
follicles and increased numbers of Collagenases
lymphocytes and macrophages
Integrins
2nd line of defense

REACTIONS OF LEUKOCYTES IN
INFLAMMATION
Chemotaxis
Recruitment of Leukocytes to Sites of
- leukocytes emigrate in tissues toward the site
Infection and Injury
of injury
1. In the lumen: margination, rolling, and
adhesion to endothelium. Vascular endothelium
Endogenous chemoattractants include several
in its normal, unactivated state does not bind
chemical mediators:
circulating cells or impede their passage. In
(1) cytokines, particularly those of the
inflammation the endothelium is activated and
chemokine family (e.g., IL-8)
can bind leukocytes, as a prelude to their exit
(2) components of the complement system,
from the blood vessels.
particularly C5a
2. Migration across the endothelium and vessel
(3) arachidonic acid (AA) metabolites, mainly
wall
leukotriene B4 (LTB4)
3. Migration in the tissues toward a chemotactic
stimulus
In most forms of acute inflammation
Margination & Rolling neutrophils predominate in the
inflammatory infiltrate during the first 6
With increased vascular permeability,
to 24 hours and are replaced by
fluid leaves the vessel causing
monocytes in 24 to 48 hours
leukocytes to settle-out of the central
Leukocytes express several receptors that
flow column & marginate along the
recognize external stimuli and deliver activating
endothelial surface
signals:
Endothelial cells & leukocytes have
Receptors for microbial products:
complementary surface adhesion
Toll-like receptors (TLRs) recognize
molecules which briefly stick & release
components of different types of
causing the leukocyte to roll along the
microbes
endothelium until it eventually comes to
G proteincoupled receptors found
a stop as mutual adhesion reaches a
peak on neutrophils, macrophages, and
most other types of leukocytes
Early rolling adhesion mediated by
recognize short bacterial peptides
selectin family:
containing N-formylmethionyl residues.
E-selectin (endothelium), P-selectin
(platelets, endothelium), L-selectin
Receptors for opsonins: Leukocytes A fibrinous exudate develops when the
express receptors for proteins that coat vascular leaks are large or there is a local
microbes procoagulant stimulus
Receptors for cytokines: Leukocytes Ex. Conversion of the fibrinous exudate
express receptors for cytokines that are to scar tissue (organization) within the
produced in response to microbes. One pericardial sac
of the most important of these cytokines
is interferon- (IFN-) SUPPURATIVE OR PURULENT
INFLAMMATION; ABSCESS
Phagocytosis characterized by the production of large
(1) recognition and attachment of the amounts of pus or purulent exudate
particle to be ingested by the leukocyte consisting of neutrophils, liquefactive
(2) its engulfment, with subsequent formation necrosis, and edema fluid
of a phagocytic vacuole pyogenic - pus-producing (ex.
(3) killing or degradation of the ingested Staphylococci)
material Ex. Appendicitis
Abscess - localized collections of purulent
Outcomes of Acute Inflammation
All acute inflammatory reactions may have one inflammatory tissue caused by
of three outcomes: suppuration buried in a tissue, an organ,
Complete resolution or a confined space
there has been little tissue destruction
ULCERS
and the damaged parenchymal cells can
a local defect, or excavation, of the
regenerate
surface of an organ or tissue that is
removal of cellular debris and microbes
produced by the sloughing (shedding) of
by macrophages, and resorption of
inflamed necrotic tissue
edema fluid by lymphatics
Healing by connective tissue replacement It is most commonly encountered in:
(fibrosis) (1) the mucosa of the mouth, stomach,
tissues that are incapable of intestines, or genitourinary tract; and
regeneration (2) the skin and subcutaneous tissue of
the lower extremities in older persons
when there is abundant fibrin exudation
who have circulatory disturbances that
in tissue or serous cavities (pleura,
predispose to extensive ischemic
peritoneum) that cannot be adequately
necrosis
cleared
mass of fibrous tissue
Progression of the response to chronic Chronic Inflammation
inflammation - Inflammation of prolonged duration (weeks or
months) in which inflammation, tissue injury,
and attempts at repair coexist, in varying
combinations
Morphologic Patterns of Acute
Inflammation CAUSES OF CHRONIC INFLAMMATION
Persistent infections by microorganisms
SEROUS INFLAMMATION that are difficult to eradicate, such as
marked by the outpouring of a thin fluid mycobacteria, and certain viruses, fungi,
that may be derived from the plasma or and parasites. These organisms often
from the secretions of mesothelial cells evoke an immune reaction called
lining the peritoneal, pleural, and delayed-type hypersensitivity
pericardial cavities Immune-mediated inflammatory
ex. skin blister resulting from a burn or diseases. Chronic inflammation plays an
viral infection important role in a group of diseases that
effusion are caused by excessive and
inappropriate activation of the immune
FIBRINOUS INFLAMMATION system. Under certain conditions
immune reactions develop against the
large molecules such as fibrinogen pass
individual's own tissues, leading to
the vascular barrier, and fibrin is formed
autoimmune diseases. In other cases,
and deposited in the extracellular space
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