C h a p t e r 3
Inflammation, the Inflammatory Response, and Fever
61
Chronic Inflammation
In contrast to acute inflammation, which is usually self-
limited and of short duration, chronic inflammation is
self-perpetuating and may last for weeks, months, or
even years.
1,2,23
It may develop as a result of a recurrent
or progressive acute inflammatory process or from low-
grade, smoldering responses that fail to evoke an acute
response. Instead of the vascular permeability changes,
edema, and predominantly neutrophilic infiltration seen
in acute inflammation, chronic inflammation is charac-
terized by infiltration with mononuclear cells (macro-
phages, lymphocytes, and plasma cells) and attempted
connective tissue repair involving angiogenesis and
fibrosis. Although it may follow acute inflammation,
chronic inflammation often begins insidiously as a low-
grade, smoldering, and asymptomatic process. This type
of process is the cause of tissue damage in some of the
most common disabling diseases such as atherosclerosis,
chronic lung disease, rheumatoid arthritis, and inflam-
matory bowel disease.
There is also evidence that recurrent and persistent
inflammation induces, promotes, and/or influences sus-
ceptibility to cancer by causing deoxyribonucleic acid
(DNA) damage, inciting tissue reparative proliferation,
and/or creating an environment that is enriched with
cytokines and growth factors that favor tumor develop-
ment and growth (see Chapter 7).
23
Among the cancers
associated with chronic infection and inflammation are
cervical cancer (human papillomavirus [HPV]), cancer
of the liver (hepatitis B and C), cancer of the stomach
(
Helicobacter pylori
), and cancer of the gallbladder
(chronic cholecystitis and cholelithiasis).
Causes of Chronic Inflammation
Agents that evoke chronic inflammation typically are
low-grade, persistent infections or irritants that are
unable to penetrate deeply or spread rapidly.
1,2
Among
the causes of chronic inflammation are foreign agents
such as talc, silica, asbestos, and surgical suture mate-
rials. Many viruses provoke chronic inflammatory
responses, as do certain bacteria, such as the tubercle
bacillus and the actinomyces, as well as fungi, and larger
parasites of moderate to low virulence. The presence of
injured tissue such as that surrounding a healing frac-
ture also may incite chronic inflammation. Diseases
that cause excessive and inappropriate activation of
the immune system are increasingly being recognized as
causes of chronic inflammation. Under certain condi-
tions, immune reactions may develop against the per-
son’s own tissues, leading to autoimmune disease.
Obesity is a newly suspected cause of chronic inflam-
mation.
24–26
During the last decade, white adipose tis-
sue was recognized to be an active endocrine organ and
a source of a number of proinflammatory mediators.
Many of the mediators appear to play an important role
in the pathogenesis of obesity-related diseases includ-
ing accelerated atherosclerosis and diabetes mellitus.
The link between obesity and inflammation dates back
to the discovery that adipose tissue was a source of the
proinflammatory cytokine TNF-
α
, and that adipose tis-
sue TNF-
α
concentrations are correlated with insulin
resistance both in persons with and without type 2 dia-
betes mellitus. It was later found that obesity is related
not only to increased number and size of adipocytes,
but also to infiltration of adipose tissue by macrophages
that possess the ability to produce TNF-
α
, nitric oxide,
and other inflammatory mediators. The mechanisms
mediating the proinflammatory state associated with
obesity are still unclear, but recent studies suggest that
circulating free fatty acids may play a role.
Granulomatous Inflammation
A granulomatous lesion is a distinctive form of chronic
inflammation.
1,2
A granuloma typically is a small,
1- to 2-mm lesion in which there is a massing of macro-
phages surrounded by lymphocytes. The macrophages
are modified and, because they resemble epithelial cells,
sometimes are called epithelioid cells. Like other mac-
rophages, these epithelioid cells are derived originally
from blood monocytes. Granulomatous inflammation is
associated with foreign bodies such as splinters, sutures,
silica, and asbestos and with microorganisms that
cause tuberculosis, syphilis, sarcoidosis, deep fungal
permeability), the influx of inflammatory cells
such as neutrophils, and, in some cases, the
widespread effects of inflammatory mediators,
which produce fever and other systemic signs
and symptoms.
■■
Chemical mediators are integral to initiation,
amplification, and termination of inflammatory
processes.The plasma is the source of mediators
derived from three major protein cascades that
are activated during inflammation.These protein
cascades include the kallikrein-kininogen system,
the coagulation system, and the complement
system. Cell-derived mediators, including
histamine, bradykinin, the arachididonic
metabolites, platelet activating factor (PAF), and
many others are released from cells at the site of
inflammation.
■■
Acute inflammation may involve the production
of exudates containing serous fluid (serous
exudate), red blood cells (hemorrhagic exudate),
fibrinogen (fibrinous exudate), or tissue debris
and white blood cell breakdown products
(purulent exudate).
■■
The outcome of acute inflammation generally
results in one of three processes: resolution,
progression to chronic inflammation, or
substantial scarring and fibrosis.
