CHRONIC INFLAMMATION

Chronic inflammation is inflammation of prolonged

duration (weeks or months) in which active
inflammation, tissue destruction, and attempts at repair
are proceeding simultaneously.
 Causes of chronic inflammation
1. Persistent infections by certain microorganisms, such
as tubercle bacilli, Treponema pallidum (the causative
organism of syphilis), and certain viruses, fungi, and
parasites.

2. Prolonged exposure to toxic agents, either exogenous or

endogenous. For example, silicosis is a chronic inflammation
of the lungs caused by silica when inhaled for a prolonged
time. Atherosclerosis is a chronic inflammation of the arterial
walls induced by endogenous toxic plasma lipid components.
3. Autoimmunity. In autoimmune diseases, autoantigens
produce immune reaction that results in chronic
inflammation and tissue damage.

Immune reactions play an important role in several common

chronic inflammatory diseases, such as rheumatoid arthritis
and lupus erythematosus.
MORPHOLOGICAL FEATURES
Chronic inflammation is characterized by;

1. Infiltration with mononuclear cells, which include

macrophages, lymphocytes, and plasma cells.

2. Tissue destruction, induced by the persistent

offending agent or by the inflammatory cells.

3. Healing: Connective tissue replaces the damaged tissue,

angiogenesis and fibrosis.
MONONUCLEAR CELL INFILTRATION
IN CHRONIC INFLAMMATION
Mononuclear Phagocyte System (MPS)
Mononuclear phagocyte system, MPS (reticuloendothelial system)

Blood monocytes and tissue macrophages are the main cells of

mononuclear phagocyte system (MPS). From the blood,
monocytes migrate into various tissues and differentiate into
macrophages.

Macrophages are diffusely scattered in the connective tissue or

located in organs such as the liver (Kupffer cells), spleen and
lymph nodes (sinus histiocytes), and lungs (alveolar
macrophages).
The half-life of blood monocytes is about 1 day,
whereas the life span of tissue macrophages is several
months or years.

The journey of a monocyte from bone marrow stem

cell to tissue macrophage is regulated by a variety of
growth and differentiation factors, cytokines, adhesion
molecules, and cellular interactions.
Extravasation of monocytes is governed by the same
factors that are involved in neutrophil emigration, that
is, margination, adhesion, rolling, migration and
chemical mediators with chemotactic and activating
properties.

When the monocyte reaches the extravascular tissue, it

undergoes transformation into a larger phagocytic cell,
the macrophage.
Macrophages are activated by a variety of stimuli,
including cytokines (e.g., IFN-γ) secreted by
sensitized T lymphocytes.

Activation results in increased cell size, increased

levels of lysosomal enzymes, more active metabolism,
and greater ability to phagocytose and kill ingested
microbes.
Activated macrophages secrete a wide variety of biologically
active products that, if unchecked, result in the tissue injury and
fibrosis characteristic of chronic inflammation.
PDGF, platelet-derived   
growth factor;
FGF, fibroblast growth
factor;
TGFβ, transforming
growth factor β.
In short-lived inflammation, if the irritant is eliminated,
macrophages eventually disappear. In chronic
inflammation, macrophage accumulation persists under
following mechanisms;
1. Recruitment of monocytes from the circulation. It results from the
expression of adhesion molecules and chemotactic factors.

Chemotactic stimuli for monocytes include;

(a). Chemokines produced by activated macrophages and lymphocytes.

(b). Product of complement system, C5a.
(c). Growth factors such as platelet-derived growth factor (PDGF) and
transforming growth factor-α (TGF-α).
(d). Fragments from the breakdown of collagen and fibronectin; and
fibrinopeptides.

Most of the macrophages present at the site of chronic inflammation are

recruited from circulating monocytes.
2. Local proliferation (division) of macrophages occurs at the focus of
chronic inflammation. Macrophage proliferation occurs prominently in
some chronic inflammatory lesions, such as atheromatous plaques.

3. Immobilization of macrophages occurs within the site of inflammation.

Certain cytokines and oxidized lipids can cause such immobilization.
Tissue injury in chronic inflammation
Tissue destruction is hallmark of chronic inflammation.

(A). Macrophage based tissue injury in chronic inflammation

Activated macrophages eliminate injurious agents such as

microbes and initiate the process of repair. The products
produced by macrophages are also responsible for much of the
tissue injury in chronic inflammation.
Some macrophage products causing tissue injury are,

1. Toxic to host cells: Reactive oxygen and nitrogen intermediates and

extracellular matrix proteases.

2. Increase influx of other cells: Some chemical mediators of

macrophages origin , such as cytokines.

3. Growth factors: Such as fibroblast growth factor (FGF), platelet derived

growth factor (PDGF) and transforming growth factor (TGF), causing
fibroblast proliferation, collagen deposition, and angiogenesis.
(B). Other substances causing tissue injury in chronic inflammation

Necrotic tissue itself can activate complement, kinin, coagulation, and

fibrinolytic systems, the release of mediators from leukocytes, and
liberation of substances like uric acid from dying cells.

T lymphocytes may directly kill cells.

OTHER CELLS IN CHRONIC INFLAMMATION

1. Lymphocytes and macrophages interact in a bidirectional way, and

these reactions play an important role in chronic inflammation.
Macrophages display antigens to T cells, and produce membrane
molecules (costimulators) and cytokines (IL-12) that stimulate T-cell.
Activated T lymphocytes produce cytokines, and one of these IFN-γ, is a
major activator of macrophages.
 OTHER CELLS IN CHRONIC INFLAMMATION

2. Eosinophils are abundant in immune reactions mediated by IgE and in

parasitic infections. The recruitment of eosinophils involves
extravasation from the blood and their migration into tissue by processes
similar to those for other leukocytes. One of the chemokines that is
especially important for eosinophil recruitment is eotaxin.

Eosinophils have granules that contain major basic protein, that is toxic
to parasites but also causes lysis of mammalian epithelial cells.
OTHER CELLS IN CHRONIC INFLAMMATION

3.Mast cells are widely distributed in connective tissues and

participate in both acute and chronic inflammatory reactions.

In acute inflammation mast cells are major source of histamine.

In chronic inflammatory reactions mast cells produce cytokines
that contribute to fibrosis.
Figure: Macrophage-
lymphocyte
interactions in chronic
inflammation.
Activated lymphocytes
and macrophages
influence each other
and also release
inflammatory
mediators that affect
other cells
OTHER CELLS IN CHRONIC INFLAMMATION

4. Neutrophils are characteristic of acute inflammation but

many forms of chronic inflammation continue to show large
numbers of neutrophils, induced either by persistent
microbes or by mediators produced by macrophages and T
lymphocytes.

In chronic bacterial infection of bone (osteomyelitis), a

neutrophilic exudate can persist for many months.
Neutrophils are also important in the chronic damage
induced in lungs by smoking and other irritant stimuli.
GRANULOMATOUS INFLAMMATION
Granulomatous inflammation is a type of chronic
inflammation characterized by focal accumulations of
activated macrophages, which often develop an epithelial-
like (epithelioid) appearance.

It is encountered in a number of infectious and some

noninfectious conditions.
Examples of granulomatous inflammation are tuberculosis,
sarcoidosis, cat-scratch disease, lymphogranuloma
inguinale, leprosy, brucellosis, syphilis, some mycotic
infections, berylliosis.

Recognition of the granulomatous pattern in a biopsy

specimen is important because of the limited number of
possible conditions that cause it and the significance of the
diagnoses associated with the lesions.
Granuloma

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.

In the usual hematoxylin and eosin stains, the epithelioid cells

have a pale pink granular cytoplasm with indistinct cell
boundaries.
Older granulomas develop an enclosing rim of fibroblasts
and connective tissue.

Frequently, epithelioid cells fuse to form giant cells in the

periphery or sometimes in the center of granulomas.
These giant cells may attain diameters of 40 to 50 µm.
They have a large mass of cytoplasm containing 20 or
more small nuclei arranged either peripherally (Langhans-
type giant cell) or haphazardly (foreign body-type giant
cell).
Types of granulomas

There are two types of granulomas.

1. Foreign body granulomas are incited by relatively inert

foreign bodies. These granulomas are formed when material
such as talc, sutures, or other fibers are in the focus
Epithelioid cells and giant cells formed and are
apposed to the surface and surround the foreign body. The
foreign material can usually be identified in the center of the
granuloma.
2. Immune granulomas are caused by insoluble particles,
such as microbes which are poorly degradable.
In these responses, macrophages engulf the foreign
material and present some of it to T lymphocytes, causing
them to become activated.
The responding T cells produce cytokines, such as
IL-2, which activates other T cells, and IFN-γ, which
activates macrophages and transforming them into
epithelioid cells and multinucleate giant cells.
The prototype of the immune granuloma is that caused by the
mycobacterium tuberculosis. In this disease, the granuloma
is called a tubercle and is classically characterized by the
presence of central caseous necrosis.