Inflammation Lecture4

Acute Inflammation
CELLULAR EVENTS:
LEUKOCYTE EXTRAVASATION AND PHAGOCYTOSIS
A critical function of inflammation is to deliver

leukocytes to the site of injury and to activate the
leukocytes to perform their normal functions in host
defense.
Leukocytes ingest offending agents, kill bacteria and
other microbes, and get rid of necrotic tissue and
foreign substances.
they may induce tissue damage and prolong
inflammation, since the leukocyte products that
destroy microbes and necrotic tissues can also injure
normal host tissues.
Acute Inflammation
CELLULAR EVENTS:
• The sequence of events of moving leukocytes from the vessel

lumen to the interstitial tissue, called extravasation, can
be divided into :
1. In the lumen:
i. Margination because blood flow slows early in inflammation (stasis), the
endothelium can be virtually lined by white cells (pavementation)
ii. rolling
iii. adhesion to endothelium
Vascular endothelium normally does not bind circulating cells
2. Transmigration across the endothelium (also called
diapedesis)
3. Migration in interstitial tissues toward a chemotactic stimulus
Acute Inflammation
CELLULAR EVENTS:
Margination
Slide 3.11
Margination
rolling
adhesion to endothelium
Neutrophils, monocytes, lymphocytes, eosinophils, and basophils all use the same
pathway to migrate from the blood into tissues.
Acute Inflammation
CELLULAR EVENTS:
Leukocyte Adhesion and Transmigration
• Leukocyte adhesion and transmigration are regulated
by the binding of complementary adhesion molecules
on the leukocyte and endothelial surfaces, and
chemical mediators-chemoattractants and certain
cytokines-affect these processes by modulating the
surface expression or avidity of such adhesion
molecules.
• The adhesion receptors involved belong to four
molecular families-the selectins, the immunoglobulin
superfamily, the integrins, and mucin-like
glycoproteins.
The adhesion receptors
Selectins, consist of
– E-selectin (CD62E, ELAM-1)which is confined to
endothelium
– P-selectin (CD62P, GMP140 or PADGEM), which is present
in endothelium and platelets
– L-selectin (CD62L, LAM-1), which is expressed on most
leukocyte Selectins bind, through their lectin domain, to
sialylated forms of oligosaccharides (e.g., sialylated Lewis
X), which themselves are covalently bound to various mucin-
like glycoproteins (GlyCAM-1, PSGL-1, ESL-1, and CD34).
The immunoglobulin family molecules include two

endothelial adhesion molecules:
– ICAM-1 (intercellular adhesion molecule 1)
– VCAM-1 (vascular cell adhesion molecule 1).
Both these molecules serve as ligands for integrins found on

leukocytes.
Integrins
• are transmembrane heterodimeric glycoproteins,
made up of α and β chains
• expressed on many cell types and bind to ligands on
endothelial cells, other leukocytes, and the
extracellular matrix
• The β2 integrins LFA-1 and Mac-1 bind to ICAM-1,
and the β1 integrins bind VCAM-1.
Mucin-like glycoproteins
- such as heparan sulfate, serve as ligands for the
leukocyte adhesion molecule called CD44.
- these glycoproteins are found in the extracellular
matrix and on cell surfaces.
Recruitment of leukocytes
• The recruitment of leukocytes to sites of injury and infection is a

multistep process involving attachment of circulating leukocytes to
endothelial cells and their migration through the endothelium
• The first events are the induction of adhesion molecules on endothelial
cells
• Resident tissue macrophages, mast cells, and endothelial cells respond
to injurious agents by secreting the cytokines TNF, IL-1, and
chemokines (chemoattractant cytokines). TNF and IL-1 act on the
endothelial cells of postcapillary venules adjacent to the infection and
induce the expression of several adhesion molecules. Within 1 to 2
hours, the endothelial cells begin to express E-selectin. Leukocytes
express at the tips of their microvilli carbohydrate ligands for the
selectins, which bind to the endothelial selectins. These are low-affinity
interactions with a fast off-rate, and they are easily disrupted by the
flowing blood. As a result, the bound leukocytes detach and bind again,
and thus begin to roll along the endothelial surface.
Mediators such as histamine, thrombin, and platelet activating factor (PAF) stimulate
the redistribution of P-selectin from its normal intracellular stores in granules (Weibel-
Palade bodies) to the cell surface.
•Resident tissue macrophages, mast cells, and endothelial cells respond to injurious
agents by secreting the cytokines TNF, IL-1, and chemokines
•TNF and IL-1 act on the endothelial cells of postcapillary venules adjacent to the
infection and induce the expression of several adhesion molecules (ligands for integrins,
mainly VCAM-1 and ICAM-1). Within 1 to 2 hours, the endothelial cells begin to express
E-selectin.
•Leukocytes express at the tips of their microvilli carbohydrate ligands for the selectins,
which bind to the endothelial selectins.
•These are low-affinity interactions with a fast off-rate, and they are easily disrupted by
the flowing blood. As a result, the bound leukocytes detach and bind again, and thus
begin to roll along the endothelial surface.
Activation of integrins on the leukocytes results in firm integrin-
mediated binding of the leukocytes to the endothelium at the site
of infection. The leukocytes stop rolling, their cytoskeleton is
reorganized, and they spread out on the endothelial surface.
• The next step in the process is migration of the leukocytes through the
endothelium, called transmigration or diapedesis. Chemokines act on the
adherent leukocytes and stimulate the cells to migrate through interendothelial
spaces toward the chemical concentration gradient, that is, toward the site of injury
or infection.
• Diapedesis, similar to increased vascular permeability, occurs predominantly in the
venules
• Once leukocytes enter the extravascular connective
tissue, they are able to adhere to the extracellular
matrix by virtue of β1 integrins and CD44 binding to
matrix proteins. Thus, the leukocytes are retained at
the site where they are needed.
Slide 3.19
• The type of emigrating leukocyte varies with the age of the
inflammatory response and with the type of stimulus.
• In most forms of acute inflammation, neutrophils predominate in
the inflammatory infiltrate during the first 6 to 24 hours, then are
replaced by monocytes in 24 to 48 hours
• Several reasons account for this sequence:
– neutrophils are more numerous in the blood, they respond more
rapidly to chemokines, and they may attach more firmly to the
adhesion molecules that are rapidly induced on endothelial cells,
such as P- and E-selectins
– after entering tissues, neutrophils are short-lived; they undergo
apoptosis and disappear after 24 to 48 hours, whereas monocytes
survive longer.
In viral infections, lymphocytes may be the first cells to arrive

In some hypersensitivity reactions, eosinophil may be the main cell
type

Inflammation Lecture4

Uploaded by

Copyright:

Available Formats

Inflammation Lecture4

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Inflammation Lecture4

Uploaded by

Copyright:

Available Formats

Acute Inflammation

LEUKOCYTE EXTRAVASATION AND PHAGOCYTOSIS

A critical function of inflammation is to deliver

• The sequence of events of moving leukocytes from the vessel

The immunoglobulin family molecules include two

Both these molecules serve as ligands for integrins found on

• The recruitment of leukocytes to sites of injury and infection is a

In viral infections, lymphocytes may be the first cells to arrive

You might also like