The inflammatory response is initiated within hours of infection or wounding and is characterized
by edema, or swelling, heat, redness, and pain at the site of an infection or injury.
These characteristics reflect four changes in local blood vessels.
1. The heat and redness during inflammation is the result of an increase in vascular diameter.
The increase in vascular diameter also results in slower blood flow.
2. There is also an increase in vascular permeability. The endothelial cells that line the blood vessel walls are usually packed tightly together, but during inflammation, they have
gaps between them - This results in fluid from the blood exiting and accumulating in the local tissues, and this results
in edema and pain. The fluid contains plasma proteins such as complement proteins and mannose
binding lectin, which aid in defending against pathogens.
3. Endothelial cells, which line the walls of blood vessels, are “activated” during
inflammation. That is, endothelial cells express cell-adhesion molecules that promote the binding
of circulating leukocytes, otherwise known as white blood cells.
4. There is clotting in the microvessels at the site of infection, which prevents pathogens
from spreading via the blood. The purpose of the inflammatory response is
threefold: 1. Allows the body to defend itself from invading
microorganisms. The increase in vascular diameter, along with the activated endothelial cells,
results in leukocytes being able to attach to the endothelium, and then migrate into
the tissues where they can attack pathogens. This process of leukocytes leaving the bloodstream
and entering tissues is called extravasation. 2. Induces local blood clotting, and this
creates a physical barrier preventing the infection from spreading into the bloodstream.
3. Promotes the repair of injured tissue. But what triggers the inflammatory response? The state of inflammation is set up when tissues
are physically damaged, or when pathogens are recognized by macrophages and later by
other white blood cells. These circumstances induces the release of a variety of inflammatory
mediators which cause the inflammatory response. Macrophages and neutrophils secrete prostaglandins,
leukotrienes, and platelet-activating factor (PAF), which are lipid mediators of inflammation. These are produced rapidly because they are made from degraded membrane phospholipids.
Then, macrophages secrete cytokines, which are substances released by cells of the immune
system that affect other cells. One kind of cytokine are chemokines, which act as chemoattractants.
Chemokines cause directed chemotaxis, which is the movement of cells or parts of cells in a direction corresponding to a gradient of increasing or decreasing concentration of a substance. In the case of chemokines, they direct phagocytes to move towards the source
of the chemokines, which is where they are needed.
Now I'd like to point out two cytokines important to the inflammatory response are C5a and Tumor Necrosis Factor-α
, or TNF-α. The complement fragment C5a plays multiple important roles in the inflammatory response. For instance, it stimulates respiratory, or oxidative burst, which is the rapid release of reactive oxygen
species. At the same time it attracts neutrophils and monocytes. So it essentially preps them for battle as they arrive. It also increases vascular permeability, increases
expression of adhesion molecules on the endothelium, and causes local mast cells to release granules
containing the inflammatory molecule histamine, and TNF-α. TNF-α is also an important cytokine, which is produced rapidly by macrophages upon pathogen detection and is a potent activator of
endothelial cells. Activation of endothelial cells is central
to the inflammatory response. Cytokines produced by macrophages, especially TNF-α, cause endothelial
cells to rapidly externalize granules called Weibel-Palade bodies containing P-selectin within minutes
of pathogen detection by macrophages. P-selectin now appears on the surfaces of local endothelial
cells. Selectins are one of three structural families of adhesion molecules important for
leukocyte recruitment, with the other two being intercellular adhesion molecules (ICAMs)
and leukocyte integrins. Later, within 2 hours of pathogen detection, the endothelial cells
express mainly E-selectin. Shortly after P-selectin gets to the cell surface, mRNA encoding E-selectin
is synthesized. Both selectins interact with the sulfated sialyl-LewisX that is present
on the surface of neutrophils. Once inflammation has begun, neutrophils make
up the first wave of cells that cross the blood vessel wall to enter an inflamed tissue.
After this, monocytes cross the blood vessel wall and differentiate into tissue macrophages.
In later stages of inflammation, other leukocytes such as eosinophils and lymphocytes also enter
the infected site. Usually, leukocytes travel in the center of small blood vessels, where
blood flow is fastest. However, in inflamed tissues, the slower blood flow allows leukocytes
to interact in large numbers with the endothelial cells lining the blood vessels.
In addition, injury to blood vessels triggers two enzyme cascades – the kinin cascade
and the coagulation cascade. The kinin system consists of plasma proteases. The eventual
result of this cascade is the production of several inflammatory mediators, including
bradykinin, a vasoactive peptide that increases vascular permeability and causes pain. Pain
makes you aware of the problem and causes you to immobilize that part of your body,
helping prevent the spread of infection. The coagulation system is another protease cascade
whose activation leads to formation of a fibrin clot.