During an immune response, often a set of processes occur that create
a condition known as inflammation. These processes include many of the
innate effector mechanisms we have been discussing. But also some
additional events occur as well. Here we pull together the various
processes that collectively are called inflammation.
Inflammation is divided into
acute inflammation, which occurs over seconds, minutes, hours, and days, and
chronic inflammation, which occurs over longer times.
Events in Acute Inflammation
Acute inflammation begins within seconds to minutes following the
injury of tissues. The damage may be purely physical, or it may involve
the activation of an immune response. Three main processes occur:
- Increased blood flow due to dilation of blood vessels (arterioles) supplying the region
- Increased permeability of the capillaries, allowing fluid and blood proteins to move into the interstitial spaces
- Migration of neutrophils (and perhaps a few macrophages) out of the capillaries and venules and into interstitial spaces
Increased Blood Flow and Edema
The first two of the above effects are readily visible within a few
minutes following a scratch that does not break the skin. At first, the
scratch is visible as a pale red line. Then the surrounding few
millimeters of tissue on both sides of the scratch becomes red as blood
flow increases locally. Finally, the area swells as additional fluid
accumulates in the interstitial spaces of the region, a condition known
as
edema. The increased permeability of the capillaries occurs because the endothelial cells separate from one another at their edges.
Cell Adhesion Molecules
As described when we were discusssing the migration of neutrophils
from blood vessels into the tissues, the first step is the binding of
the neutrophils to the endothelium of the blood vessels. The binding is
due to molecules, called
cell adhesion molecules (CAMs), found
on the surfaces of neutrophils and on endothelial cells in injured
tissue. The binding occurs in two steps. In the first, adhesion
molecules called
selectins lightly tether the neutrophil to the
endothelium, so that it begins rolling along the surface. In a second
step, a much tighter binding occurs through the interaction of
ICAMs on the endothelial cells with
integrins on the neutrophil.
The figure below is the same as that on the earlier page describing the recruitment of neutrophils.
In this light micrograph of a blood vessel in the lungs you can see a
layer of neutrophils adhering to the inner surface of the blood vessel.
(Recall that a neutrophils can be identified by its nucleus, which is
divided into
several lobes. Note that the histology stains used in this picture and the next are not the same as was used for the blood slide in lab.)
Notice in the above micrograph that you can also observe neutrophils
outside as well as inside the blood vessel. Once bound to the
endothelium, neutrophils squeeze through gaps between adjacent
endothelial cells into the interstitial fluid, a process called
diapedesis.
Sometimes pus forms at the site of acute inflammation, especially if a
foreign body is present to continually aggravate the tissue. This light
micrograph
of pus from an inflammed appendix shows that pus is packed with
neutrophils, the primary cells typically present during acute
inflammation. (How can you tell these are neutrophils?)
Chemotaxis
Once outside the blood vessel, a neutrophil is guided towards an infection by various diffusing
chemotactic factors. Examples include the
chemokines and the
complement peptide C5a, which is released when the complement system is activated either via specific immunity or innate immunity.
Eosinophils
However, in some circumstances
eosinophils rather than
neutrophils predominate in acute inflammation. This tends to occur with
parasitic worms, against which neutrophils have little success, or with
a response involving the antibody
IgE. Eosinophils release several proteins, such as
major basic protein,
which are often effective against parasites. Eosinophils also release
several regulatory molecules that increase endothelial permeability.
Note that eosinophils are also linked to certain types of allergies.
Inflammatory Paracrines
What causes the characteristic sequence of events in acute
inflammation? Various cells at the site of tissue damage or of a
specific immune response release regulatory molecules that act locally
as
paracrines.
- Macrophages and lymphocytes are important sources of inflammatory paracrines. As we have discussed, macrophages release IL-1 and TNF-alpha, which have powerful, widespread effects.
- Also important are mast cells, which are found throughout the body, especially under epithelia. Mast cells are filled with large vesicles containing histamine
and other inflammatory paracrines (They also release PG D2, several
LTs and TNF-alpha, described below). Factors associated with tissue
damage can trigger the exocytosis. But sometimes it is a specific
immune response that triggers the release of the inflammatory
paracrines.
- Also, various arachidonic acid derivatives are important.
Both prostaglandins (notably PG D2) and leukotrienes (LT) can be
important, depending on the tissue. Note the effectiveness of aspirin
and various NSAIDs in quieting inflammation.
- Complement peptides, C3a and C5a
- Various other molecules including nitric oxide, certain platelet
products, kinins, and certain other substances we will not discuss
(serotonin, etc)
