Acute Inflammation

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)