Inflammatory Disorders

William D. Leslie and Pierre Plourde Pathophysiology of Inflammation

Inflammation is the organized reaction of the microcirculation to tissue injury. Tissue injury sets in motion a carefully orchestrated complex cascade of events in an attempt to eliminate the offending agent and repair any damage. Acute inflammation is typically brief (lasting minutes to days) and features the neutrophil as the dominant cell. In contrast, chronic inflammation persists much longer (from weeks to months) and the cellular response is dominated by tissue macrophages and lymphocytes. It is important to recognize that there is a continuum in these two processes, and most inflammatory responses consist of a measure of both.

Acute inflammation leads to three basic tissue responses: (a) vasodilation and increased blood flow (hyperemia) with slowing of the microcirculation (stasis), (b) loss of endothelial integrity with leakage of fluid and plasma components, and (c) emigration of leukocytes into the extravascular tissue. The clinical counterparts of these pathologic events are local hyperemia, swelling and pain. Acute inflammation is mediated by plasma-derived and cellular components (Fig. 1). The importance of adhesion molecules has recently been recognized. These are membrane glycoproteins found on the surface of activated endothelial cells, leukocytes and platelets. The complementary expression of these molecules on leukocyte and endothelial surfaces induces an interaction characterized initially by rolling, subsequent adhesion and finally transmigration of the leukocyte between adjacent endothelial cells.

Granulocytes combat invading microorganisms in several ways. If possible, the organisms are phagocytosed and then destroyed with powerful oxidants such as superoxide and hydrogen peroxide generated through a "respiratory burst". Other microorganisms are rendered susceptible to phagocytosis through opsonization with immunoglobulins or activated complement. Lactoferrin is discharged from the granulocytes' secondary granules and binds iron, an essential growth factor for many bacteria and fungi. Neutrophils predominate in the inflammatory infiltrate during the initial 6-24 hours but have a short life span. They spend a brief period of time in the circulation (half-life about 6 hours) and, having migrated out of the vascular space, are then unable to reenter it. In the extracellular space neutrophils undergo programmed cell death (apoptosis) after only 24-48 hours.

In some situations chronic inflammation evolves from an acute inflammatory process, but in other scenarios (including viral, parasitic, autoimmune, foreign body, and malignant inflammatory processes) it represents the primary immune response. The chronic tissue response is often characterized by fibrosis, cellular proliferation and granulation tissue formation. The activated T-lymphocyte is responsible for the production of chemotactic and growth factors which act to recruit monocytes and induce tissue proliferation of macrophages. Activated tissue macrophages may fuse

Nuclear Medicine, edited by William D. Leslie and I. David Greenberg. ©2003 Landes Bioscience.

Figure 1. Mediators of the inflammatory response can be divided into vasoactive and chemotactic factors.

to form the multinucleated giant cells found in granulomata. Granulomatous inflammation is often used for dealing with indigestible materials, and is the form of chronic inflammation typically seen in fungal infections, tuberculosis, foreign body reactions and sarcoidosis.

Technical Considerations

From the foregoing discussion it can be seen that several points in the inflammatory cascade are potential targets for nuclear medicine scanning techniques. There are two primary mechanisms that cause tracers to localize at sites of inflammation: active migration and passive diffusion (Fig. 2). Active migration exploits chemotaxin-directed motility of leukocytes that have been labeled ex vivo or after injection of anti-granulocyte antibodies. In contrast, passive diffusion occurs when the agent—usually a large metal-protein chelate—leaks through inflamed permeable capillary walls and is the primary mechanism of accumulation for gallium, polyclonal immunoglobulins and nanocolloids.


Indium is a heavy metal that shares many of the chemical properties of iron and gallium. The mIn radioisotope is linked to host leukocytes which are actively recruited to sites of inflammation. Following reinjection, mIn-leukocytes rapidly leave the intravascular space to enter the liver (10- 20%), spleen (20-40%) and hematopoietic bone marrow (30-60%) (Fig. 3). By 24 hours, there is minimal residual intravascular activity, although some blood pool may persist if excessive numbers of labeled erythrocytes are present. Identification of inflammatory foci in the liver or spleen is therefore very difficult due to the normal levels of accumulation. Inflammatory lesions in areas of hematopoietic marrow, such as the spine, may also be hard to detect. The absence of appreciable leukocyte accumulation in most soft tissue areas is a considerable advantage, however, as inflammatory lesions are usually very striking against the low background.

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