Neutrophils play an important role in inflammatory reactions, both in the removal of microorganisms and aged and damaged cells, as well as in the generation of inflammatory agents (chemotactic peptides, cytokines, leukotrienes and other lipid mediators). Moreover, neutrophils also mediate tissue injury. This last reaction is a necessary evil, meant to remove alien material from the tissues. Under normal conditions, when the causative agent has been removed and chemotactic factors are no longer produced, neutrophil (and macrophage) invasion stops and tissue repair commences; however, when neutrophil infiltration does not stop, as in chronically inflamed areas, the tissues may be permanently damaged.
Plasma and tissue fluids contain large amounts of a series of proteinase inhibitors, such as serine proteinase inhibitors (serpins, e.g. c^-proteinase inhibitor, arantichymotrypsin, plasminogen-activator inhibitor) and a2-macroglobulin. These inhibitors are very efficient in blocking serine proteinase activity. However, during neutrophil activation, reactive oxygen compounds are released and inactivate these inhibitors. Additionally, elastase, if not blocked by aj-proteinase inhibitor, is able to inactivate many of these tissue-protecting inhibitors. Moreover, the met-alloproteinases collagenase and gelatinase, which are secreted by neutrophils as inactive precursors, are activated by the reactive oxygen compounds from these cells.
Thus, the following situation exists. Oxidative products of neutrophils are either short lived (HOC1) or - even more importantly - they act very non-specifically by oxidizing methionine residues in all proteins; therefore, these oxidative agents will quickly be scavenged by albumin or other abundant proteins surrounding the neutrophil. On the other hand, the proteinases released by neutrophils are also harmless because they are either secreted as inactive precursors (metalloproteinases) or will be quickly inactivated by serpins in the extracellular fluid. In combination, however, the neutrophil products act synergistically and become highly toxic for the surrounding tissues.
Well-known noninfectious conditions accompanied by neutrophil infiltrations are gout, rheumatoid arthritis, autoimmune vasculitis and some forms of glomerulonephritis. Tissue injury in these inflammatory conditions is at least in part due to products from neutrophils. Neutrophils are also involved in some inflammatory reactions in the lung. Adult respiratory distress syndrome (ARDS) may develop in combination with, or as a consequence of, pulmonary aspiration, diffuse intravascular coagulation, severe pneumonia, hypertransfusion or sepsis. Inflammatory mediators generated under these conditions may cause intravascular aggregation of neutrophils, leading to obstruction of pulmonary capillaries and localized release of toxic mediators from these cells. The effects of TNF on lung cells may also play a role in ARDS and endotoxin shock. Lung emphysema is supposed to be caused at least in part by elastase released from neutrophils. Also, in the second phase of acute allergic asthma, infiltrating neutrophils (and eosinophils) probably contribute to the tissue damage.
Thus, although neutrophils form an indispensable element in our host-defense system, conditions exist in which the powerful mediators from these cells are harmful to the host. Therapeutic amelioration of these reactions is then necessary, but care must be taken to preserve the antimicrobial potential of the neutrophils.
See also: Acute inflammatory reaction; Chemotaxis; Chemotaxis of neutrophils; Complement receptors; Diapedesis; Fc receptors; Immunodeficiency, primary; Microbicidal mechanisms, oxygen-dependent; Microbicidal mechanisms, oxygen-independent; Platelet-activating factor (PAF).
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